CADTH Reimbursement Review

Calaspargase Pegol (Asparlas)

Sponsor: Servier Canada Inc.

Therapeutic area: Acute lymphoblastic leukemia

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information on Application Submitted for Review

ALL = acute lymphoblastic leukemia; NOC = Notice of Compliance.

The sponsor’s application was filed with CADTH on a pre-Notice of Compliance basis and the CADTH clinical report is reflective of the proposed Health Canada indication and information incorporated into the draft product monograph that was submitted to Health Canada and CADTH. The proposed Health Canada indication was not limited to a certain age group, whereas the final indication was limited to patients aged 1 year to 21 years.

Introduction

Acute lymphoblastic leukemia (ALL) is the least common type of leukemia diagnosed in adults; however, it is the most common type of leukemia diagnosed in young children.¹ It is estimated that ALL represents 75% to 80% of acute leukemias among children and 20% of all leukemias among adults.² In 2018, the incidence rate of ALL for all ages in Canada (excluding Quebec) was 1.3 patients per 100,000, with the majority of patients being younger than 19 years.^3,4 ALL is a heterogeneous group of disorders that results from the clonal proliferation and expansion of malignant lymphoid cells in the bone marrow, blood, and extramedullary sites,⁵ classified into 2 major subtypes: B-lymphoblastic and T-lymphoblastic leukemia, with further division according to the presence and type of genetic abnormalities.^5,6 ALL of the B-cell phenotypes occurs in approximately 80% to 85% of pediatric patients and nearly 75% of adult patients. The frequency of the Philadelphia chromosome in patients with ALL is about 3% to 5% in pediatric patients, and 25% to 30% in adult patients.⁷ Signs and symptoms of ALL are highly variable, with most patients experiencing bruising, bleeding, dyspnea, dizziness, infections due to neutropenia, anemia, thrombocytopenia, and pain. Multiagent chemotherapeutic (MAC) is the established standard of care (SOC) treatment for newly diagnosed patients with ALL, and asparaginase (e.g., pegaspargase) is an essential component of these regimens. Two different childhood ALL treatment strategies are commonly used across Canada, originating from the Children’s Oncology Group (COG) and the Dana-Farber Cancer Institute (DFCI) consortia.^8,9 Both protocols include pegaspargase. According to the clinical experts consulted by CADTH, patients who are unable to receive asparaginase treatment (e.g., they lack access to a consistent supply of treatment drug, they experience allergy intolerance) are less likely to be cured with chemotherapy alone.

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of calaspargase pegol 2,500 units/m² given intravenously no more frequently than every 21 days as a component of an MAC regimen for the treatment of ALL in children and adults. Calaspargase pegol has not been previously reviewed by CADTH.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

CADTH received 1 patient group submission from the Leukemia & Lymphoma Society of Canada (LLSC), which conducted an online survey of 47 patients or caregivers of patients with ALL from all 10 provinces in Canada during April to May 2023. Patients reported that ALL progresses quickly and aggressively and that to prevent disease progression, the immediate start of treatment upon diagnosis is vital. However, patients’ experience with drug shortages at some point during their ALL treatment were extremely stressful, impacting their mental health, physical health, quality of life, home life, social life, work life, and finances. In addition to secure, readily accessible, and effective treatment, factors important to patients when evaluating new treatments for ALL included side effects, a physician’s recommendation, quality of life, cost, secure supply, and the number of treatments.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Two clinical specialists with expertise in the diagnosis and management of ALL reported that the goal of treatment for patients with ALL is curative, aimed at maximizing survival while minimizing short-term and long-term toxicities. Current treatment for ALL in Canada was identified by the clinical experts consulted by CADTH as comprising MAC regimens that include pegylated asparaginase, using pediatric protocols developed by the COG or the DFCI among children or pediatric-inspired protocols among adults, estimated to be 2.5 years to 3.5 years in duration. The clinical experts consulted by CADTH noted that patients who do not respond to treatment require high-dose chemotherapy and/or allogeneic stem cell transplant and experience high rates of treatment failure. According to the clinical experts consulted by CADTH, patients would benefit from a consistent supply of asparaginase, with a shorter frequency of dosing, and treatments with improved tolerability.

Asparaginase is an essential component of front-line ALL therapy, and 2 extended half-life formulations have been developed for clinical use. Pegylated asparaginase has a half-life of 5.7 days and is administered every 14 days. Calaspargase pegol has a half-life of 16.1 days and is administered every 21 days. The clinical experts consulted by CADTH do not expect a shift in the current treatment paradigm with calaspargase pegol; rather, they believe that it will replace pegaspargase, given its prolonged half-life, longer dosing interval, and the need for fewer administrations (10 versus 15) over the course of treatment.

The clinical experts consulted by CADTH indicated that all patients with newly diagnosed ALL would benefit from treatment with calaspargase pegol, since asparaginase has a unique mechanism of action and is considered to comprise an essential component of therapy in ALL. Patients with relapsed ALL were also considered by the clinical experts consulted by CADTH to potentially benefit from calaspargase pegol, if there was no known prior intolerance to other forms of asparaginase. Patients of any age with Philadelphia chromosome–positive (Ph-positive) status (except for adult patients due to potential overlapping toxicities with tyrosine kinase inhibitors) and B-cell or T-cell immunophenotype were considered by the clinical experts consulted by CADTH to be eligible for asparaginase treatment and therefore appropriately targeted for treatment with calaspargase pegol. The clinical experts consulted by CADTH specified that several risk factors are considered before starting treatment to help inform the protocol used, including age older than 10 years, white blood cell (WBC) count below 50 × 10⁹/L at presentation or diagnosis, adverse genetic features including karyotype (e.g., the translocation t(9;22)(q34;q11), hypodiploidy), molecular studies (e.g., BCR-ABL, KMT2A mutations), and gene expression (e.g., IKZF, CRLF2).

The clinical experts consulted by CADTH reported that a clinically meaningful treatment response should be assessed using overall survival (OS), complete remission (CR) postinduction, minimal residual disease (MRD)–negative status postinduction, and serum asparaginase activity (SAA) levels following the administration of asparaginase to monitor adequate asparaginase depletion and clinical reactions (e.g., allergic or infusion-related reaction, silent inactivation). According to the clinical experts consulted by CADTH, treatment with asparaginase including calaspargase pegol should be discontinued in the event of notable adverse events (AEs) (e.g., hypersensitivity reaction including silent inactivation, allergic reaction, development of neutralizing antibodies, severe liver toxicity, severe pancreatitis, severe thrombotic or hemorrhagic event, persistent severe hepatic dysfunction). The clinical experts consulted by CADTH indicated that patients with ALL are often treated in hospital or cancer centres as inpatients or outpatients by hematologists or oncologists.

Clinician Group Input

CADTH received 1 clinician group submission from the Ontario Health (Cancer Care Ontario) (OH-CCO) Hematology Cancer Drug Advisory Committee comprising 2 clinicians. The clinician group noted no significant unmet need among patients who are eligible for standard induction of ALL treatment with pegaspargase; however, patients treated with calaspargase pegol as a component of MAC could benefit from less frequent dosing and should be assessed for treatment response using standard leukemia response criteria, with treatment to be discontinued upon progressive disease or significant intolerance. OH-CCO noted that the appropriate setting for treatment with calaspargase pegol is acute leukemia treatment centres with the presence of leukemia specialists.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially affect the implementation of a CADTH recommendation for calaspargase pegol: relevant comparators, consideration for the initiation of therapy, consideration for the prescribing of therapy, generalizability, care provision issues, and system and economic issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs. Refer to Table 5 for more details.

Clinical Evidence

Systematic Review

Description of Studies

Two phase II, multicentre, randomized, open-label trials assessed the efficacy and safety of calaspargase pegol 2,500 IU/m² compared with pegaspargase 2,500 IU/m². The COG study AALL07P4 (known as the COG AALL07P4 study) enrolled 166 patients aged 1 year to 30 years in 23 study sites, all located in the US, with newly diagnosed high-risk B-cell ALL. The primary objective of the COG AALL07P4 trial was to determine the pharmacokinetic (PK) comparability (asparaginase activity) of the interventions during induction and consolidation while patients were receiving augmented Berlin-Frankfurt-Münster therapy. Secondary objectives of the COG AALL07P4 trial included pharmacodynamic (PD) parameters during induction and consolidation, MRD (day 29), CR rate (day 29), survival (event-free survival [EFS], disease-free survival [DFS] of CR, and OS), and treatment-emergent adverse events (TEAEs). The DFCI study 11 to 001 (known as the DFCI 11-001 study) enrolled 239 patients aged 1 year to 21 years in the US (in 6 sites) and Canada (in 3 sites) with newly diagnosed ALL or lymphoblastic lymphoma (LL). The primary objective of the DFCI 11-001 trial was to determine the PK comparability of the interventions during remission induction and postinduction (i.e., determine SAA levels and assess toxicity). Secondary end points of the DFCI 11-001 trial included MRD (day 32), CR rate (day 32), EFS, DFS from the attainment of CR, and OS.

Across both the COG AALL07P4 and DFCI 11-001 trials, there were notable similarities and differences in baseline demographics. In the COG AALL07P4 trial, most patients were older than 10 years (66.3%). In the DFCI 11-001 trial, most patients were younger than 10 years (75%). All patients in the COG AALL07P4 study and nearly all patients in the DFCI 11-001 study (96%) had ALL. Most patients in the DFCI 11-001 study had B-cell ALL (87%) including patients with T-cell ALL, whereas patients with B-cell immunophenotype were exclusively enrolled in the COG AALL07P4 trial. Most patients had a central nervous system (CNS) status of 1 in both trials with a minority of patients designated as having a central nervous system status of 3 (CNS3) in the COG AALL07P4 trial (fewer than 10% of patients) and the DFCI 11-001 trial (fewer than 2% of patients). Most patients did not have steroid therapy before study treatment in the COG AALL07P4 ||||| or DFCI 11-001 (|||) study. While the majority of patients were older than 10 years in the COG AALL07P4 study (median = 11 years), most patients were younger than 10 years in the DFCI 11-001 study (median = 4 years to 5 years). Approximately 62% of patients were diagnosed when they were 10 years or older in the COG AALL07P4 trial, whereas nearly 75% of patients were diagnosed aged younger than 10 years in the DFCI 11-001 trial. Patients in the COG AALL07P4 study were distributed equally across combined age and WBC categories, whereas more than 70% of patients in the DFCI 11-001 study were younger than 10 years, with WBC count below 50 × 10⁹/L.

Efficacy Results

The key efficacy results from the COG AALL07P4 trial and the DFCI 11-001 trial are summarized in Table 2 and Table 3, respectively. Results in the COG AALL07P4 trial were based on the December 31, 2015, data cut-off date. Results in the DFCI 11-001 trial were based on the October 5, 2016, data cut-off date and, where indicated, from a day 120 follow-up with an updated data cut-off date of June 12, 2017.

Overall Survival

In the COG AALL07P4 study, the median OS was not reached at the data cut-off on December 31, 2015. Patients had been followed for a median of 62.6 months (range = ||| || ||||). The 1-year OS rate (95% confidence interval [CI]) among patients in the full analysis set (FAS) population was ||||| ||||| || ||||| and ||||| ||||| || ||||| in the calaspargase pegol and pegaspargase group, respectively. The 4-year OS rate among patients in the FAS population was ||||| ||||| || ||||| in the calaspargase pegol and ||||| ||||| || ||||| in the pegaspargase group, respectively. The hazard ratio (HR) in the FAS population was |||| ||||| || ||||| in the calaspargase pegol versus pegaspargase group. Findings of the intention-to-treat (ITT) population were consistent with results for the FAS population.

In the DFCI 11-001 study, the median OS was not reached at the data cut-off on October 5, 2016. Patients had been followed for a median of |||| months (range = ||| || ||||). The 1-year OS rate among patients in the FAS ALL population was ||||| |||| ||| |||| || ||||| for calaspargase pegol and |||||| |||| ||| ||||| || |||||| for pegaspargase. At the day 120 cut-off, the median follow-up duration was |||| months and |||| months for the calaspargase pegol and pegaspargase groups, respectively. The 2-year OS rate among patients in the FAS ALL population was ||||| |||| ||| |||| || ||||| for calaspargase pegol and unchanged for pegaspargase. Findings of the ITT ALL population were consistent with results for the FAS population.

DFS From CR

In the COG AALL07P4 study, the 1-year DFS rate among patients in the FAS population was ||||| ||||| || ||||| and ||||| ||||| || ||||| in the calaspargase pegol group and the pegaspargase group, respectively. The 4-year DFS rate among patients in the FAS population was ||||| ||||| || ||||| and ||||| ||||| || ||||| in the calaspargase pegol group and the pegaspargase group, respectively. The HR in the FAS population was |||| ||||| || ||||| in the calaspargase pegol group versus the pegaspargase group. DFS results were identical to the FAS population.

In the DFCI 11-001 study, the 1-year DFS rate among patients in the FAS ALL population who attained CR was ||||| |||| ||| |||| || ||||| in the calaspargase pegol group and ||||| |||| ||| |||| || ||||| in the pegaspargase group. At the day 120 follow-up, the 2-year DFS rate among patients in the FAS ALL population who attained CR was ||||| ||||| || ||||| and ||||| ||||| || ||||| for calaspargase pegol versus pegaspargase, respectively. The results of DFS among patients attaining CR in the ITT ALL population were identical to those of the FAS ALL population.

Event-Free Survival

In the COG AALL07P4 study, the 1-year EFS rate among patients in the FAS population was ||||| ||||| || ||||| and 89.6% (95% CI, 74.0% to 96.1%) in the calaspargase pegol group and the pegaspargase group, respectively. The 4-year EFS rate was ||||| ||||| || ||||| and ||||| ||||| || ||||| in the calaspargase pegol group and the pegaspargase group, respectively. The HR was |||| ||||| || ||||| for the calaspargase pegol group when compared with the pegaspargase group. Findings for EFS in the ITT population were consistent with results for the FAS population.

In the DFCI 11-001 trial, the 1-year EFS rate among patients in the FAS ALL population was ||||| |||| ||| |||| || ||||| and ||||| |||| ||| |||| || ||||| in the calaspargase pegol group and pegaspargase group, respectively. At the day 120 follow-up, the 2-year EFS rate in the FAS population was ||||| |||| ||| |||| || ||||) and ||||| |||| ||| |||| || ||||| in the calaspargase pegol group and pegaspargase group, respectively. Results of EFS among patients in the ITT ALL population were consistent with results for the FAS ALL population.

Complete Remission

In the COG AALL07P4 study, the proportion of patients in the FAS population who attained CR by day 29 was || || || ||||||| ||| ||| |||| || ||||| in the calaspargase pegol group and || || || ||||||| ||| ||| |||| || ||||| in the pegaspargase group. Findings for CR at the end of induction day 29 for the ITT population were consistent with results for the FAS population.

In the DFCI 11-001 study, the proportion of patients in the FAS ALL population who attained CR by day 32 was ||| || ||| ||||||| ||| ||| |||| || ||||| in the calaspargase pegol group and ||| || ||| ||||||| ||| ||| |||| || ||||) in the pegaspargase group. Results for CR by day 32 in the ITT ALL population were consistent with results for the FAS ALL population.

Minimal Residual Disease

In the COG AALL07P4 study, the proportion of patients in the MRD-evaluable FAS population with positive MRD (≥ 0.1% detectable leukemia cells in a bone marrow biopsy or aspirate with validated 6-colour multiparameter flow cytometry) at induction day 29 were ||| || || ||||||| in the calaspargase pegol group and || || || ||||||| in the pegaspargase group. Findings for positive MRD (≥ 0.1%) at the end of induction day 29 in the ITT population were consistent with results in the FAS population.

In the DFCI 11-001 study, the proportion of patients in the FAS ALL population with MRD of 0.01 or greater by PCR assay were |||| ||| |||||| in the calaspargase pegol group and | || ||| in the pegaspargase group. Findings for MRD of 0.01 or greater at the end of induction day 32 in the ITT ALL population were consistent with results in the FAS ALL population.

Serum Asparaginase Activity

SAA levels were not reported in the COG AALL07P4 trial.

In the DFCI 11-001 trial, the proportion of patients with SAA levels of 0.10 IU/mL or greater were ||||| |||| ||| |||| || |||||| for calaspargase pegol versus ||||| |||| ||| |||| || |||||| for pegaspargase at 5 minutes to 10 minutes after infusion on induction day 7 (odds ratio [OR] |||||; 90% CI, ||||| || |||||). The proportion of patients with SAA levels of 0.10 IU/mL or greater were |||||| (95% CI | |||| || |||||) for calaspargase pegol versus ||||| (95% CI, |||| || |||||) for pegaspargase at 4 days after infusion on day 11 (OR |||||| 90% CI, ||||| || |||||). The proportion of patients with SAA levels of 0.10 IU/mL or greater were 100.0% (95% CI, 96.8% to 100.0%) for calaspargase pegol versus 100.0% (95% CI, 95.0% to 100.0%) for pegaspargase at 11 days after infusion on day 18 (OR = 0.479; 90% CI, 0.063% to 3.626%). The proportion of patients with SAA levels of 0.10 IU/mL or greater were ||||| (95% CI, |||| || ||||) for calaspargase pegol versus ||||| (95% CI, |||| || ||||) for pegaspargase at 18 days after infusion on day 25 (OR |||||; 90% CI, ||||| || ||||||). The proportion of patients with SAA levels of 0.10 IU/mL or greater were ||||| (95% CI, |||| || ||||) for calaspargase pegol versus ||||| (95% CI, |||| || ||||) for pegaspargase at 25 days after infusion on day 32 (OR ||||||; 90% CI, |||||| || ||||||). Estimates of treatment effect on SAA levels using adjusted analyses (controlled for age, sex, initial risk group, disease type, and baseline WBC count) were similar to unadjusted analyses.

Harms Results

The analysis population for harms included all patients who received at least 1 dose of any study drug, with patients grouped according to the treatment received. Safety data were from the primary safety analyses for the COG AALL07P4 study (data cut-off date of December 31, 2015) and the DFCI 11-001 study (data cut-off date of October 5, 2016).

In the COG AALL07P4 trial, the percentage of patients reporting any TEAEs was ||||| for calaspargase pegol and ||||| for pegaspargase. In the DFCI 11-001 trial, the percentage of patients who experienced any TEAEs was ||||| for the calaspargase pegol group and |||||| patients in the pegaspargase group. In the COG AALL07P4 trial, the most common TEAEs occurring in at least 25% of patients in either treatment group (calaspargase pegol versus pegaspargase) were hypoalbuminemia (27.9% versus 5.8%); hyperglycemia (79.1% versus 50.0%); blood bilirubin, increased (62.8% versus 50.0%); neutrophil count, decreased (55.8% versus 51.9%); febrile neutropenia (55.8% versus 42.3%); alanine aminotransferase, increased (34.9% versus 38.5%); platelet count, decreased (34.9% versus 25.0%); WBC count, decreased (37.2% versus 28.5%); hypokalemia (27.9% versus 11.5%); anemia (25.6% versus 26.9%); activated partial thromboplastin time, prolonged (30.2% versus 19.2%); peripheral motor neuropathy (27.9% versus 19.2%); and abdominal pain (32.6% versus 11.5%). In the DFCI 11-001 trial, the most common TEAEs occurring in at least 25% of patients in either treatment group (calaspargase pegol versus pegaspargase) were hypoalbuminemia (81.4% versus 82.4%); alanine transaminase, increased (78.8% versus 77.3%); aspartate aminotransferase, increased (53.4% versus 58.8%); blood bilirubin, increased (45.8% versus 43.7%); hypokalemia (45.8% versus 39.5%); febrile neutropenia (33.9% versus 40.3%); hyperglycemia (33.9% versus 28.6%); hypoglycemia (30.5% versus 36.1%); hypertriglyceridemia (28.0% versus 36.1%); and stomatitis (25.4% versus 20.2%).

In the COG AALL07P4 study, the number of patients with at least 1 serious adverse event (SAE) was not reported. The percentage of patients with at least 1 grade 3 or grade 4 TEAE was 97.7% in the calaspargase pegol group and 90.4% in the pegaspargase group. The most common grade 3 or grade 4 TEAEs in the calaspargase pegol group and the pegaspargase group, respectively, were neutrophil count, decreased (55.8% versus 51.9%); febrile neutropenia (55.8% versus 42.3%); WBC count, decreased (37.2% versus 28.8%); and hyperglycemia (37.2% versus 17.3%). In the DFCI 11-001 study, the percentage of patients who experienced grade 3 or grade 4 TEAEs was ||||| in the calaspargase pegol group and ||||| in the pegaspargase group. The most common grade 3 or grade 4 TEAEs in the calaspargase pegol and pegaspargase groups, respectively, were alanine aminotransferase, increased (49.2% versus 60.5%); hypokalemia (43.2% versus 36.1%); febrile neutropenia (33.9% versus 40.3%); and hypoalbuminemia (27.1% versus 27.7%). The percentage of patients who experienced at least 1 SAE was 24.6% and 21.8% in the calaspargase pegol group and the pegaspargase group, respectively. SAEs that occurred in at least 2% of patients in either the calaspargase pegol group or the pegaspargase group, respectively, were lipase, increased (4.2% versus |||||); pancreatitis (5.9% versus ||||); sepsis (3.4% versus |||||| hyperglycemia (2.5% versus ||||); febrile neutropenia (1.7% versus ||||); amylase, increased (0.8% versus ||||); alanine aminotransferase, increased (2.5% versus ||||); aspartate aminotransferase, increased (2.5% versus |||); and neutropenic colitis (2.5% versus |||).

In the COG AALL07P4 study, the percentage of patients who stopped study treatment due to an AE was ||||| and ||||| in the calaspargase pegol group and the pegaspargase group, respectively. The reasons for stopping study treatment due to an AE were not reported. In the DFCI 11-001 study, the percentage of patients who stopped study treatment due to an AE was 28.0% in the calaspargase pegol group and 19.3% in the pegaspargase group. Withdrawals due to adverse events (WDAEs) in the calaspargase pegol group compared with the pegaspargase group, respectively, were due to hypersensitivity (8.5% versus |||||; lipase, increased (6.8% versus ||||); pancreatitis (5.9% || |||| ||||||); drug hypersensitivity (5.1% versus ||||); amylase, increased (4.2% versus ||||); and anaphylactic reaction (1.7% versus |).

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Notable harms identified in the CADTH review included hypersensitivity reactions, anaphylactic reactions, silent inactivation, pancreatitis, thrombosis, hemorrhage, and hepatotoxicity. In the COG AALL07P4 trial, |||| of patients in the calaspargase pegol group and |||| of patients in the pegaspargase group experienced hypersensitivity events. In the DFCI 11-001 trial, ||||| of patients in the calaspargase pegol group and ||||| of patients in the pegaspargase group experienced hypersensitivity events. In the COG AALL07P4 trial, 25.6% of patients in the calaspargase pegol group and 19.2% of patients in the pegaspargase group experienced anaphylactic reactions. In the DFCI 11-001 trial, |||| of patients in each treatment group experienced anaphylactic reactions. In the COG AALL07P4 study, silent inactivation was not reported by any patient. In the DFCI 11-001 study, 1.7% of patients in the calaspargase pegol group experienced silent inactivation and were switched to Erwinia asparaginase treatment. In the COG AALL07P4 study, 18.6% and 7.7% of patients experienced pancreatitis in the calaspargase pegol group and the pegaspargase group, respectively. In the DFCI 11-001 study, 11.9% and 16.8% of patients experienced pancreatitis in the calaspargase pegol group and the pegaspargase group, respectively. In the COG AALL07P4 study, venous thrombosis was ||| |||||||| || ||| |||||||. In the DFCI 11-001 study, |||| of patients experienced venous thrombosis in each of the calaspargase pegol and pegaspargase groups. || ||||||| experienced hemorrhage in the COG AALL07P4 study or the DFCI 11-001 study. In the COG AALL07P4 trial, the percentage of patients who experienced increased blood bilirubin was 62.8% and 50.0% and who experienced increased alanine aminotransferase was 34.9% and 38.5% in the calaspargase pegol group and the pegaspargase group, respectively. In the DFCI 11-001 trial, the percentage of patients who experienced increased blood bilirubin was 45.8% and 43.7% and who experienced increased alanine aminotransferase was 78.8% and 77.3% in the calaspargase pegol group and the pegaspargase group, respectively. ||| ||||||| in the calaspargase pegol group experienced hepatic failure.

Critical Appraisal

The COG AALL07P4 and DFCI 11-001 trials were phase II, randomized, open-label randomized controlled trials (RCTs). Randomization appeared to be adequate in the COG AALL07P4 and DFCI 11-001 studies since treatment groups were generally balanced for key baseline characteristics and therefore likely to be at low risk for selection bias. The open-label study design may have biased outcomes with subjective assessments for harms due to knowledge of the assigned treatment, although the direction for potential bias is unclear. The phase II study design of the COG AALL07P4 and DFCI 11-001 trials did not allow the trials to assess comparative efficacy between calaspargase pegol and pegaspargase. The sample sizes (97 patients in the COG AALL07P4 study and 239 patients in the DFCI 11-001 study) were relatively small and the magnitude of the treatment effect estimates observed in a small study sample may not be replicable in a larger study sample. Findings from the COG AALL07P4 and DFCI 11-001 studies were not controlled for multiple comparisons. There were balanced between-group proportions of patients who were censored or had missing outcome data that were unlikely to substantially impact findings in the COG ALL07P4 study or the DFCI 11-001 study despite lack of imputation. Differences in trial population and backbone treatment protocols in the COG AALL07P4 and DFCI 11-001 trials precluded the ability to combine findings across outcomes. In the COG AALL07P4 and DFCI 11-001 trials, median survival estimates were not reached at the time of data cut-off. Assessments for CR and MRD at day 29 appeared to be appropriate to capture the presence or absence of disease at the end of remission induction. SAA levels were a primary end point in the DFCI 11-001 study and have been reported to serve as an important end point in assessing calaspargase pegol’s ability to maintain asparagine suppression in plasma, its half-life duration, and its ability to be administered with less dosing frequency than pegaspargase. Outcomes that were not assessed included health-related quality of life (HRQoL) (the COG AALL07P4 and DFCI 11-001 studies) and silent inactivation (the COG AALL07P4 study). The comparator used in the COG AALL07P4 and DFCI 11-001 trials was appropriate as pegaspargase is a pegylated formulation of asparaginase (calaspargase pegol uses the same mechanism of action as pegaspargase) and has been a component of current SOC. Calaspargase pegol is intended to substitute for pegaspargase and would be used for patients who would have otherwise received a pegaspargase-containing MAC.

The COG AALL07P4 and DFCI 11-001 studies were phase II trials and enrolled small samples of patients with ALL. Nevertheless, clinical experts consulted by CADTH remarked that a small patient population is expected, given the disease area, and a phase III RCT would neither be feasible nor ethical to conduct. While patients in the COG AALL07P4 and DFCI 11-001 trials were considered representative of patients with ALL, subpopulations of patients excluded from enrolment included pediatric patients with Ph-positive status (excluded from the COG AALL07P4 and DFCI 11-001 trials), patients with T-cell ALL (excluded from the COG AALL07P4 trial), and patients with relapse or refractory disease (excluded from the COG AALL07P4 and DFCI 11-001 trials). According to the clinical experts consulted by CADTH, the effects of treatment with calaspargase pegol could be generalizable to these patients. The clinical experts consulted by CADTH noted that it is anticipated that patients would benefit from treatment with calaspargase pegol based on its similarity to and extrapolation of findings for pegaspargase. Different backbone therapies were employed, with an intermittent asparagine depletion versus continuous asparagine depletion protocol for the COG AALL07P4 study versus the DFCI 11-001 study, respectively. The clinical experts consulted by CADTH observed that both COG-based and DFCI-based protocols were employed by institutions across Canada. The clinical experts consulted by CADTH expected outcomes to be similar regardless of the treatment protocol employed for patients with ALL. Outcomes reported in the COG AALL07P4 and DFCI 11-001 studies appeared to be aligned with outcomes of interest for patients with ALL, according to the clinical experts consulted by CADTH. The clinical experts consulted by CADTH highlighted the importance of SAA levels in therapeutic drug monitoring (TDM) for both efficacy (i.e., adequate asparagine depletion and sustained SAA levels of 0.10 IU/mL or greater) and safety (e.g., hypersensitivity reactions including silent inactivation). In general, the clinical experts consulted by CADTH did not anticipate clinically meaningful differences in efficacy between calaspargase pegol and pegaspargase.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^10,11 Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias.

The selection of outcomes for the GRADE assessment was based on the sponsor’s Summary of Clinical Evidence,¹² discussions with clinical experts consulted by CADTH, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: survival (OS, DFS from CR, and EFS), CR at the end of induction, MRD at the end of induction, SAA, and harms (WDAEs, hypersensitivity reactions, anaphylactic reactions, and silent inactivation).

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of a clinically important effect for CR at the end of induction based on a threshold informed by the clinical experts consulted by CADTH for this review. The target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for survival rates (OS, DFS from CR, EFS), MRD at the end of induction, SAA during induction, and harms.

For the GRADE assessments, findings from the COG AALL07P4 and DFCI 11-001 studies were assessed individually because the trials were different in terms of enrolled populations (patients with high-risk B-cell ALL in the COG AALL07P4 trial and patients with ALL and LL in the DFCI 11-001 trial) and employed different treatment protocols (intermittent asparagine depletion in the COG AALL07P4 trial and continuous asparagine depletion in the DFCI 11-001 trial).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for calaspargase pegol versus pegaspargase in patients with high-risk B-cell ALL in the COG AALL07P4 trial. Table 3 presents the GRADE summary of findings for calaspargase pegol versus pegaspargase in patients with ALL in the DFCI 11-001 trial.

Table 2: Summary of Findings for Calaspargase Pegol Versus Pegaspargase for Patients With High-Risk B-Cell ALL in COG AALL07P4 Study

AE = adverse event; ALL = acute lymphoblastic leukemia; CI = confidence interval; COG = Children’s Oncology Group; HRQoL = health-related quality of life; NA = not applicable; NR = not reported; RCT = randomized controlled trial; WDAE = withdrawal due to adverse event.

Notes: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 2 levels for very serious imprecision. There is no established minimal important difference and clinical experts consulted by CADTH could not provide a threshold of important difference. In the absence of a known threshold, the null was used. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the upper and lower bounds of the 95% CI for difference between groups suggested a possibility of both benefit and harm.

^bRated down 2 levels for very serious imprecision. No threshold was identified in the literature, but according to the clinical experts consulted by CADTH for the review, any difference in disease-free survival could be considered clinically meaningful, so the null was used as the threshold. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the upper and lower bounds of the 95% CI for difference between groups suggested a possibility of both benefit and harm.

^cRated down 1 level for serious imprecision. No threshold was identified in the literature, but according to the clinical experts consulted by CADTH for the review, any difference in disease-free survival could be considered important, so the null was used as the threshold. The CADTH review team judged that the effect estimate was unlikely to include any important effect; however, the upper bound of the 95% CI for difference between groups suggested a possibility of benefit.

^dRated down 2 levels for very serious imprecision. No threshold was identified in the literature, but according to the clinical experts consulted by CADTH for the review, a 5% difference between groups in complete remission could be considered clinically meaningful; however, the upper and lower bounds of the 95% CI for difference between groups suggested a possibility of both important benefit and important harm.

^eRated down 1 level for risk of bias. The open-label study design may have biased WDAEs from patients’ and assessors’ knowledge of assigned treatment, although the direction of potential bias is unclear. Moreover, the clinical experts consulted by CADTH noted that since asparaginase is given as part of a multiagent chemotherapeutic protocol, it is challenging to attribute differences in AEs observed in small numbers of patients to a single treatment protocol component.

^fRated down 2 levels for very serious imprecision. In the absence of an established threshold, the null was used. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the effect estimate was based on very few events. Moreover, the clinical experts consulted by CADTH noted that since asparaginase is given as part of a multiagent chemotherapeutic protocol, it is challenging to attribute differences in AEs observed in small numbers of patients to a single treatment protocol component.

Source: COG AALL07P4 Clinical Study Report.¹³ Details included in the table were provided from sponsor in response to additional data request.¹⁴

Table 3: Summary of Findings for Calaspargase Pegol Versus Pegaspargase for Patients With ALL in DFCI 11-001 Study

AE = adverse event; ALL = acute lymphoblastic leukemia; CI = confidence interval; DFCI = Dana-Farber Cancer Institute; GEE = generalized estimating equation; HRQoL = health-related quality of life; NA = not applicable; NR = not reported; SAA = serum asparaginase activity; WDAE = withdrawal due to adverse event.

Notes: Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 1 level for serious imprecision. There is no known threshold and clinical experts consulted by CADTH could not provide a threshold of important difference. In the absence of a known threshold, the null was used. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the lower bound of the 95% CI for the difference between groups suggested a possibility of harm.

^bRated down 2 levels for very serious imprecision. In the absence of a known threshold, the CADTH team rated their certainty in a non-0 effect. Although no threshold (i.e., the null) was crossed, the effect estimate was based on very few events in each group.

^cRated down 2 levels for very serious imprecision. According to the clinical experts consulted by CADTH for the review, any difference in disease-free survival could be considered clinically meaningful, so the null was used as the threshold. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the effect estimate was based on very few events.

^dRated down 1 level for serious imprecision. According to the clinical experts consulted by CADTH for the review, any difference in disease-free survival could be considered clinically meaningful, so the null was used as the threshold. The CADTH review team judged the between-group difference was unlikely to include an important effect; however, the lower bound of the 95% CI for the difference between groups suggested a possibility of harm.

^eRated down 2 levels for very serious imprecision. There was no established minimal important difference and clinical experts consulted by CADTH could not provide a threshold of important difference. In the absence of a known threshold, the null was used. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the upper and lower bounds of the 95% CI for difference between groups suggested a possibility of both benefit and harm.

^fRated down 1 level for serious imprecision. No known threshold was identified but according to the clinical experts consulted by CADTH for the review, a 5% difference between groups in complete remission could be considered clinically meaningful. The CADTH review team judged that the effect estimate was unlikely to include an important effect; however, the lower bound of the 95% CI for difference between groups suggested a possibility of important harm.

^gOdds ratios of SAA levels were estimated using a GEE model for comparing categorical SAA levels between treatments, with 90% CIs, adjusted for the following: treatment, actual sampling time points, and the interaction of treatment and actual sampling time points as effects.

^hRated down 2 levels for very serious imprecision. In the absence of a known threshold, the null was used. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the effect estimate was based on very few events.

ⁱRated down 1 level for serious imprecision. There was no known threshold and clinical experts consulted by CADTH could not provide a threshold of important difference, so the null was used as the threshold. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the 95% CI for the difference between groups suggested a possibility of benefit.

^jRated down 1 level for serious imprecision. There was no known threshold and clinical experts consulted by CADTH could not provide a threshold of important difference, so the null was used as the threshold. The CADTH team judged that the point estimate for the between-group difference was likely to include an important benefit. Both lower and upper boundaries of the 95% CI of the between-group difference suggested a possibility of benefit. Although no threshold (i.e., the null) was crossed, the effect estimate was based on relatively few events in each group.

^kRated down 1 level for risk of bias due to open-label study design and patients’ and assessors’ knowledge of assigned treatment. The open-label study design may have biased WDAEs from knowledge of assigned treatment, although the direction of potential bias is unclear. Moreover, the clinical experts consulted by CADTH noted that since asparaginase is given as part of a multiagent chemotherapeutic protocol, it is challenging to attribute differences in AEs observed in small numbers of patients to a single treatment protocol component.

^lRated down 2 levels for very serious imprecision. In the absence of an established threshold, the null was used. The CADTH review team judged that the point estimate for the between-group difference was unlikely to include an important effect; however, the effect estimate was based on very few events. Moreover, the clinical experts consulted by CADTH noted that since asparaginase was given as part of a multiagent chemotherapeutic protocol, it was challenging to attribute differences in AEs observed in small numbers of patients to a single treatment protocol component.

Source: DFCI 11-001 Clinical Study Report.¹⁵ Details included in the table were provided from sponsor in response to additional data request.¹⁴

Long-Term Extension Studies

No long-term extension studies were submitted in the systematic review evidence.

Indirect Comparisons

No indirect treatment comparisons were submitted in the systematic review evidence.

Studies Addressing Gaps in the Evidence From the Systematic Review

No additional studies addressing important gaps in the systematic review evidence were identified.

Conclusions

Evidence from a randomized phase II, open-label trial (the COG AALL07P4 study) in patients aged 1 year to 30 years with high-risk B-cell ALL suggested that calaspargase pegol likely results in little to no difference in DFS rates from the attainment of CR at 4 years (moderate certainty) and may result in an increase in CR at the end of induction (low certainty) compared with pegaspargase. Furthermore, the COG AALL07P4 trial suggested that compared with pegaspargase, calaspargase pegol may result in little to no difference in OS rates at 1 year and 4 years, DFS rates from the attainment of CR at 1 year, EFS rates at 1 year and 4 years, and MRD at the end of induction (low certainty).

Evidence from a randomized phase II, open-label trial (the DFCI 11-001 trial) in patients aged 1 year to 21 years with ALL suggested that calaspargase pegol likely results in a greater proportion of patients with SAA of at least 0.10 IU/mL at day 32 (moderate certainty) when compared with pegaspargase and likely results in little to no difference in OS rates at 1 year, DFS rates from the attainment of CR at 2 years, EFS rates at 2 years, and CR at the end of induction (moderate certainty) compared with pegaspargase. Furthermore, the DFCI 11-001 study suggested that compared with pegaspargase, calaspargase pegol may result in little to no difference in OS at 2 years, DFS rates from the attainment of CR at 1 year, EFS rates at 1 year, and MRD at the end of induction (low certainty).

SAA is an established surrogate measure of asparagine depletion. SAA levels above 0.10 IU/mL have been shown to be associated with complete asparagine depletion and therefore, therapeutic benefit. The clinical experts consulted by CADTH considered the results for SAA measured during induction to be supportive of calaspargase pegol’s greater biological stability compared with pegaspargase, of calaspargase pegol’s ability to maintain asparagine suppression in plasma, of its longer half-life duration compared to pegaspargase, and of its ability to be administered with less dosing frequency than pegaspargase (i.e., a schedule of every 3 weeks versus every 2 weeks).

No unexpected safety signals were identified with treatment of calaspargase pegol in the COG AALL07P4 or the DFCI 11-001 trial. The clinical experts consulted by CADTH noted that asparaginase is given as part of an MAC protocol and it is challenging to attribute differences in AEs observed in small numbers of patients to a single treatment protocol component. The COG AALL07P4 and DFCI 11-001 trials did not report data on HRQoL.

Confidence in the effect estimates from the COG AALL07P4 and the DFCI 11-001 studies was limited, primarily due to both studies not being designed to assess comparative efficacy between calaspargase pegol and pegaspargase, relatively small sample sizes, and the open-label design, which may have biased subjective outcomes such as harms.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of calaspargase pegol 2,500 units/m² given intravenously no more frequently than every 21 days as a component of an MAC regimen in the treatment of ALL in children and adults.

Disease Background

The content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

ALL is a heterogeneous group of disorders that results from the clonal proliferation and expansion of malignant lymphoid cells in the bone marrow, blood, and extramedullary sites.⁵ WHO classifies ALL into 2 major subtypes: B-lymphoblastic and T-lymphoblastic leukemia, which are further divided according to the presence and type of genetic abnormalities.^5,6 The frequency of ALL B-cell phenotypes is approximately 80% to 85% in pediatric patients and close to 75% in adult patients. The frequency of the Philadelphia chromosome in patients with ALL is about 25% to 30% in pediatric patients and about 3% to 5% in adult patients.⁷

Although ALL primarily starts from the bone marrow and peripheral blood, any organ or tissue may be infiltrated.¹⁶ Signs and symptoms of ALL are highly variable. At presentation, patients may have easy bruising, bleeding, dyspnea, dizziness, infections due to anemia, thrombocytopenia, and neutropenia. In some patients, extremity and joint pain present. Twenty percent of patients have lymphadenopathy, splenomegaly, and/or hepatomegaly, and 10% of patients have symptoms of CNS involvement.¹⁷ The symptoms burden is high as patients report a median of 9 physical and 2 psychological symptoms, and 61% of patients report 10 or more concurrent symptoms.¹⁶

Multiple factors affect prognosis in ALL and are used for risk stratification, which is the basis for treatment planning and management of disease.⁵ These factors include demographic, clinical, biological, or genetic features of leukemia, and response to treatment.¹⁸

The US Surveillance, Epidemiology, and End Results database has shown improvements in survival with 5-year OS rates of 89% for children and 89% for adolescents and young adults (AYAs) (15 years to 39 years). However, 5-year survival rates for the other adult patients remain low at approximately 20% to 40%. Five-year survival rates are especially poor in older adult patients at approximately 20%.²

ALL is the least common type of leukemia diagnosed in adults; however, it is the most common type of leukemia diagnosed in young children, occurring more often in boys than girls.¹ It is estimated that ALL represents 75% to 80% of acute leukemias among children and 20% of all leukemias among adults.² The median age of diagnosis is 17 years with 53.5% of patients diagnosed before the age of 20 years.² In 2018, the incidence rate of ALL for all ages in Canada (excluding Quebec) was 1.3 per 100,000, with the majority of patients being younger than 19 years.^3,4

In general, the diagnosis of ALL requires the demonstration of 20% or greater bone marrow lymphoblasts on bone marrow aspirate and biopsy materials, which includes morphologic assessment of Wright-Giemsa–stained bone marrow aspirate smears, and hematoxylin-stained and eosin-stained core biopsy and clot sections; comprehensive flow cytometric immunophenotyping; baseline flow cytometric and/or molecular characterization of leukemic clone to facilitate subsequent MRD analysis; and karyotyping of G-banded metaphase chromosomes.¹⁹

Optimal risk stratification and treatment planning require testing marrow or peripheral blood lymphoblasts for specific recurrent genetic abnormalities using interphase fluorescence in situ hybridization testing, including probes capable of detecting the major recurrent genetic abnormalities; reverse transcriptase-polymerase chain reaction testing for BCR-ABL1 in B-cell ALL (quantitative or qualitative), including the determination of transcript size; and comprehensive testing by next-generation sequencing for gene fusions and pathogenic mutations.¹⁹

Standards of Therapy

The content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

Pretreatment Phase

To manage potential hypersensitivity and infusion reactions with any asparaginase treatment, some Canadian institutions have integrated the administration of premedication such as acetaminophen, diphenhydramine, and corticosteroids into their treatment protocols.^20,21 Studies have shown that the administration of premedication before pegylated asparaginase treatment results in significant reductions in severe, clinically evident hypersensitivity reactions.^20,22,23 Currently, the use of premedication varies across Canada. Some clinicians prefer to avoid masking any occurrence of hypersensitivity, using it as an indicator to further investigate the occurrence of silent inactivation (subclinical asparaginase activity levels). Still, TDM is required to detect subclinical asparaginase activity levels, with or without the use of premedication.^20,21,24

Treatment Phase

The goal of first-line treatment of ALL is curative, requiring the attainment of CR.²⁵ Treatment consists of multiple phases of MAC: the induction phase, the intensification and/or consolidation phase, the CNS therapy phase, and the maintenance phase.^1,2,18

Escherichia coli–derived asparaginase is a cornerstone component of the induction and intensification and/or consolidation phases of first-line treatment,^1,2,18 and for more than 30 years, has been a significant chemotherapeutic addition, ultimately becoming part of the WHO list of essential drugs.^26,27 Pegaspargase, a pegylated form of E. coli–derived asparaginase, is the established SOC asparaginase product incorporated across Canada as part of standard clinical practice and clinical trials.

Two different childhood ALL treatment strategies are commonly used across Canada, originating from the COG and DFCI consortia.^8,9 Both COG and DFCI protocols include the use of pegaspargase. There is also consensus that AYA patients demonstrate improved outcomes when treated with a pediatric-inspired regimen.²⁸ According to the clinical expert consulted by CADTH, most pediatric patients with ALL are treated using COG protocols in Canada except in Quebec, where they are treated using DFCI protocols. AYA patients are predominantly treated with a modified DFCI regimen or another pediatric-inspired regimen.²⁸ Adult patients (non-AYA) with ALL also commonly receive a dose-modified DFCI pediatric-inspired regimen containing pegaspargase.

There are key differences in COG and DFCI protocols regarding backbone therapies, phases, schedules, and duration and frequency of asparaginase. COG protocols are aimed at intermittent asparagine depletion with rotating phases lasting 1 month to 2 months from induction through delayed intensification. In contrast, DFCI protocols are aimed at continuous asparagine depletion with a prolonged intensification phase that is employed within cycles of MAC. In COG protocols, patients receive a single dose of the study drug at induction (and at extended induction for slow early responders), followed by additional doses of the study drug at each subsequent phase (consolidation, interim maintenance phase I, delayed intensification I, interim maintenance phase II [as applicable], delayed intensification phase II [as applicable], and maintenance). In DFCI protocols, however, patients receive a single dose of the study drug during remission induction, and then every 2 weeks during intensification.

While Erwinia-derived asparaginase is available in Canada (e.g., Rylaze [crisantaspase recombinant]), as per its Health Canada indication, it is reserved for patients who have developed hypersensitivity to E. coli–derived L-asparaginase (such as pegaspargase or calaspargase pegol),^29-32 and is not considered for initial first-line treatment.

In general, the goal of the induction phase, which is typically 4 weeks to 6 weeks in duration, is to rid the blood and marrow of visible leukemic blast cells and attain CR. A combination of chemotherapy is used during induction, such as vincristine, an anthracycline, a glucocorticoid, and asparaginase. A CNS therapy phase designed to provide adequate CNS prophylactic or actual treatment is generally planned after induction or consolidation. The goal of the intensification and/or consolidation phase is to reduce or eliminate any remaining leukemic cells. Specifically, for consolidation, several short sequential courses of chemotherapy are employed, usually with cytarabine, high-dose methotrexate, vincristine, asparaginase, mercaptopurine, and glucocorticoids. This sequence is sometimes followed by a late intensification phase (reinduction therapy) that includes a combination of drugs similar to that used during the induction therapy. Altogether, the intensification and/or consolidation phase is 4 months to 6 months in duration.

Though the efficacy of asparaginase products in ALL treatment is dependent on the depletion of asparagine, the direct measurement of asparagine depletion is difficult and not practical as a routine clinical test. As such, asparaginase levels are measured in serum as a surrogate marker for asparagine depletion. This has been validated as a method of quantifying the efficacy of asparaginase formulations.³³

“Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation,” an article from international journal Haematologica that includes Canadian clinical expert Dr. James Whitlock as a principal author, outlines how asparaginase activity levels should be used in identifying patients with subtherapeutic asparaginase activity from silent inactivation in clinical practice, which is reflected in pediatric clinical trials in Canada.³⁴ Hypersensitivity reactions to asparaginase can occur with or without clinical symptoms of an allergy, the latter referred to as silent inactivation; in both situations, the drug is completely neutralized. Just as importantly, patients may also develop atypical allergies without inactivation (allergic-like reactions), which does not require a discontinuation. Overall, the importance of TDM in the management of patients treated with any of the asparaginase products is recognized; however, the routine use of TDM may vary in different settings across Canada.

Post-Treatment Phase

Patients concluding the asparaginase-containing phases of an MAC protocol will continue to receive maintenance therapy, typically consisting of daily mercaptopurine and weekly methotrexate, with or without vincristine, and glucocorticoid pulses every 1 month to 3 months over the course of 2 years to 3 years.

Drug Under Review

Key characteristics of calaspargase pegol are summarized in Table 3 with other treatments available for the treatment of patients with ALL.

The recommended dosage under review by Health Canada for calaspargase pegol is 2,500 units/m² given intravenously no more frequently than every 21 days. Calaspargase pegol is indicated as a component of an MAC regimen for the treatment of patients with ALL. It has not been previously reviewed by CADTH.

Calaspargase is a conjugate of L-asparaginase (L-asparagine amidohydrolase) and monomethoxy polyethylene glycol. L-asparaginase is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The depletion of L-asparagine in blood serum results in the inhibition of protein synthesis, DNA synthesis, and ribonucleic acid synthesis — especially in leukemic blasts that are not able to synthesize L-asparagine, thus undergoing programmed cell death. Normal cells, in contrast, are capable of synthesizing L-asparagine and are less affected by its rapid withdrawal during treatment with the enzyme L-asparaginase. The mechanism of action of calaspargase pegol is the same as that of the established SOC pegaspargase. To mitigate the risk of drug shortages, the sponsor developed calaspargase pegol to extend the shelf life and half-life relative to the sponsor’s original product, pegaspargase. Both calaspargase pegol and pegaspargase contain the same asparagine-specific enzyme derived from E. coli, as a conjugate of L-asparaginase linked to a similar monomethoxy polyethylene glycol. The only difference between the 2 products is the linker connecting the 2 components. Pegaspargase contains a succinimidyl succinate linker, while calaspargase pegol contains a succinimidyl carbonate linker, the latter being less prone to enzymatic hydrolysis and more stable. As a result of the improved stability, calaspargase pegol has a 36-month shelf life compared to 8 months for the pegaspargase formulation.³⁵

Calaspargase pegol is currently under review by Health Canada as a component of an MAC regimen for the treatment of patients with ALL. The Notice of Compliance for this indication was expected on November 8, 2023. The sponsor requested reimbursement as per the indication to be reviewed by CADTH.

The FDA approved calaspargase pegol on December 20, 2018, as a component of an MAC regimen for the treatment of ALL in pediatric and young adult patients aged 1 month to 21 years.

Table 4: Key Characteristics of Calaspargase Pegol and Pegaspargase

RNA = ribonucleic acid.

^aHealth Canada–approved indication.

Sources: Draft Product Monograph for calaspargase pegol³⁶ and Product Monograph for pegaspargase.³⁷

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient input received by CADTH has been included in the Stakeholder section of this report.

CADTH received 1 patient group submission from LLSC. LLSC is a national charitable status organization dedicated to finding a cure for blood cancers and to improving the quality of life of people affected by blood cancers and their families by funding life-enhancing research and providing educational resources, services, and support.

LLSC conducted an online survey with 74 respondents from 10 provinces in Canada during April to May 2023. The majority of respondents (n = 47) identified as patients with ALL and 20 respondents indicated that they were caregivers of patients with ALL. Respondents who indicated that they were neither a patient with ALL nor a caregiver of a patient with ALL were disqualified from the survey. About half of the patients with ALL indicated that they were older than 30 years at the time of their ALL diagnosis while the other half was younger than 30 years.

LLSC stated that the questions in this survey were not intended to measure the efficacy of the drug under review because it was assumed to be as effective as current treatment options and was also budget-neutral. The questions in this survey were aimed at highlighting the importance of safeguarding the health care system to ensure that treatment medications are supply-secure for those experiencing ALL.

Survey respondents reported their experience with drug shortages at some point during their ALL treatment. Reponses highlighted extremely stressful conditions, fear that the treatment would be unsuccessful, the feeling of powerlessness and being let down by the system, poor quality of life, and lack of sleep because of stress, anxiety, mood swings, and spending time trying to find an alternative solution. Some respondents noted financial impacts, as they had to pay for alternative therapies and buy products to help them cope.

Respondents indicated that they needed to feel included in decision-making as their treatment plan for ALL would have effects on many areas of their lives. In addition to the effectiveness of the treatment, there were other factors that are important to patients when evaluating new treatments for ALL, including side effects, a physician’s recommendation, quality of life, cost, secure supply, and number of treatments.

LLSC highlighted that ALL progresses quickly and aggressively and that to prevent disease progression, the immediate start of treatment upon diagnosis is vital. Survey respondents expressed that delaying the start of treatment may lead to cancer progression, to their bodies being less receptive and tolerable to treatment, and potentially to death.

LLSC noted the importance of having alternative treatments available to ensure treatment can continue should manufacturers run into supply issues. Having supply-secure treatment options would provide comfort and peace of mind to patients and their caregivers during an already difficult and challenging time. Most of the survey respondents indicated that they would be supportive of a government providing public funding for an alternative treatment option for ALL that would work equally well with similar costs to the health care system and would provide treatment assurance in case an alternative ALL medication became unavailable.

Most of the survey respondents reported that the availability of treatment throughout the entire course of therapy is extremely important to them. Some of the respondents commented that ensuring a secure and readily available supply of medications for treatment is something that can be done and would remove stress from patients and caregivers and improve patients’ outcomes.

LLSC asked survey respondents to rate the level of impact that a treatment shortage due to supply issues would have on their lives. Respondents noted the following areas as being most impacted (listed in order of importance to survey respondents): mental health, physical health, quality of life, home life, social life, work life, and finances.

Respondents were asked by LLSC to describe in 3 words their emotional response to being told that a drug that was part of their treatment regimen was suddenly not available due to supply issues. Survey respondents mostly reported words associated with fear, stress, despair, and defeat.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of ALL.

Unmet Needs

The clinical experts consulted by CADTH reported that the goal of treatment for patients with ALL is curative, aimed at maximizing survival while minimizing short-term and long-term toxicities. The clinical experts consulted by CADTH also noted the growing number of clinical-, genetic-, and response-based risk stratification factors that support better survival and/or reduce toxicities.

Current treatment for ALL in Canada was identified by the clinical experts consulted by CADTH as comprising MAC regimens that include pegylated asparaginase, using pediatric protocols developed by COG or DFCI in centres treating children, or pediatric-inspired protocols in centres that treat adults, respectively. The clinical experts consulted by CADTH estimated that the total duration of MAC treatment for patients with ALL who respond is approximately 2.5 years to 3.5 years. Asparaginase is incorporated into the first phases of MAC treatment during the first year. The clinical experts consulted by CADTH noted that patients who do not respond to treatment (e.g., patients who become refractory to current treatment options, patients who receive lower than 80% of the recommended dose of asparaginase) require high-dose chemotherapy and/or allogeneic stem cell transplant and experience high rates of treatment failure. According to the clinical experts consulted by CADTH, current suppliers of L-asparaginase (pegaspargase) in Canada have been unable to provide a consistent supply that sufficiently meet the needs of all patients due to the drug’s relatively short half-life (2 weeks). The clinical expert consulted by CADTH noted that new treatments with a prolonged half-life may make treatments more convenient for patients and care teams by leading to reduced frequency of administration. Pegaspargase’s half-life requires a relatively high frequency of dosing (e.g., 15 treatments during the intensification phase). The clinical experts consulted by CADTH agreed that patients with ALL would benefit from treatments that are better tolerated and more convenient, which may lead to improved compliance.

Place in Therapy

The clinical experts consulted by CADTH anticipated that calaspargase pegol would become the new standard for prolonged asparaginase therapies and would replace the current SOC due to its incorporation of a more stable linker, which in turn is expected to lead to a prolonged shelf life, more stable supply chain, and comparatively shorter frequency of dosing (e.g., approximately 10 treatments during the intensification phase). The clinical experts consulted by CADTH did not expect calaspargase pegol to cause a shift in the current treatment paradigm.

Patient Population

The clinical experts consulted by CADTH indicated that all patients with newly diagnosed ALL would benefit from treatment with calaspargase pegol, since asparaginase has a unique mechanism of action playing an essential part in adequate asparagine depletion and is considered to comprise an essential component of therapy in ALL. Patients with relapsed ALL were also considered by the clinical experts consulted by CADTH to potentially benefit from calaspargase pegol, if there was no known prior intolerance to other forms of asparaginase given that such intolerance applies to any patient receiving an E. coli–derived enzyme. The clinical experts consulted by CADTH noted that misdiagnosis of ALL is unlikely. The clinical experts consulted by CADTH reported that all patients with ALL are tested for the presence of the BCR-ABL fusion gene (gene sequence; Philadelphia chromosome) by nested polymerase chain reaction (PCR), where patients who test positive for this gene are treated with tyrosine kinase inhibitors; therefore, treatment with L-asparaginase should be avoided due to overlapping toxicities. Patients with Ph-positive ALL were excluded from the COG AALL07P4 and DFCI 11-001 studies. The clinical experts consulted by CADTH noted that currently, pediatric patients and adult patients with Ph-positive ALL are on distinct treatment protocols that include tyrosine kinase inhibitor therapy. The clinical experts noted that while adult patients would not receive asparaginase therapy concurrently with tyrosine kinase inhibitor therapy due to overlapping toxicities, they considered asparaginase therapy an option for pediatric patients with Ph-positive ALL and would not expect PK and safety outcomes to differ in these patients compared to pediatric patients with Ph-negative ALL. Other patient subgroups excluded from clinical trial populations were infants aged up to 1 year (in the COG AALL07P4 and DFCI 11-001 trials), adults (patients older than 21 years in the DFCI 11-001 trial and older than 30 years in the COG AALL07P4 trial), and patients with disease immunophenotype (T-cell ALL in the COG AALL07P4 trial), who were considered by the clinical experts consulted by CADTH to be eligible for asparaginase treatment and therefore appropriately targeted for treatment with calaspargase pegol. The clinical experts consulted by CADTH specified that several risk factors are considered before starting treatment, including age older than 10 years, WBC count below 50 × 10⁹/L at presentation or diagnosis, adverse genetic features including karyotype (e.g., the translocation t(9;22)(q34;q11), hypodiploidy), molecular studies (e.g., BCR-ABL, KMT2A mutations), and gene expression (e.g., IKZF, CRLF2). Regardless of risk classification, the clinical experts consulted by CADTH highlighted MRD response as a key on-treatment prognostic factor such that patients at standard risk or high risk but with inadequate MRD response are treated using high-risk or very high-risk protocols incorporating asparaginase, respectively.

Assessing the Response Treatment

The clinical experts consulted by CADTH reported that a clinically meaningful treatment response should be assessed using OS, CR postinduction, MRD-negative status postinduction, and SAA levels following the administration of asparaginase to monitor adequate asparagine depletion and clinical reactions (e.g., allergic or infusion-related reaction, silent inactivation).

Discontinuing Treatment

According to the clinical experts consulted by CADTH, treatment with asparaginase including calaspargase pegol should be discontinued in the event of notable AEs (e.g., hypersensitivity reaction including silent inactivation, allergic reaction, development of neutralizing antibodies, severe liver toxicity, severe pancreatitis, severe thrombotic or hemorrhagic event, persistent severe hepatic dysfunction).

Prescribing Considerations

The clinical experts consulted by CADTH indicated that patients with ALL are treated in specialized treatment centres as inpatients or outpatients by hematologists or oncologists with significant training and experience. The clinical experts consulted by CADTH also noted that ALL treatment has to be administered in a setting where the urgent recognition of, and intervention for, serious immediate AEs such as anaphylaxis or other hypersensitive reactions can occur. The relevant specialists would be oncologists and critical care staff.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the Stakeholder section of this report.

CADTH received 1 clinician group submission from the OH-CCO Hematology Cancer Drug Advisory Committee. OH-CCO’s cancer drug advisory committees provide evidence-based clinical and health system guidance on drug-related issues in support of OH-CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. Information for this review was collected through videoconferencing and 2 clinicians contributed to this submission.

According to the OH-CCO, the current standard treatment for patients with ALL is pegaspargase, which is potentially curative. The clinicians providing input noted that there is no large unmet need as pegaspargase is available; however, less frequent dosing may be beneficial.

OH-CCO stated that calaspargase pegol is a standard component of an MAC for ALL. Patients who are eligible for the standard induction of ALL treatment would be best suited for treatment with calaspargase pegol. The clinicians providing input noted that to determine the treatment response, the standard leukemia response criteria should be applied, and treatment should be discontinued upon progressive disease or significant intolerance. OH-CCO noted that the appropriate setting for treatment with calaspargase pegol is acute leukemia treatment centres with the presence of leukemia specialists.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

ALL = acute lymphoblastic leukemia; COG = Children’s Oncology Group; DFCI = Dana-Farber Cancer Institute; LL = lymphoblastic lymphoma; PAG = Provincial Advisory Group; pERC = pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of calaspargase pegol 2,500 units/m² given intravenously no more frequently than every 21 days as a component of an MAC regimen for the treatment of patients with ALL. The focus will be placed on comparing calaspargase pegol to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of calaspargase pegol is presented in 4 sections with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach follows critical appraisal of the evidence. The sponsor did not include long-term extension studies, indirect evidence, or additional studies addressing important gaps in the pivotal and RCT evidence.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• 1 pivotal phase II study and 1 phase II study identified in the systematic review.

Systematic Review

The content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Description of Studies

Characteristics of the included studies are summarized in Table 6.

Table 6: Details of Studies Included in the Systematic Review

AE = adverse event; AESI = adverse event of special interest; ALL = acute lymphoblastic leukemia; AUC_0–25d = area under the curve plasma asparaginase activity from time 0 to 25 days; AUC 0-inf = area under the curve plasma asparaginase activity from time 0 to infinity; C_max = maximum asparaginase activity exposure peak concentration; CNS = central nervous system; COG = Children’s Oncology Group; CR = complete remission; CSF = cerebrospinal fluid; DFCI = Dana-Farber Cancer Institute; DFS = disease-free survival; EFS = event-free survival; MRD = minimal residual disease; NA = not applicable; NR = not reported; NSAA = nadir serum asparaginase activity; OS = overall survival; PD = pharmacodynamic; PEG = pegaspargase; PK = pharmacokinetic; SAA = serum asparaginase activity; WBC = white blood cell.

Note: Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

^aOne additional patient in the DFCI 11-001 study, who had an initial pathology report indicative of precursor B-cell ALL, had a subsequent pathology report indicative of leukemia of ambiguous lineage. Therefore, this patient was no longer eligible to participate in the study and did not receive any doses of the study drug.

Sources: COG AALL07P4 Clinical Study Report^13,15 and DFCI 11-001 Clinical Study Report.¹⁴

Two phase II, multicentre, randomized, open-label trials (the COG AALL07P4 and DFCI 11-001 trials) assessed the efficacy and safety of calaspargase pegol in pediatric and AYA patients. According to the sponsor, the clinical safety and efficacy of calaspargase pegol was built on pegaspargase. The primary objectives of the clinical development program for calaspargase pegol were focused on the feasibility (i.e., feasibility referring to the evaluation of PK end points) of use and safety, as well as PD comparability versus pegaspargase in anticipation of this formulation soon becoming the only available commercial pegaspargase-asparaginase preparation.^35,44

The COG AALL07P4 study enrolled 166 patients aged 1 year to 30 years with newly diagnosed high-risk B-cell ALL in 23 US sites. Patients were considered high risk as defined by the WHO 2008 classification if they had precursor B-cell ALL. Patients were randomized in a 2:1 ratio to calaspargase pegol (2,500 IU/m² or 2,100 IU/m²) or pegaspargase 2,500 IU/m². As the proposed Health Canada indication recommends a dose for calaspargase pegol of 2,500 IU/m², this CADTH clinical report will present data for patients who were randomized to receive calaspargase pegol 2,500 IU/m² and will exclude data that refer to patients who were first randomized to receive calaspargase pegol 2,100 IU/m² and subsequently switched to receive pegaspargase 2,500 IU/m². Details regarding the cohort of patients who were randomized to receive calaspargase pegol 2,100 IU/m² and later switched to pegaspargase 2,500 IU/m² are provided in the Interventions section of this clinical report (refer to protocol amendments in this report in the COG AALL07P4 study).

The primary objective of the COG AALL07P4 trial was to determine the PK comparability (asparaginase activity) of the interventions during induction and consolidation while patients were receiving augmented Berlin-Frankfurt-Münster therapy. Secondary objectives of the COG AALL07P4 study included PD parameters during induction and consolidation, MRD (day 29), CR rate (day 29), survival (EFS, DFS of CR, and OS), and TEAEs. The Clinical Study Report with a data cut-off date of December 31, 2015, was the primary data source for the COG AALL07P4 study.

The DFCI 11-001 study enrolled 239 patients in the US (in 6 sites) and Canada (in 3 sites) with newly diagnosed ALL or LL. Patients were randomized in a 1:1 ratio to calaspargase pegol 2,500 IU/m² or pegaspargase 2,500 IU/m² and stratified into 4 risk groups based on disease type, age, and initial risk-group classification: 1) patients with ALL younger than 10 years and standard risk, 2) patients with ALL younger than 10 years and initial high risk, 3) patients with ALL 10 years and older (and by definition initial high risk), and 4) patients with LL. Three final risk groups (standard risk, high risk, very high risk) were assigned after the completion of the remission induction phase for patients who attained CR (refer to Table 7 for risk group criteria). The DFCI 11 to 011 trial assigned patients in the final very high-risk group to receive more intensive treatment (refer to the Intervention section as follows and to Figure 2). There were 2 primary objectives of the DFCI 11-001 trial. One primary objective was to assess the toxicity associated with calaspargase pegol administration and determine if it was different from the toxicity associated with pegaspargase 2,500 IU/m² given as a single dose during remission induction and then every 2 weeks for 30 weeks during postinduction therapy. Another primary objective was to determine the SAA levels associated with calaspargase pegol administered as a single dose during remission induction and then every 2 weeks for 30 weeks during postinduction therapy, and to compare them to the SAA associated with pegaspargase as a single dose during remission induction and then every 2 weeks for 30 weeks during postinduction therapy. Primary end points included AEs and laboratory AEs, adverse events of special interest (AESIs), SAA levels and nadir serum asparaginase activity (NSAA) levels, the SAA level of 0.10 IU/mL or greater at induction phase day 7, day 11, day 18, day 25, and day 32, the NSAA level of 0.10 IU/mL or greater during the postinduction phase overall and by visit day, and the SAA level at week 7. Secondary end points of the DFCI 11-001 trial included MRD (day 32), CR rate (day 32), EFS, DFS of CR, OS, and TEAEs. The Clinical Study Report with a data cut-off date of October 5, 2016, was the primary data source for the DFCI 11-001 study, with an additional Day 120 Report that reported updated survival data (data cut-off date of June 12, 2017) and safety data (data cut-off date of February 1, 2017).

Populations

Inclusion and Exclusion Criteria

In the COG AALL07P4 trial, patients first needed to be eligible for, and enrolled in, the COG study AALL03B1 (Classification of Acute Lymphoblastic Leukemia) or any successor classification study. Eligible patients were aged between 1 year and 30 years at the time of diagnosis and had newly diagnosed high-risk B-precursor ALL with no prior cytotoxic chemotherapy except for steroids and intrathecal cytarabine. For patients younger than 10 years, WBC count had to be 50,000/μL or greater. Patients who were older than 10 years or had received prior steroids could have any WBC count. Key exclusion criteria included patients with Down syndrome, testicular leukemia, prior cytotoxic chemotherapy, pregnancy, and those who were breastfeeding.

In the DFCI 11-001 trial, eligible patients were aged 1 year to 21 years, with newly diagnosed ALL or LL and no prior therapy (except for short courses of corticosteroid, a single dose of intrathecal cytarabine at the time of a diagnostic lumbar puncture, and/or emergent radiation to the mediastinum or other life-threatening masses). Key exclusion criteria included patients who had received more than 7 days of corticosteroids in the preceding 4 weeks or more than 28 days of corticosteroids in the preceding 6 months; any chemotherapy or radiotherapy for a previous malignancy; any antineoplastic drug (except for intrathecal cytarabine); and any other investigational drugs.

Table 7: Final Risk Group Classification in DFCI 11-001 Study

ALL = acute lymphoblastic leukemia; CNS = central nervous system; CSF = cerebrospinal fluid; DFCI = Dana-Farber Cancer Institute; LL = lymphoblastic lymphoma; MRD = minimal residual disease; WBC = white blood cell.

Note: MRD was not to be used to change risk group of patients with T-ALL. Patients with LL were to be treated as standard risk, high risk, or very high risk based on age, immunophenotype, CNS status, and cytogenetics, as specified in Table 7. Presenting WBC count and end of induction MRD were not to be used in LL for risk-group classification. Patients with t(9;22) were removed from protocol therapy at day 15 and not assigned a final risk group.

Source: DFCI 11-001 Clinical Study Report.¹⁵

There were key similarities and differences in eligibility criteria between the COG AALL07P4 and DFCI 11-001 trials. Notably, the DFCI 11-001 trial was inclusive of most patients with any ALL or LL (except Burkitt lymphoma) while the COG AALL07P4 trial focused on patients with high-risk ALL (B-precursor ALL). While both trials included children and adolescents, a higher age limit was used in the COG AALL07P4 study (30 years) compared with the DFCI 11-001 study (21 years). Due to the potential teratogenic effects of the study drugs, people who were pregnant were excluded from the COG AALL07P4 and DFCI 11-001 trials. The trials differed in populations that were ineligible. Patients with Down syndrome and testicular leukemia were excluded from the COG AALL07P4 study. Patients with B-cell (Burkitt lymphoma) ALL, an HIV-positive status, or a history of previous malignancy were excluded from the DFCI 11-001 study. With respect to laboratory measures, the COG AALL07P4 study stipulated WBC count as a criterion, whereas the DFCI 11-001 study used direct bilirubin for eligibility. In both trials, patients who had had prior chemotherapy were not eligible but patients with intrathecal cytarabine were allowed before registration in both trials. In the COG AALL07P4 trial, patients who received prior steroid therapy (duration of therapy and time frame not specified) were eligible whereas in the DFCI 11-001 trial, patients with short courses of steroids (nonchronic steroid therapy) were eligible for enrolment.

Interventions

The treatment schemas for the COG AALL07P4 study and the DFCI 11-001 study are depicted in Figure 1 and Figure 2, respectively, and the full treatment protocols for the COG ALL074 study and the DFCI 11-001 study are depicted in Figure 10 and Figure 11, respectively, in Appendix 1.

There were key differences in treatment protocols between the COG AALL07P4 trial and the DFCI 11-001 trial in backbone therapies, phases, schedules, and duration and frequency of asparaginase (calaspargase pegol or pegaspargase). Notably, the COG AALL07P4 study group protocol was adapted from Berlin-Frankfurt-Münster group protocols and contained rotating phases lasting 1 month to 2 months from induction through delayed intensification. In contrast, the DFCI protocol employed a prolonged intensification phase of 20 weeks to 30 weeks (CNS therapy phase and consolidation phase II) aimed at continuous asparagine depletion within 3-week cycles of MAC. In the COG AALL07P4 trial, patients received a single dose of the study drug at induction (and at extended induction for slow early responders), followed by 2 doses of the study drug at each subsequent phase (consolidation, interim maintenance phase I, delayed intensification, and interim maintenance phase II [as applicable], delayed intensification phase II [as applicable], and maintenance), for a total of up to 12 doses of asparaginase. In the DFCI 11-001 trial, however, patients received a single dose of a study drug (calaspargase pegol or pegaspargase) during remission induction, and then calaspargase pegol every 3 weeks or pegaspargase every 2 weeks during intensification, for a total of 11 doses of calaspargase pegol or 16 doses of pegaspargase.

COG AALL07P4 Study

In the COG AALL07P4 study, the treatment periods included remission induction (5 weeks), extended induction (2 weeks; for patients with M1 or M2 morphology with MRD ≥ 0.1% at day 29), consolidation (8 weeks), interim maintenance (up to two 8-week periods), delayed intensification (up to two 8-week periods), and maintenance therapy (12-week cycles for a total of 2 years from the start of interim maintenance phase I for females and 3 years from the start of interim maintenance phase I for males). Patients in the study received the randomly assigned asparaginase product (i.e., calaspargase pegol or pegaspargase) on the same schedule. Prior to randomization, patients were permitted to receive intrathecal cytarabine. After randomization, remission induction was initiated with vincristine (day 1, day 8, day 15, and day 22), daunorubicin (day 1, day 8, day 15, and day 22), prednisone or dexamethasone (day 1 through day 14 for patients aged younger than 10 years, or day 1 through day 28 for patients aged 10 years and older), asparaginase (day 4), and methotrexate (day 8, day 15, day 22, and day 29; patients with CNS3 were dosed on day 15 and day 22). Following induction, extended induction was employed based on the results of the day 29 bone marrow evaluation. A further treatment course following extended induction was based on early response using a cut-off of MRD of 0.1% for treatment stratification. Patients with M1 bone marrow status (< 5% blasts by morphologic bone marrow analysis) on day 8 or day 15, and day 29, and MRD of less than 0.1% were considered rapid early responders, with all other patients considered slow early responders. Following induction, patients classified as rapid early responders received 1 interim maintenance course followed by 1 delayed intensification phase. Patients classified as slow early responders and/or CNS3-positive received the same therapy plus a second interim maintenance and delayed intensification phase before maintenance therapy.

Figure 1: Treatment Schema for the COG AALL07P4 Study

MRD = minimal residual disease; RER = rapid early responder; SER = slow early responder.

Source: COG AALL07P4 Clinical Study Report.¹³

Figure 2: Treatment Schema for the DFCI 11-001 Study

Source: DFCI 11-001 Clinical Study Report.¹⁵

Protocol Amendments in COG AALL07P4 Study

There were ||| protocol amendments (||||| ||||| |||||||| ||| ||||) in the COG AALL07P4 study. A key change (|||||||| ||||||||| ||) was for patients randomized to calaspargase pegol at 2,100 IU/m² dose who were redirected to receive pegaspargase 2,500 IU/m², as described in more detail as follows. All other amendments were minor and administrative in nature.

Patients in the COG AALL07P4 study were initially randomized to calaspargase pegol 2,500 IU/m² or pegaspargase 2,500 IU/m² as a 1-hour IV infusion on day 4 of induction, on day 4 of extended induction, on day 15 and day 43 of consolidation, on day 2 and day 22 of both interim maintenance periods, and on day 4 and day 43 of both delayed intensification periods. Patients enrolled before protocol amendment 2 (September 9, 2009) were randomized to 2,500 IU/m² of calaspargase pegol or pegaspargase. A planned analysis of preliminary PK data from an initial cohort of 18 patients suggested that the 2,500 IU/m² dose of calaspargase pegol was associated with prolonged exposure to asparaginase. Therefore, patients newly enrolled after amendment 2 were randomized in a 2:1 ratio to calaspargase pegol 2,100 IU/m² or pegaspargase 2,500 IU/m²; patients who were already randomized to calaspargase pegol 2,500 IU/m² continued on this dose for the remainder of the study. Regardless of the pegylated asparaginase formulation or dose, dosing schedules (i.e., intervals between doses) were the same in the calaspargase pegol and pegaspargase treatment groups. The number of total scheduled asparaginase doses in the first 7 months to 11 months of therapy was dependent on whether the patient was a rapid early responder receiving 7 doses, a slow early responder receiving 11 doses, or a slow early responder with extended induction receiving 12 doses.

After a planned interim analysis of rapid early responder and MRD data by the COG independent Data Safety Monitoring Committee in late 2010 || ||| |||||||| |||||||| ||| |||||||| || |||||||||||| ||||| ||||| |||||| || |||||||| || |||||||||||| ||||| ||||| |||||| ||| || |||||||| || |||||||||||| ||||| ||||||| it was determined that patients receiving 2,100 IU/m² calaspargase pegol had a lower rate of rapid early responders and higher rate of positive MRD at the end of induction compared to patients in the other groups. As such, this met predefined protocol criteria for halting enrolment on December 22, 2010, with 166 patients enrolled (69 patients on calaspargase pegol 2,100 IU/m², 42 patients on calaspargase pegol 2,500 IU/m², and 55 patients on pegaspargase 2,500 IU/m²). Subsequently, patients in the calaspargase pegol 2,100 IU/m² group were nonrandomly assigned to receive pegaspargase 2,500 IU/m² for the remaining duration of therapy. Of note, at the time of this interim analysis, all participants who had been randomized to receive calaspargase pegol 2,500 IU/m² had completed study drug treatment.

As the proposed Health Canada indication recommends a dose for calaspargase pegol of 2,500 IU/m², this clinical report presents data for patients who were randomized to receive calaspargase pegol 2,500 IU/m² and excludes data that refers to patients who were randomized to receive calaspargase pegol 2,100 IU/m² and were subsequently switched to pegaspargase 2,500 IU/m². Since data for the calaspargase pegol 2,100 IU/m² group are excluded, any analyses related to this dose — including sensitivity analyses for patients who were switched from calaspargase pegol 2,100 IU/m² to pegaspargase 2,500 IU/m² — is also excluded from this clinical report.

DFCI 11-001 Study

In the DFCI 11-001 study, treatment periods included a steroid prophase (3 days), remission induction (29 days), consolidation phase I (3 weeks for standard-risk or high-risk patients, 9 weeks for very high-risk patients), CNS therapy phase (3 weeks), consolidation phase II (27 weeks), and continuation phase (until 24 months from the date when CR was attained). Remission induction was initiated following a diagnostic lumbar puncture and intrathecal cytarabine (plus IV methylprednisolone therapy unless a patient had already received steroid pretreatment before beginning study treatment) and included a 4-week multiagent regimen of vincristine (day 4, day 11, day 18, and day 25), prednisone (day 4 to day 32), doxorubicin (day 4 and day 5), and methotrexate (day 6). On day 7 of remission induction, patients in the DFCI 11-001 study received a single dose of the assigned asparaginase treatment as a 1-hour infusion. Beginning at week 7 of treatment, patients in the calaspargase pegol group received 1 dose every 3 weeks for a total of 10 doses and patients in the pegaspargase group received 1 dose every other week for a total of 15 doses. In both groups, treatment started with CNS therapy for standard-risk and high-risk patients or consolidation IC for very high-risk patients.

Remission assessment was performed on day 32. For patients with ALL, CR was defined as less than 1% marrow malignant lymphoblasts with peripheral blood count recovery and the absence of extramedullary disease. For patients with LL, CR required a 70% or greater reduction in the size of the largest nodes and/or masses, normalization of physical examination, and no cerebrospinal fluid (CSF) or marrow disease. Patients with persistent morphologic leukemia (≥ 1% leukemic blasts in marrow) or less than 70% reduction in the size of the largest nodes and/or masses at the end of induction were classified as induction failure and removed from the study protocol. Patients who did not meet these criteria (e.g., had 5% or greater blasts among patients with leukemia, or lower than 70% reduction in size of largest nodes or masses among patients with LL) were considered to have induction failure, and were removed from the protocol. Patients with greater than 5% lymphoblasts identified morphologically in bone marrow aspirate or biopsy as leukemic by flow cytometry, cytogenetics, fluorescence in situ hybridization, immunohistochemistry, or other tests, or who developed biopsy-proven extramedullary site of disease (e.g., CSF, testicle, lymph node) were considered to have met the criteria for relapse. For all others, treatment continued through the consolidation and continuation phases, with a total planned duration of treatment of 24 months from the CR date. In total, patients in the pegaspargase 2,500 IU/m² group received a total of 16 doses, while patients who were part of the calaspargase pegol 2,500 IU/m² group received a total of 11 doses.

Protocol Amendments in DFCI 11-001 Study

There were ||| protocol amendments (final dated February 24, 2016) in the DFCI 11-001 study. Key changes to the planned analyses (||||||||| ||||||| |||| ||| ||||) were the inclusion of an ITT analysis set for efficacy data, summarizing demographic and baseline characteristics using the FAS population, specifying the definition for TEAEs, revising the definitions of EFS and OS, adding and defining DFS, and clarifying subgroup analyses.

Prior Therapy

In the COG AALL07P4 study, patients were not to receive prior cytotoxic chemotherapy with the exception of steroids and intrathecal cytarabine. Patients who were receiving prior steroid therapy were monitored for the dose and duration (refer to the Prior Therapy for Determining Patient Eligibility and Risk Stratification section in Appendix 1).

In the DFCI 11-001 study, prior therapies of corticosteroids, intrathecal cytarabine, and emergent radiation were permitted. Short courses of corticosteroids (defined as up to 7 days of corticosteroids in the 4 weeks before study registration) were permitted before registration; patients with corticosteroid use of more than 7 days within the same time frame or more than 28 days over the preceding 6 months were not eligible for the study. Patients who received pretreatment with corticosteroids were not to receive steroid prophase. A single dose of intrathecal cytarabine at the time of a diagnostic lumbar puncture was allowed before registration; if this was done, a patient was not to receive day 1 intrathecal cytarabine thereafter.

Concomitant Therapy

In the COG AALL07P4 trial, calaspargase pegol and pegaspargase were considered study drugs, and the other chemotherapy drugs administered as part of the study protocol were considered concomitant therapy. These medications included cytarabine, vincristine, daunorubicin, methotrexate, steroids (prednisone and dexamethasone), cyclophosphamide, mercaptopurine, thioguanine, and doxorubicin. Administration of the protocol-specified chemotherapy was documented in the patient’s medical records and recorded in the case report form. No other concomitant medications were recorded in the case report form. Drugs with known potential interactions with antileukemic drugs were avoided. Anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine) were to be avoided due to induction of drug-metabolizing enzymes and being associated with decreased EFS. The use of azole antifungals may have required dose reductions of vincristine, anthracyclines, etoposide, and steroids due to induction of drug-metabolizing enzymes. Macrolide antibiotics were to be avoided due to the induction of drug-metabolizing enzymes. Rifampin was not to be used.

In the DFCI 11-001 trial, supportive care at diagnosis and during treatment (e.g., blood transfusions, growth factors, the use of corticosteroids other than as antileukemic drugs, folinic acid as methotrexate rescue, management of febrile neutropenia) was permitted. Antibiotic prophylaxis was permitted during the steroid prophase and remission induction for the management of fever.

Removal of Patients From Therapy or Assessment

In the COG AALL07P4 study, patients who discontinued protocol therapy were to be followed until they met the criteria for being off study (i.e., death, lost to follow-up, enrolment in another COG study with tumour therapeutic intent, withdrawal of consent, or the 10th anniversary of study entry). Patients were removed from protocol therapy if any of the following criteria were met: M3 bone marrow status on day 29, the identification of very high-risk ALL features, patients requiring extended induction (i.e., patients with M2 or M3 bone marrow status or who had MRD of 1% or greater following extended induction), recurrent leukemia following CR, the refusal of further protocol therapy by the patient (or parent or guardian), the completion of planned therapy, physician determination in a patient’s best interest, the development of a second malignancy, patient off-treatment for an unrelated disease, disease progression before active treatment, alternative therapy, the patient becoming pregnant, or the patient not being evaluable for postinduction therapy. Patients who withdrew consent for any further data submission, enrolled in another COG study with tumour therapeutic intent, were lost to follow-up, or died were removed from the study.

In the DFCI 11-001 study, patients who were removed from protocol therapy but continued to be followed up included patients who had failed to attain remission at the end of the remission induction phase, patients with Ph-positive (BCR/ABL) ALL, patients with disease recurrence, patients with the development of a second malignancy, patients who withdrew from the study, and patients with general or specific changes in their condition or compliance with protocol therapy, rendering the patient unacceptable for further treatment according to the opinion of the treating investigator. Patients who withdrew consent, were lost to follow-up, or died were removed from the study.

Outcomes

Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical experts consulted by CADTH and stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected the end points considered to be most relevant to inform CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points in Table 8 were assessed using the GRADE tool. Select notable harms outcomes considered important for informing CADTH’s expert committee deliberations were also assessed using GRADE.

Overall Survival

In the COG AALL07P4 trial, OS was defined as the time from randomization to death. OS by responder status (rapid early responders, slow early responders, extended induction at day 43) were conducted for the FAS population.

In the DFCI 11-001 trial, OS was defined as the time from randomization to death.

DFS From CR

In the COG AALL07P4 study, DFS was defined as the time from the attainment of CR to the documented relapse, diagnosis of a second malignant neoplasm, or death for patients who attain CR.

In the DFCI 11-001 study, DFS was defined as the time from the attainment of CR to the documented relapse, diagnosis of a second malignant neoplasm, or death for patients who attain CR.

Event-Free Survival

In the COG AALL07P4 trial, EFS was defined as the time from randomization to date of the documented relapse, induction failure (induction day 29 or day 43), the diagnosis of a second malignant neoplasm, or death from any cause, whichever came first. EFS was assessed during augmented postinduction intensification therapy among patients with high-risk ALL.

In the DFCI 11-001 trial, EFS was defined as the time from randomization to the date of the documented relapse, including induction failure, diagnosis of a second malignant neoplasm, or death from any cause, whichever comes first.

Complete Remission

Patients aged 1 year to 18 years with ALL can expect CR rates in about 98% of cases at 5 years postdiagnosis. For patients with standard-risk average disease, the 6-year continuous CR for standard 4-week consolidation versus 8-week intensified augmented Berlin-Frankfurt-Münster consolidation was 87.8% (standard deviation [SD] = 1.3%) versus 89.1% (SD = 1.2%) (P = 0.52).⁴⁵ The clinical experts consulted by CADTH indicated that a clinically meaningful difference in CR would be a 5% difference between groups without overlapping CIs, with patients matched between groups, and where all confounders and molecular subtypes have been accounted for.

In the COG AALL07P4 trial, CR was defined as attaining M1 bone marrow (< 5% lymphoblasts) on day 29 of induction.

In the DFCI 11-001 trial, among patients with leukemia, CR was defined as an interpretable bone marrow with fewer than 1% lymphoblasts and peripheral blood without lymphoblasts, and an absolute phagocyte count of at least 1,000/mm³ and no evidence of extramedullary leukemia (no blasts in spinal fluid, at least a 70% reduction in the size of masses noted on imaging at diagnosis as defined for patients with LL) on day 32. Among patients with LL, CR was defined as having at least a 70% reduction in the size of the largest nodes or masses at diagnosis on day 32, where reduction could be measured as a decrease in a sum of the products of the 2 greatest diameters of the largest dominant nodes or nodal masses.

Minimal Residual Disease

MRD is considered to be 1 of the most significant prognostic factors in ALL, independent of patient age, B-cell or T-cell origin, or genetic subtype.⁴⁶ An MRD level of 0.1% has been accepted by the FDA to identify patients with ALL with a high risk of relapse.⁴⁶

MRD assessed by the COG AALL07P4 trial using flow cytometry at the end of 4 weeks of induction therapy among patients with newly diagnosed ALL has been considered to be strongly associated with outcome in children and AYAs with B-precursor ALL.^47,48 In the COG AALL07P4 trial, MRD was measured in bone marrow biopsy or aspirate at day 29 of induction using a 6-colour multiparameter flow cytometry method. The COG AALL07P4 trial assigned patients with high levels of MRD to receive more intensive treatment. Flow cytometric detection of leukemia-associated immunophenotypes and PCR amplification of antigen-receptor genes appear to be the most reliable methods for detecting MRD in patients with ALL.⁴⁹ MRD-positive was defined as 0.1% or greater and MRD-negative as less than 0.1% detectable leukemia cells.

In the DFCI 11-001 trial, MRD was measured using a PCR technique targeting lymphoblast-specific immunoglobulin gene rearrangements.

In the DFCI 11-001 trial, patients with high end-of-induction MRD (≥ 0.001) were assigned to the very high-risk final risk group (refer to Figure 7). MRD at the end of induction status was 1 of the efficacy outcomes in the DFCI 11-001 trial, measured as high end-of-induction MRD (defined as ≥ 0.001 by PCR assay) and low end-of-induction MRD (< 0.001). The end of induction MRD of 0.01 or greater was also reported for both groups.

Serum Asparaginase Activity

The clinical effectiveness of asparaginase is considered to be based upon the adequate depletion of asparagine.³⁴ The cornerstone of PK assessment in the clinical pharmacology program of calaspargase pegol is the measurement of plasma asparagine.⁵⁰ The FDA’s multidisciplinary review report of calaspargase pegol in combination with chemotherapy for ALL reported that asparaginase depletion is considered a valid surrogate end point for clinical efficacy of asparaginase treatment.⁵¹ However, it is not feasible to accurately measure plasma asparagine outside the context of a clinical trial due to rapid ex vivo breakdown.⁹ SAA is more easily measured using surrogate assays and is well correlated with asparagine depletion and clinical effectiveness.³⁴ The current consensus guidelines have advocated for a threshold of 0.1 IU/mL. This cut-off of 0.1 IU/mL or greater measured either after a single dose or at steady state has been used in many research and treatment protocols to determine therapeutic asparaginase activity and levels above this cut-off have been shown to result in complete asparagine depletion.^34,51 The FDA has approved previous asparaginase products in combination with chemotherapy, including calaspargase pegol for ALL, on the basis of accepting evidence of asparaginase activity as a surrogate for clinical efficacy in these asparaginase treatments.^50,51

In the DFCI 11-001 study, SAA was measured predose and after a single dose of calaspargase pegol during remission induction at 5 minutes to 10 minutes, and then once on day 7, day 11, day 18, day 25, and day 32. The proportion of patients with an SAA level of 0.10 IU/mL or greater (and the proportion of patients with an SAA level of 0.40 IU/mL or greater) was assessed for each treatment group.

Harms

In the COG AALL07P4 study, safety information included AEs and was recorded throughout the course of the study. AEs were any event that resulted in persistent or significant disabilities or incapacities, congenital anomalies, medically important events or experiences, or birth defects following protocol treatment. SAEs were not specifically defined in the study protocol; rather, categories of events relevant to the safety profile assessment were considered serious: all grade 3 and higher hyperbilirubinemia, systemic infections and pneumonias, osteonecrosis, all grade 2 and higher pancreatitis or convulsions, and all anaphylactic reactions. The grading of AEs was categorized according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, and per amendment 5, switched to version 4.0 to retrospectively apply to all previously reported AE data, including the following adjudicated as serious: CTCAE grade 4 life-threatening consequences, CTCAE grade 3 medical intervention or hospitalization indicated, CTCAE grade 3 with laboratory findings and bleeding, CTCAE grade 3 limiting self-care, and transfusion, radiologic, endoscopic, or elective operative intervention indicated. AEs were coded into system organ classes and preferred terms using Medical Dictionary for Regulatory Activities, version 19.0.

In the DFCI 11-001 study, toxicities included AEs, SAEs, and AESIs reported by patients, discovered during questioning, directly observed, or detected by physical examination, laboratory test, or other means. AEs were any undesirable sign, symptom, or medical condition or experience that developed or worsened in severity after a patient started the first dose of study treatment or any procedure specified in the protocol (including abnormal laboratory values or diagnostic test results if they induced clinical signs or symptoms requiring treatment or further diagnostic tests), even if the event was not considered related to the study. SAEs were any AE, regardless of causality, that resulted in death, was life-threatening, required intensive inpatient medical interventions, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was considered to be an important medical event based on medical judgment that could jeopardize the patient and require medical or surgical intervention. The descriptions and grading of AEs were categorized according to CTCAE version 4.0.

Table 8: Outcomes Summarized From the Studies Included in the Systematic Review

AE = adverse event; CR = complete remission; COG = Children’s Oncology Group; CSF = cerebrospinal fluid; DFCI = Dana-Farber Cancer Institute; DFS = disease-free survival; EFS = event-free survival; HRQoL = health-related quality of life; MRD = minimal residual disease; OS = overall survival; SAA = serum asparaginase activity; TEAE = treatment-emergent adverse event.

Statistical testing for all end points were not adjusted for multiple comparisons (e.g., hierarchical testing).

^aOutcome identified of importance according to patient group input.

Sources: COG AALL07P4 Clinical Study Report^13,15 and DFCI 11-001 Clinical Study Report.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

Considerations that informed the selection of efficacy outcomes to be summarized and assessed using GRADE included the following.

• Survival outcomes were identified by the clinician group input and specified by the clinical experts consulted by CADTH to include OS, DFS from CR, and EFS. EFS and OS were also key inputs in the sponsor’s pharmacoeconomic model.

• CR at the end of induction was identified as important by the clinical experts consulted by CADTH and by clinician group input (as response to treatment).

• MRD at the end of induction was identified as important by the clinical experts consulted by CADTH and by clinician group input (as a measurement of progressive disease). Specifically, the clinical experts consulted by CADTH highlighted MRD levels of 0.1% or greater as well as 0.01 or greater as most clinically relevant; these were included in GRADE assessments. Results for high end-of-induction MRD (≥ 0.001) and low end-of-induction MRD (< 0.001) are included in Appendix 1 in Table 18.

• SAA levels were measured during induction in the DFCI 11-001 trial to assess calaspargase pegol’s ability to maintain an SAA level of 0.1 UI/mL or greater 3 weeks to 4 weeks after a single dose and to assess its half-life duration compared to pegaspargase.⁴⁴ According to the clinical experts consulted by CADTH, calaspargase pegol was developed with greater biological stability than pegaspargase and SAA levels during induction compared to pegaspargase could provide an indication of calaspargase pegol’s ability to maintain asparagine suppression in plasma, its half-life duration, and its ability to be administered with less dosing frequency than pegaspargase (i.e., a schedule of every 3 weeks versus every 2 weeks). Therefore, SAA levels during induction were identified as a relevant outcome by the clinical experts consulted by CADTH. However, the clinical experts consulted by CADTH noted that SAA assessment during induction as performed in the DFCI 11-001 trial is not routinely performed in clinical practice, where SAA assessments are done according to a different schedule for the purpose of identifying and managing asparaginase hypersensitivity and silent inactivation.³⁴

• The assessments of SAA every 3 weeks for 30 consecutive weeks during postinduction therapy in the DFCI 11-001 trial was done to further determine how best to dose calaspargase pegol during postinduction therapy.⁴⁴ SAA assessments during postinduction in the DFCI 11-001 trial were not reported to be 1 of the most important outcomes to routinely guide treatment selection in clinical practice and was not included in GRADE assessments. The SAA assessment during postinduction served to assess the appropriate dosage of calaspargase pegol but may have provided less relevant information about the comparative efficacy between drugs in clinical practice. In the COG AALL07P4 trial, plasma asparaginase activity (PAA) levels after an induction dose (measured on day 4, day 15, day 22, day 29, and day 43 of induction; this included the proportion of patients with a PAA level of 0.10 IU/mL or greater [and the proportion of patients with a PAA level of 0.40 IU/mL or greater] for each study group) were measured rather than SAA levels. Since PAA levels were specified by consensus guidelines to be difficult to reliably ascertain, and reported by clinical experts consulted by CADTH to be unfeasible to measure in clinical practice and not used to make treatment selection in clinical practice, data for this outcome were not included in the GRADE assessment.³⁴ Results for PAA after induction dose are displayed in ||||| || in Appendix 1.

• HRQoL due to treatment and HRQoL due to drug shortage were identified as important by patient input. No data on HRQoL were collected in either the COG AALL07P4 trial or the DFCI 11-001 trial.

• Harms of treatment were identified as important by patient input (as side effects of treatment), clinician group input (as significant treatment intolerance), and the clinical experts consulted by CADTH (including hypersensitivity reactions, anaphylactic reactions, silent inactivation, and WDAEs). Hypersensitivity reactions, anaphylactic reactions, silent inactivation, and WDAEs were highlighted by the clinical experts consulted by CADTH as specifically relevant AEs for the management of patients in clinical practice.

Statistical Analysis

Sample Size and Power Calculation

COG AALL07P4 Study

The aims of the COG AALL07P4 study were to assess the PK (including maximum asparaginase activity exposure [C_max]_, area under the curve from time 0 to 25 days[AUC_0–25d], and area under the curve from time 0 to infinity [AUC_0–inf]) and PD properties (asparagine depletion from plasma and CSF) of calaspargase pegol and pegaspargase during induction and consolidation.¹³ C_max and AUC_0–25d were assessed by the ratio of geometric means and corresponding 2-sided 90% CIs. If a 2-sided 90% CI was totally contained within the conventional bioequivalence limits ranging from 0.8 to 1.25, PK comparability in treatment exposure between calaspargase pegol and pegaspargase could be claimed. The 2-step approach as outlined in the protocol was not required as a lower limit greater than 80% of a 2-sided 90% CI for the ratio was equal to rejecting the null hypothesis of an exposure of 80% or lower compared to pegaspargase 2,500 IU/m² at the 5% level of statistical significance (Schuirman [1987]⁵²). The original study design was based on a planned preliminary PK evaluation of 18 patients (11 patients in the calaspargase pegol 2,500 IU/m² group and 7 patients in the pegaspargase group) as well as MRD and other safety end points of pegaspargase 2,500 IU/m² with a contemporary benchmark of calaspargase pegol 2,500 IU/m². A sample size of 90 patients was based on the precision analysis of the estimation of the true induction day 29 MRD rate for patients receiving the calaspargase pegol regimen. Based on a blinded review of MRD data from previous studies (the COG P9900 study and the COG AALL0232 study), baseline MRD negativity (defined as < 0.01% detectable disease in bone marrow on day 29 of induction) was estimated to be 70%. Assuming similar treatment effect between the calaspargase pegol 2,500 IU/m² regimen and pegaspargase 2,500 IU/m² regimen, 60 evaluable patients in the calaspargase pegol group would result in approximately 12% of patients attaining a negative MRD with 95% CI.¹³ The COG AALL07P4 study was not adequately powered to evaluate clinical efficacy end points (i.e., day 29 end-of-induction MRD status, CR, EFS, DFS from the attainment of CR, and OS).⁵¹

In total, 123 patients were randomized in a 2:1 ratio between calaspargase pegol 2,500 IU/m² and pegaspargase 2,500 IU/m². Eighteen (15%) patients were expected to be removed from therapy during induction for reasons such as having very high-risk features or being unevaluable for postinduction therapy. Therefore, a total of 105 patients was available to meet study end points, with 90% of patients evaluable for MRD, and 75% to 80% of patients considered rapid early responders, and 2% of patients requiring extended induction therapy. Thus, it was expected that, with 105 patients, there would be at least 90 patients evaluable for MRD who had not received extended induction therapy.

DFCI 11-001 Study

Sample size calculations in the DFCI 11-001 trial were based on NSAA levels for having 112 evaluable patients in each group from 240 enrolled patients. Assuming 99% of patients in the pegaspargase group had at least 1 NSAA level of 0.10 IU/mL or greater (considered therapeutic) during the postinduction asparaginase consolidation, it was expected to detect a 10% reduction in the proportion of patients who had at least 1 NSAA level of 0.10 IU/mL or greater with 89% power during the postinduction asparaginase consolidation, using a 1-sided Fisher exact test at the 0.025 significance level. The rationale for a 10% reduction in the proportion of patients with 1 NSAA level of 0.10 IU/mL or greater was not reported. A total of 224 evaluable patients (112 in each group) would provide 96% power to detect a mean difference of 0.15 IU/mL in the asparaginase activity level at the week-7 time point (estimated to be steady state) based on data from DFCI protocol 05 to 001 (Place et al. [2015]⁵³), using a 2-sided t test and assuming an SD of 0.30. The rationale for a mean difference of 0.15 IU/mL in asparaginase activity level was not reported.

Statistical Testing

COG AALL07P4 Study

The COG AALL07P4 trial was not designed to assess efficacy (i.e., MRD at end of induction day 29, CR at end of induction day 29, EFS, DFS from the attainment of CR, and OS) of calaspargase pegol in terms of superiority or noninferiority to pegaspargase. In the COG AALL07P4 study, the number of patients with negative MRD (< 0.1% detectable disease) with 95% CI were reported for each treatment group. Adjusted analyses were conducted using logistic regression for covariates of age, baseline WBC count, baseline body mass index (BMI), and asparaginase activity (by time point). The number of patients with CR with 95% CI were reported for each treatment group after patients completed induction therapy. Patients were to be followed for a minimum of 3 years for survival estimates (EFS, DFS, and OS). The product-limited Kaplan-Meier method was used to estimate survival probabilities by treatment with curves presented for calaspargase pegol and pegaspargase groups, and HRs were estimated using the Cox model with 95% CIs. Adjusted analyses of survival estimates were conducted using the Cox model for covariates of age, sex, baseline WBC count, and baseline BMI. For OS, the duration of follow-up since randomization to last contact or death was tabulated for each treatment group. The number and proportion of patients experiencing TEAEs were summarized by treatment group.

No adjustment for multiple testing or control of type I error was conducted for any end point, and there was no imputation for missing data.

The Clinical Study Report with a data cut-off date of December 31, 2015, was the most recent one available for the COG AALL07P4 trial and was the data source used for all efficacy and safety end points in this clinical report.

DFCI 11-001 Study

No prespecified criteria were defined to determine comparative efficacy between trial groups. The trial was not designed to assess the efficacy of calaspargase pegol in terms of superiority or noninferiority to pegaspargase. In the DFCI 11-001 study, the number and proportion of patients with high end-of-induction MRD (≥ 0.001 by PCR assay) and low end-of-induction MRD (< 0.001) with 2-sided 95% exact binomial CIs were reported for each treatment group. The number and proportion of patients with MRD (≥ 0.01 by PCR assay) were also reported for each treatment group. The number and proportion of patients attaining CR were summarized by treatment. Patients were to be followed for 5-year survival estimates of EFS, DFS, and OS. The Kaplan-Meier method was used to estimate the survival probabilities by treatment. One-year estimates were provided with 95% CIs estimated using the Greenwood formula. Additional time point estimates were to be considered when data are more mature. The number and proportion of patients with an SAA level of 0.10 IU/mL or greater were summarized by treatment and visit with 2-sided Clopper-Pearson CIs. Linear mixed effects and generalized estimating equation models were used to compare SAA levels longitudinally between treatment groups, and estimates were reported using geometric means and ORs. Models were fitted with and without covariates (included individually as fixed effects) for age, sex, initial risk classification, disease type (ALL or LL), and baseline WBC count. The number and proportion of patients experiencing TEAEs were reported, including AESIs with 80% CIs.

No adjustment for multiple testing was conducted for any end point, and there was no imputation for missing data.

The Clinical Study Report for the DFCI 11-001 study with a data cut-off date of October 5, 2016, for PK, PD, and efficacy analyses was the primary data source. A Day 120 Report provided additional data with a data cut-off date of June 12, 2017, for survival data and of February 1, 2017, for safety data. The Vrooman et al. (2021)⁴² publication reported a median 5-year follow-up for EFS and OS but did not report a cut-off date for these data. The Clinical Study Report (data cut-off date of October 5, 2016) was the data source for all efficacy (MRD, CR, 1-year EFS rate, 1-year DFS, 1-year OS, and SAA levels) and safety end points in this clinical report. Data from the Day 120 Report provided updated survival data (2-year rates for EFS, DFS, and OS with a CCOD of June 12, 2017) and safety data (CCOD of February 1, 2017).

Subgroup Analyses

COG AALL07P4 Study

In the COG AALL07P4 study, subgroup analyses were prespecified for MRD, CR, EFS, OS, DFS, and TEAEs. Subgroup analyses of interest for this clinical report focused on primary end points; therefore, subgroup analyses for these secondary end points were not included.

DFCI 11-001 Study

In the DFCI 11-001 study, subgroup analyses were prespecified for MRD, CR, EFS, OS, DFS, and TEAEs. Subgroup analyses of interest for this clinical report focused on primary end points of SAA levels and TEAEs. Subgroup analyses compared SAA levels longitudinally between treatment groups for age (< 10 years, ≥ 10 years), sex, initial risk-group classification (standard risk, high risk), disease type (ALL, precursor B-cell ALL), and baseline WBC count (< 50,000 × 10⁹/L, ≥ 50,000 × 10⁹/L). Subgroup analysis of TEAEs was conducted for initial risk classification. No tests of interaction were conducted for subgroup analyses.

Sensitivity Analyses

COG AALL07P4 Study

In the COG AALL07P4 study, a sensitivity analysis for MRD was conducted for patients with low end-of-induction MRD versus high end-of-induction MRD among the ITT and per-protocol (PP) populations. For EFS, OS, and DFS, sensitivity analyses were conducted for induction failure as an event at time 0, including data after Erwinia substitution, and including data after other new anticancer therapies.

DFCI 11-001 Study

In the DFCI 11-001 study, a sensitivity analysis for MRD was conducted for patients with high end-of-induction MRD (≥ 0.001 by PCR assay) among the PP population. For EFS and DFS, sensitivity analyses were conducted for the PP population, initial diagnosis (ALL, precursor B-cell ALL), induction failure as an event at time 0, including data after Erwinia substitution, and including data after other new anticancer therapies.

Table 9: Statistical Analysis of Efficacy End Points

CI = confidence interval; COG = Children’s Oncology Group; CR = complete remission; DFCI = Dana-Farber Cancer Institute; DFS = disease-free survival; EFS = event-free survival; GEE = generalized estimating equation; HR = hazard ratio; ITT = intention-to-treat; KM = Kaplan-Meier; MRD = minimal residual disease; OS = overall survival; Ph-positive = Philadelphia chromosome positive; PP = per protocol; RER = rapid early responder; SAA = serum asparaginase activity; SER = slow early responder; TEAE = treatment-emergent adverse event; vs. = versus; WBC = white blood cell.

Sources: COG AALL07P4 Clinical Study Report^13,15 and DFCI 11-001 Clinical Study Report.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

Analysis Populations

Analysis sets for each study included in the systematic review are summarized in Table 10.

Table 10: Analysis Populations of COG AALL07P4 Study and DFCI 11-001 Study

ALL = acute lymphoblastic leukemia; COG = Children’s Oncology Group; CR = complete remission; DFCI = Dana-Farber Cancer Institute; DFS = disease-free survival; EFS = event-free survival; FAS = full analysis set; ITT = intention-to-treat; MRD = minimal residual disease; NSAA = nadir serum asparaginase activity; OS = overall survival; PK = pharmacokinetic; PKAS = pharmacokinetic analysis set; PPAS = per-protocol analysis set; SAS = safety analysis set.

^aPatients were considered to have valid PK assessments, and evaluable for PKAS, if their NSAA levels were below the limit of quantification set to half of the lower limit of quantification (0.025 IU/mL) for statistical analyses.

Sources: COG AALL07P4 Clinical Study Report^13,15 and DFCI 11-001 Clinical Study Report.¹⁴Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

Results

Patient Disposition

Patient disposition in the COG AALL07P4 trial (CCOD of December 31, 2015) and the DFCI 11-001 trial (CCOD of October 5, 2016) is summarized in Table 11.

In the COG AALL07P4 trial, || || || ||||||| patients in the calaspargase pegol ||| || || || ||||||| patients in the pegaspargase group discontinued the study drug, all due to an AE. Similar proportions of patients between treatment groups discontinued protocol therapy (i.e., randomized treatment). Twenty-nine (70.7%) patients in the calaspargase pegol group and 37 (68.5%) patients in the pegaspargase group were continuing on study protocol at the time of data cut-off.

In the DFCI 11-001 trial, 49 of 118 (41.5%) patients in the calaspargase pegol group and 36 of 199 (30.3%) patients in the pegaspargase group discontinued the study drug; of these, 17.8% and 13.4% of patients discontinued due to an AE in the calaspargase pegol group and the pegaspargase group, respectively. A total of 69 (58.5%) patients in the calaspargase pegol group and 83 (69.7%) patients in the pegaspargase group completed study drug treatment.

A higher proportion of patients discontinued the study drug in the COG AALL07P4 study than in the DFCI 11-001 study. More patients in the COG AALL07P4 study (44.2%) compared with the DFCI 11-001 study (12.2%) discontinued protocol therapy. |||||| |||||||||| of patients in the DFCI 11-001 study completed protocol therapy compared with approximately 56% of patients in the COG AALL07P4 study. Finally, a comparatively higher proportion of patients discontinued the study in the COG AALL07P4 trial (24.2%) compared with the DFCI 11-001 trial (|||||| ).

In the DFCI 11-001 study, some patients’ risk classification shifted from initial risk at time of diagnosis to final risk at the end of induction using the final risk classification tool (refer to Table 7 in this report). Among || || ||| ||||||| patients in the calaspargase group who were designated as standard risk at the time of diagnosis, the number of patients who shifted to high risk, very high risk, Ph-positive, and unknown status were || | ||||||| | ||||||| and | ||||||, respectively. Among || ||||||| patients in the calaspargase pegol group who were designated as high risk at the time of diagnosis, the number of patients who shifted to very high risk, Ph-positive, and unknown status were | ||||||| | ||||||| and | ||||||| Among || || ||| ||||||| patients in the pegaspargase group who were designated as standard risk at the time of diagnosis, the number of patients who shifted to high risk, very high risk, Ph-positive, and unknown status were | ||||||| ||||||| | ||||||| and | ||||||| respectively. Among || ||||||| patients in the pegaspargase group who were designated as high risk at the time of diagnosis, the number of patients who shifted to very high risk, Ph-positive, and unknown status were | |||||||| | ||||||| and |||, respectively.

Table 11: Summary of Patient Disposition From the Studies Included in the Systematic Review — FAS

AE = adverse event; ALL = acute lymphoblastic leukemia; COG = Children’s Oncology Group; DFCI = Dana-Farber Cancer Institute; FAS = full analysis set; ITT = intention-to-treat; NA = not applicable; NR = not reported; Ph-positive = Philadelphia chromosome–positive; PI = postinduction; PKAS = pharmacokinetic analysis set; PP = per protocol; VHR = very high risk.

Note: The data cut-off date was December 31, 2015, in the COG AALL07P4 study (Clinical Study Report) and June 12, 2017, in the DFCI 11-001 study (Day 120 Report).

^aThree patients were randomized to receive pegaspargase 2,500 IU/m² but were inadvertently administered calaspargase pegol 2,500 IU/m².

^bIn the event of a severe systemic or recurrent local allergic reaction to the study drug, Erwinia asparaginase was to be substituted.

Sources: COG AALL07P4 Clinical Study Report¹² and DFCI 11-001 Day 120 Report.^13,54 Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

Baseline Characteristics

Baseline characteristics for the COG AALL07P4 and DFCI 11-001 trials are summarized in Table 12. The baseline characteristics outlined in Table 12 are limited to those that were most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

In the COG AALL07P4 study, patients were all newly diagnosed with high-risk B-precursor ALL. The groups were generally similar in baseline characteristics. Most patients were older than 10 years (108 of 163 patients; 66.3%), male (50.9%), and white (82.2%). More patients in the calaspargase pegol group were younger than 10 years at diagnosis (43.9%) compared with the pegaspargase group (33.3%). A lower proportion of patients was older than 10 years presenting with WBC counts below 50,000/μL at baseline in the calaspargase pegol group (43.9%) compared with the pegaspargase group (55.6%). Patients had a higher median baseline WBC count in the calaspargase pegol group (59 × 10⁹/L) compared with the pegaspargase group (27 × 10⁹/L). Steroid use before protocol therapy was similar between groups, with only 5.5% of patients having received steroids in the week preceding their diagnosis. Concomitant antileukemia medications administered per protocol were similarly dosed across the groups and data for other concomitant medications were not collected.

In the DFCI 11-001 study, patients’ baseline characteristics were balanced overall between the calaspargase pegol group and the pegaspargase group. Most patients were younger than 10 years (178 of 237 patients; 75%), male (61.6%), and white (70.5%). Most patients (84.0%) did not have steroid use before protocol treatment, with similar between-group proportions.

Table 12: Summary of Baseline Characteristics From the Studies Included in the Systematic Review — FAS

ALL = acute lymphoblastic leukemia; BMI = body mass index; CNS = central nervous system; COG = Children’s Oncology Group; DFCI = Dana-Farber Cancer Institute; FAS = full analysis set; FISH = fluorescence in situ hybridization; HR = high risk; LL = lymphoblastic lymphoma; NA = not applicable; NR = not reported; SD = standard deviation; SR = standard risk; WBC = white blood cell.

^aPatients were categorized as standard risk if they were younger than 10 years, presenting with a WBC count of less than 50,000/mm³, with B-cell phenotype, and without CNS leukemia (defined as no blast cells in spinal fluid or below 5 WBCs in spinal fluid with blasts present) at diagnosis. All other patients were categorized as high risk.

Sources: COG AALL07P4 Clinical Study Report^13,15 and DFCI 11-001 Clinical Study Report.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

Across both the COG AALL07P4 and DFCI 11-001 trials, there were notable similarities and differences in baseline demographics. All patients in the COG AALL07P4 trial and nearly all patients in the DFCI 11-001 trial (96%) had ALL. The majority of patients in the DFCI 11-001 study had B-cell ALL (87%) and 13% of patients had T-cell ALL, whereas patients with B-cell immunophenotype were exclusively enrolled in the COG AALL07P4 trial. Most patients had a CNS status of 1 in both trials, with a minority of patients designated as CNS3 in the COG AALL07P4 study (fewer than 10%) and the DFCI 11-001 study (fewer than 2%). Most patients did not have steroid therapy before study treatment in the COG AALL07P4 study (|||) or the DFCI 11-001 study (|||). While the majority of patients were older than 10 years in the COG AALL07P4 trial (median = 11 years), most were younger than 10 years in the DFCI 11-001 trial (median = 4 years to 5 years). Approximately 62% of patients were diagnosed when they were 10 years or older in the COG AALL07P4 trial, whereas nearly 75% of patients were diagnosed at younger than 10 years in the DFCI 11-001 trial. Patients in the COG AALL07P4 trial were distributed equally across combined age and WBC categories, whereas more than 70% of patients in the DFCI 11-001 trial were younger than 10 years, with a WBC count below 50 × 10⁹/L.

Exposure to Study Treatments

Patient exposure to study treatments in the COG AALL07P4 trial and the DFCI 11-001 trial is presented in Table 13.

In the COG AALL07P4 study, median (range) exposure time to the study drug was similar across treatment groups, with an exposure time of 6.9 months (range = 0.0 months to 12.7 months) in the calaspargase pegol group and 6.5 months (range = 0.0 months to 11.8 months) in the pegaspargase group. ||| |||||||||| || |||||||| ||| |||||||| || ||||| ||| || ||||| ||||||| ||||| |||| ||||| ||| || || || ||||||| || ||| |||||||||||| ||||| ||| || || || ||||||| || ||| |||||||||||| ||||| ||||||||| ||||||

In the DFCI 11-001 study, the last planned dose of calaspargase pegol was 1 week later than the last planned dose of pegaspargase due to the 3 times weekly versus twice weekly dosing of the 2 respective study drugs. The median (range) duration of exposure to study drug was 7.79 months (range = 0.0 months to 10.2 months) for calaspargase pegol and 8.05 months (range = 0.0 months to 11.4 months) for pegaspargase. ||| |||||| ||||||| |||||||||| |||| ||| |||||||||||| ||||| ||| |||||||| ||||| |||||| || ||||||| ||||| ||| ||||| |||| |||| ||| |||||||||||| || |||||||| ||||| |||||| || ||||||| ||| || ||||||||||| || |||||| ||||||||| ||| ||||| || |||||||||||| ||||| |||||| || ||||| || |||||||||||| |||| ||| |||| || ||||||||| ||||||| |||| |||||||||||||| ||||||

Concomitant Medications and Cointerventions

In the COG AALL07P4 and DFCI 11-001 trials, calaspargase pegol and pegaspargase were the study drugs, and the other chemotherapy drugs administered as part of the study protocol were considered concomitant therapy. In both studies, other concomitant medications were not required to be collected and are therefore not summarized.

Subsequent Treatment

In the COG AALL07P4 trial || || || ||||||| in calaspargase pegol and || || || ||||||| in pegaspargase and 85 patients in the DFCI 11-001 trial discontinued the study drug; among these patients, || ||||||| and || ||||||| switched to Erwinia in the COG AALL07P4 study and the DFCI 11-001 study, respectively. In the COG AALL07P4 study, patients who experienced severe systemic or recurrent local allergic reactions to the study drug were permitted to substitute the study drug with Erwinia asparaginase (protocol amendment 7a section 5.1, page 1,522) || ||| ||||||||| | ||||||| |||||||||| || |||||||||||| ||| ||||||||||||| |||||||||||| |||||||||||| ||||| ||| ||| ||||| |||| ||| ||||||||||| | ||||| | |||||||| |||||||| |||||||| |||| |||||||||||| | ||||||| |||| || |||||||||||| |||| ||| ||| ||| |||||| |||| |||||||| || ||||||| ||||||||||||||| |||| ||||||| ||| |||||||| || ||| |||||||||||| ||||| ||||| ||| ||| |||| ||| || ||| |||||||||||| ||||| ||| ||| ||| ||| |||||||| ||||| In the DFCI 11-001 study, 21 of 118 (17.8%) patients in the calaspargase pegol group switched, mostly due to hypersensitivity (19 patients). All of the patients who switched to Erwinia in the pegaspargase group did so due to hypersensitivity.

Table 13: Summary of Patient Exposure From the Studies Included in the Systematic Review — Safety Analysis Set

COG = Children’s Oncology Group; DFCI = Dana-Farber Cancer Institute.

Sources: COG AALL07P4 Clinical Study Report^13,15 and DFCI 11-001 Clinical Study Report.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

Table 14: Summary of Subsequent Treatment From the Studies Included in the Systematic Review — FAS

COG = Children’s Oncology Group; DFCI = Dana-Farber Cancer Institute; FAS = full analysis set; NA = not applicable; PEG = pegaspargase.

^aPatients who experienced severe systemic or recurrent local allergic reaction to the study drug were switched to Erwinia asparaginase as a substitute.

Sources: COG AALL07P4 Clinical Study Report^13,15 and DFCI 11-001 Clinical Study Report.¹⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

Efficacy

Findings for key efficacy outcomes in the COG AALL07P4 and DFCI 11-001 trials are summarized in Table 15.

Table 15: Summary of Key Efficacy Results From the Studies Included in the Systematic Review

CI = confidence interval; COG = Children’s Oncology Group; CR = complete remission; DCO = data cut-off; DFCI = Dana-Farber Cancer Institute; DFS = disease-free survival; EFS = event-free survival; HR = hazard ratio; ITT = intention-to-treat; MRD = minimal residual disease; NSAA = nadir serum asparaginase activity; OR = odds ratio; OS = overall survival; PKAS = pharmacokinetic analysis set; SAA = serum asparaginase activity.

^aSurvival rates for OS, DFS from CR, and EFS for the 2-year time point were based on an updated data cut-off date of June 12, 2017, with a median follow-up time of 34.73 months and 34.04 months for the calaspargase pegol group and the pegaspargase group, respectively.

^bThe HR was derived from a Cox proportional hazards model. An HR below 1 favours the calaspargase pegol treatment and an HR greater than 1 favours pegaspargase.

^cSAA levels were reported for the PKAS (patients who received at least 1 dose of calaspargase pegol or pegaspargase on induction day 7 and had at least 1 postinfusion measurement above the lower limit of quantification) in the DFCI 11-001 trial.

^dThe OR (90% CI) was estimated using a generalized estimating equation model for comparing categorical SAA levels between treatment, actual sampling time points, and the interaction of treatment and actual sampling time points as effects.

Sources: COG AALL07P4 Clinical Study Report^13,15 and DFCI 11-001 Clinical Study Report.¹⁴Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

Overall Survival

COG AALL7P4 Study

In the COG AALL07P4 study, the median OS was not reached at the data cut-off date on December 31, 2015 (refer to |||||| |). Patients had been followed for a median of 62.6 months (range = 0.5 months to 86.3 months). |||| || || ||||||| patients in the calaspargase pegol group and | || || ||||||| patients in the pegaspargase group had died. The proportion of patients who were censored (alive at the time of data cut-off) ||| || ||||||| ||| || ||||||| in the calaspargase pegol group and the pegaspargase group, respectively. Overall, ||||| |||||| for calaspargase pegol and ||||| for pegaspargase) of patients had a minimum of 4 years of follow-up for survival. The 1-year OS rate among patients in the FAS population was ||||| ||||| || |||||, ||| ||||| ||||| || ||||) in the calaspargase pegol group and the pegaspargase group, respectively. The 4-year OS rate among patients in the FAS population was ||||| ||||| || |||||, ||| ||||| ||||| || ||||| in the calaspargase pegol group and the pegaspargase group, respectively. The 2-year and 3-year OS rates were consistent with minimal differences to the 4-year OS rates. The HR in the FAS population was |||| ||||| || ||||| in the calaspargase pegol group versus the pegaspargase group. Findings of the ITT population (refer to Appendix 1, Table 17) were consistent (minimal difference) with results for the FAS population.

DFCI 11-001 Study

In the DFCI 11-001 study, at CCOD of October 5, 2016, patients had been followed for a median of 26.6 months (range = 0.5 months to 45.6 months) (|||||| |)|||| ||| |||||| patients in the calaspargase pegol group and ||| ||| |||||| patients in the pegaspargase group had died. The proportion of patients who were censored (alive at the date of analysis or lost to follow-up) were ||| ||||||| and ||| ||||||| in the calaspargase pegol group and the pegaspargase group, respectively. The 1-year OS rate among patients in the FAS ALL population was ||||| |||| ||| ||||| || |||||| for the calaspargase pegol group and |||||| |||| ||| |||||| || ||||||| for the pegaspargase group. At the day 120 cut-off, the median follow-up duration was |||| months and |||| months for the calaspargase pegol group and the pegaspargase group, respectively. The number of patients who died during the day 120 follow-up was ||||||||| || ||| |||||||||||| ||||| |||||| ||| | |||||||||| ||||||| ||| |||| || ||| |||||||||||| |||||. The 2-year OS rate among patients in the FAS ALL population was ||||| |||| ||| ||||| || |||||| for the calaspargase pegol group and ||||||||| for the pegaspargase group. The findings of the ITT ALL population (refer to Appendix 1, Table 17) were consistent (minimal difference) with the results for the FAS population.

Sensitivity analyses for OS among patients with ALL and patients with precursor B-cell in the FAS population were consistent with the primary analysis for OS.

Figure 3: Redacted

Figure 4: Redacted

DFS From CR

COG AALL7P4 Study

In the COG AALL07P4 study, median DFS was not reached at the data cut-off date of December 31, 2015 (refer to |||||| |). Patients had been followed for a median of 62.6 months (range = 0.5 months to 86.3 months). The number of patients with events were | || || |||||| in the calaspargase pegol group and | || || |||||| in the pegaspargase group. The proportion of patients who were censored and remained event-free were || ||||||| and || ||||||| in the calaspargase pegol group and the pegaspargase group, respectively. ||| |||||| || |||||||| ||| |||| |||||||| ||| || || |||||||||| |||||||| ||||||||| |||||||| |||||| ||||||||| ||||||||| || ||||| ||| || ||||||| ||| || ||||||| || ||| |||||||||||| ||| |||||||||||| |||||| ||||||||||||| ||| |||||| || |||||||| ||| |||| |||||||| ||| ||||||||| ||||||| ||| || ||||||| ||| || ||||||| ||||||||| ||||||| |||||||||||| ||||| | ||||||| |||||||| ||| | ||||||| |||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||| The 1-year DFS rate among patients in the FAS population was ||||| ||||| || ||||| and ||||| ||||| || ||||| in the calaspargase pegol group and the pegaspargase group, respectively. The 4-year DFS rate among patients in the FAS population was ||||| ||||| || ||||| and ||||| ||||| || ||||| in the calaspargase pegol group and the pegaspargase group, respectively. The 2-year and 3-year DFS rates were consistent with minimal differences to the 4-year DFS rates. The HR of DFS in the FAS population was |||| ||||| || ||||| in the calaspargase pegol group versus the pegaspargase group. Findings for the ITT population were identical to those of the FAS population.

DFCI 11-001 Study

In the DFCI 11-001 study, at the data cut-off date of October 5, 2016, patients were followed up for a median time of 26.6 months (range = 0.5 months to 45.6 months) (|||||| |). The number of patients with events were | || ||| |||||| in the calaspargase pegol group and | || ||| |||||| in the pegaspargase group. A total of ||| ||||||| patients and ||| ||||||| patients in the calaspargase pegol group and the pegaspargase group, respectively, were censored. ||| |||||| || |||||||| ||| |||| |||||||| ||| || || |||||||||| |||||||| ||||||||| |||||||| |||||| ||||||||| ||||||||| || ||||| ||| || ||||||| ||| || ||||||| |||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||| |||||| ||||||| |||||||| ||| || ||||||| |||||||| |||| |||||||| || ||||||| |||||||||||| ||||||| || ||| |||||||||||| ||||| ||| |||||||||||| ||||||| ||||||||||||. The 1-year DFS rate among patients in the FAS ALL population who attained CR was ||||| |||| ||| |||| || ||||| in the calaspargase pegol group and ||||| |||| ||| |||| || ||||| in the pegaspargase group. At day 120 follow-up, | |||||| patients in the calaspargase pegol group and | |||||| patients in the pegaspargase group had experienced a DFS event. At day 120 follow-up, the 2-year DFS rate among patients in the FAS ALL population who attained CR was ||||| ||||| || ||||| versus ||||| ||||| || ||||| for calaspargase pegol versus pegaspargase, respectively (|||||| |). The results of DFS among patients attaining CR in the ITT ALL population were identical to the results for the FAS ALL population.

Sensitivity analyses for DFS from CR among patients with ALL and patients with precursor B-cell ALL in the FAS population were consistent with the primary analysis for DFS from CR. Similarly, sensitivity analyses by initial risk diagnosis among patients in the FAS population were consistent with the primary analysis for DFS for CR.

Figure 5: Redacted

Figure 6: Redacted

Event-Free Survival

COG AALL7P4 Study

In the COG AALL07P4 study, the median EFS rate was not reached at the data cut-off on December 31, 2015 (refer to |||||| |). Patients had been followed for a median of 62.6 months (range = 0.5 months to 86.3 months). ||||| ||| || || |||||| patients in the calaspargase pegol group and | ||| || || ||||||| patients in the pegaspargase group experienced an event. A total of || ||||||| |||||||| and || ||||||| patients in the calaspargase pegol group and the pegaspargase group, respectively, were censored. ||| |||||| || |||||||| ||| |||| |||||||| ||| || || |||||||||| |||||||| ||||||||| |||||||| |||||| ||||||||| ||||||||| || ||||| |||| || ||||||| ||| || ||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||| ||| |||||| || |||||||| ||| |||| |||||||| ||| ||||||||||| ||||||| |||| || ||||||| ||| || |||||||| ||||||||| ||||||| |||||||||||| ||||| | ||||||| |||||||| ||| | ||||||| |||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||. The 1-year EFS rate among patients in the FAS population was ||||| ||||| || ||||| and ||||| ||||| || ||||| in the calaspargase pegol group and the pegaspargase group, respectively. The 4-year EFS rate among patients in the FAS population ||| ||||| ||||| || ||||| and ||||| ||||| || ||||| in the calaspargase pegol group and the pegaspargase group, respectively. The 2-year and 3-year EFS rates were consistent with minimal differences to the 4-year EFS rates. The HR was |||| ||||| || ||||| for the calaspargase pegol group when compared with the pegaspargase group. The findings for EFS in the ITT population were consistent with the results for the FAS population.

DFCI 11-001 Study

In the DFCI 11-001 study, at the data cut-off date of October 5, 2016, patients were followed up for a median time of 26.6 months (range = 0.5 months to 45.6 months) (|||||| |). ||||| ||| || ||| |||||| patients in the calaspargase pegol group and | ||| || ||| |||||| patients in the pegaspargase group had experienced an event. A total of ||| ||||||| patients and ||| ||||||| patients in the calaspargase pegol group and the pegaspargase group, respectively, were censored. ||| |||||| || |||||||| ||| |||| |||||||| ||| || || |||||||||| |||||||| ||||||||| |||||||| |||||| ||||||||| ||||||||| || ||||| |||| || ||||||| ||| || ||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||| ||| |||||| || |||||||| ||| |||| |||||||| ||| ||||||||||| ||||||| |||||||| ||||||||||||| |||| |||||||| ||| || ||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||. The 1-year EFS rate among patients in the FAS ALL population was ||||| |||| ||| ||||| || |||||| and ||||| |||| ||| ||||| || |||||| in the calaspargase pegol group and the pegaspargase group, respectively. At the day 120 follow-up with the data cut-off date of June 12, 2017, | |||||||||| ||||||| || |||| ||||| ||||||||||| || |||||| The 2-year EFS rate among patients in the FAS ALL population at the day 120 update was ||||| |||| ||| ||||| || |||||| and ||||| |||| ||| ||||| || |||||| in the calaspargase pegol group and the pegaspargase group, respectively. The results of EFS among patients in the ITT ALL population were consistent with the results for the FAS ALL population.

Sensitivity analyses for EFS among patients with ALL and patients with precursor B-cell ALL in the FAS population were consistent with the primary analysis for EFS. Sensitivity analyses for initial risk diagnosis among patients in the FAS population were consistent with the primary analysis for EFS.

Figure 7: Redacted

Figure 8: Redacted

CR at End of Induction

COG AALL7P4 Study

In the COG AALL07P4 study, the proportion of patients in the FAS population who attained CR by day 29 was || || || ||||||| ||| ||| ||||| || |||||| in the calaspargase pegol group, and || || || ||||||| ||| ||| ||||| || |||||| in the pegaspargase group. The findings for CR at the end of induction day 29 for the ITT population were consistent with the results for the FAS population.

DFCI 11-001 Study

In the DFCI 11-001 study, the proportion of patients in the FAS ALL population who attained CR by day 32 was ||| || ||| ||||||| ||| ||| ||||| || |||||| in the calaspargase pegol group and ||| || ||| ||||||| ||| ||| ||||| || |||||| in the pegaspargase group. The results for CR at the end of induction day 32 in the ITT ALL population were consistent with the results for the FAS ALL population.

Sensitivity analyses for CR for initial risk diagnosis, age group classification (< 10 years, ≥ 10 years, 10 to < 16 years, and ≥ 16 years), and BMI category (< 50th percentile versus ≥ 50th percentile) were consistent with the primary analysis for CR.

MRD at End of Induction

COG AALL7P4 Study

In the COG AALL07P4 study, the proportion of patients in the MRD-evaluable FAS population with positive MRD (≥ 0.1% detectable leukemia cells in bone marrow biopsy or aspirate with validated 6-colour multiparameter flow cytometry) at induction day 29 |||| | || || ||||||| in the calaspargase pegol group and || || || ||||||| in the pegaspargase group. Conversely, the proportion of patients in the MRD-evaluable FAS population with negative MRD (< 0.1%) at induction day 29 were || ||||||| and || ||||||| in the calaspargase pegol group and the pegaspargase group, respectively. The proportion of patients in the FAS population with MRD of 0.01 or greater at induction day 29 were | |||||| in the calaspargase pegol group and | |||||| in the pegaspargase group. The findings for positive MRD (≥ 0.1%) at the end of induction day 29 in the ITT population were consistent with the results for the FAS population.

DFCI 11-001 Study

In the DFCI 11-001 study, results for MRD were identical for the FAS and ITT populations. In the DFCI 11-001 study, the proportion of patients in the FAS ALL population with MRD of 0.01 or greater were | || ||| |||||| in the calaspargase pegol group and ||| in the pegaspargase group. ||| ||||||| |||| ||||||| ||| || ||||||| ||| || ||||||| || |||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||. The findings for MRD of 0.01 or greater at the end of induction day 32 in the ITT ALL population were consistent with the results for the FAS ALL population.

SAA During Induction

COG AALL7P4 Study

In the COG AALL07P4 study, SAA levels were not reported.

DFCI 11-001 Study

In the DFCI 11-001 study, at the data cut-off date of October 5, 2016, arithmetic mean SAA levels were between |||| ||| |||| ||||| |||||| in the pegaspargase treatment group than in the calaspargase pegol treatment group at the first (5 minutes to 10 minutes), second (4 days), and third (11 days) measurement time points after administration (|||||| |). At the fourth (18 days) and fifth (25 days) measurement time points, arithmetic mean SAA levels were |||| ||| |||| ||||| |||||| with calaspargase pegol than with pegaspargase, respectively. The arithmetic mean SAA level at day 32 (25 days after drug administration) was |||||| ||| | ||||||| in the calaspargase pegol group || | |||| and |||||| ||| | ||||||| in the pegaspargase group || | ||||. The results for geometric means were consistent with the results for arithmetic means.

The proportion of patients with SAA levels of 0.10 IU/mL or greater were ||||| |||| ||| |||| || |||||| for the calaspargase pegol group versus ||||| |||| ||| |||| || |||||| for the pegaspargase group at 5 minutes to 10 minutes after infusion on induction day 7 (OR |||||| ||| ||| ||||| || ||||||. The proportion of patients with SAA levels of 0.10 IU/mL or greater were |||||| (95% CI, |||| || |||||| for the calaspargase pegol group versus ||||| (95% CI, |||| || |||||) for the pegaspargase group at 4 days after infusion on day 11 (OR |||||; 90% CI, ||||| || |||||). The proportion of patients with SAA levels of 0.10 IU/mL or greater were |||||| (95% CI, |||| || |||||) for the calaspargase pegol group versus |||||| (95% CI, |||| || |||||) for the pegaspargase group at 11 days after infusion on day 18 (OR |||||; 90% CI, ||||| || |||||). The proportion of patients with SAA levels of 0.10 IU/mL or greater were ||||| (95% CI, |||| || ||||) for the calaspargase pegol group versus ||||| (95% CI, |||| || ||||) for the pegaspargase group at 18 days after infusion on day 25 (OR |||||; 90% CI, ||||| || ||||||). The proportion of patients with SAA levels of 0.10 IU/mL or greater were ||||| (95% CI, |||| || ||||) for the calaspargase pegol group versus ||||| (95% CI, |||| || ||||) for the pegaspargase group at 25 days after infusion on day 32 (OR ||||||; 90% CI, |||||| || ||||||).

Estimates of treatment effect on SAA levels using adjusted analyses (controlled for age, sex, initial risk group, disease type, and baseline WBC count) were similar to unadjusted analyses for each time point.

Figure 9: Redacted

Health-Related Quality of Life

HRQoL was not assessed in the COG AALL07P4 trial or the DFCI 11-001 trial.

Harms

Harms data for the COG AALL07P4 and DFCI 11-001 trials are summarized in Table 16. Safety data for the COG AALL07P4 trial were from the primary safety analyses (CCOD of December 31, 2015). Safety results for the DFCI 11-001 trial were available at the CCOD of October 5, 2016, and day 120 follow-up (CCOD of February 1, 2017). ||| ||||||| || ||| |||||||||||| ||||| ||| |||| |||||| ||| ||| ||| |||||||||| ||| || ||||||| |||||||| Findings from the updated safety data (CCOD of February 1, 2017) were ||||||||| consistent with the primary safety analyses (CCOD of October 5, 2016) and are therefore not presented.

Table 16: Summary of Harms Results From the Studies Included in the Systematic Review

AE = adverse event; AESI = adverse event of special interest; ALT = alanine transaminase; AST = aspartate aminotransferase; CI = confidence interval; COG = Children’s Oncology Group; DFCI = Dana-Farber Cancer Institute; NA = not applicable; NR = not reported; SAE = serious adverse event; TEAE = treatment-emergent adverse event; WBC = white blood cell.

^aIn the DFCI 11-001 study, the investigators did not designate some of the hypersensitivity AEs that resulted in a switch to Erwinia as AEs leading to study drug discontinuation for 6 patients in the pegaspargase 2,500 IU/m² group.

^bDeaths were reported for the full analysis set in the COG AALL07P4 trial and for the intention-to-treat population in the DFCI 11-001 trial.

^cOne patient randomized to calaspargase pegol 2,500 IU/m² who died during induction was not treated with the study drug.

^dReasons for deaths may not add up to the total number of patients who died because cause of death may be attributed to more than 1 reason (e.g., a patient who died due to primary disease and the death occurred during induction).

Sources: COG AALL07P4 Clinical Study Report¹² and DFCI 11-001 Clinical Study Report.^13,15 Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹²

Adverse Events

In the COG AALL07P4 trial, the percentage of patients reporting any TEAEs was ||||| ||| || ||| for the calaspargase pegol group and ||||| ||| || ||| for the pegaspargase group. The most common TEAEs occurring in at least 25% of patients in the calaspargase pegol group and the pegaspargase group, respectively, were hyperglycemia (79.1% versus 50.0%); blood bilirubin, increased (62.8% versus 50.0%); neutrophil count, decreased (55.8% versus 51.9%); febrile neutropenia (55.8% versus 42.3%); alanine aminotransferase, increased (34.9% versus 38.5%); platelet count, decreased (34.9% versus 25.0%); WBC count, decreased (37.2% versus 28.5%); hypokalemia (27.9% versus 11.5%); anemia (25.6% versus 26.9%); activated partial thromboplastin time, prolonged (30.2% versus 19.2%); peripheral motor neuropathy (27.9% versus 19.2%); and abdominal pain (32.6% versus 11.5%).

In the DFCI 11-001 trial, |||||| ||| |||||||| |||| || |||| |||||| experienced at least 1 TEAE. The number of patients who experienced TEAEs were ||| ||||||| patients in the calaspargase pegol group and ||| |||||||| patients in the pegaspargase group. The most common TEAEs occurring in at least 25% of patients in the calaspargase pegol group and the pegaspargase group, respectively, were hypoalbuminemia (81.4% versus 82.4%); alanine transaminase, increased (78.8% versus 77.3%); aspartate aminotransferase, increased (53.4% versus 58.8%); blood bilirubin, increased (45.8% versus 43.7%); hypokalemia (45.8% versus 39.5%); febrile neutropenia (33.9% versus 40.3%); hyperglycemia (33.9% versus 28.6%); hypoglycemia (30.5% versus 36.1%); hypertriglyceridemia (28.0% versus 36.1%); and stomatitis (25.4% versus 20.2%).

The most common TEAEs in the calaspargase pegol group in the COG AALL07P4 trial and the DFCI 11-001 trial, respectively, were hypoalbuminemia (27.9% and 81.4%); hyperglycemia (79.1% and 33.9%); alanine transaminase, increased (34.9% and 78.8%); blood bilirubin, increased (62.8% and 45.8%); and febrile neutropenia (55.8% and 33.9%). The most common TEAEs in the pegaspargase group were hyperglycemia (50.0% and 82.4%); alanine transaminase, increased (38.5% and 77.3%); blood bilirubin, increased (50.0% and 43.7%); and febrile neutropenia (42.3% and 40.3%).

Serious Adverse Events

In the COG AALL07P4 trial, the number of patients with at least 1 SAE was not reported. The number of patients with at least 1 grade 3 or grade 4 TEAE was 42 (97.7%) patients in the calaspargase pegol group and 47 (90.4%) patients in the pegaspargase group. The most common grade 3 or grade 4 TEAEs in the calaspargase pegol group were neutrophil count, decreased (55.8%); febrile neutropenia (55.8%); WBC count, decreased (37.2%); and hyperglycemia (37.2%). The most common grade 3 or grade 4 TEAEs in the pegaspargase group were neutrophil count, decreased (51.9%); febrile neutropenia (42.3%); alanine transaminase, increased (36.5%); and WBC count, decreased (28.8%).

In the DFCI 11-001 trial, a total of ||| ||||||| patients experienced grade 3 or grade 4 TEAEs. The number of patients who experienced grade 3 or grade 4 TEAEs were ||| ||||||| in the calaspargase pegol group and ||| ||||||| in the pegaspargase group. The most common grade 3 or grade 4 TEAEs in the calaspargase pegol group were alanine transaminase, increased (49.2%); hypokalemia (43.2%); febrile neutropenia (33.9%); and hypoalbuminemia (27.1%). The most common grade 3 or grade 4 TEAEs in the pegaspargase group were alanine transaminase, increased (60.5%); febrile neutropenia (40.3%); and hypokalemia (36.1%). The percentage of patients who experienced at least 1 SAE was 24.6% and 21.8% in the calaspargase pegol group and the pegaspargase group, respectively. SAEs that occurred in at least 2% of patients in either the calaspargase pegol group or the pegaspargase group, respectively, were lipase, increased (4.2% |||||| |||||); pancreatitis (5.9% |||||| |||||| sepsis (3.4% |||||| ||||); hyperglycemia (2.5% |||||| |||||| febrile neutropenia (1.7% |||||| |||||| amylase, increased (0.8% |||||| ||||); alanine transaminase, increased (2.5% |||||| ||||); aspartate aminotransferase, increased (2.5% |||||| |); and neutropenic colitis (2.5% |||||| |).

Withdrawals Due to Adverse Events

In the COG AALL07P4 trial, the number of patients who stopped study treatment due to an AE was || ||||||| and || ||||||| in the calaspargase pegol group and the pegaspargase group, respectively. The reasons for stopping study treatment due to an AE were not reported.

In the DFCI 11-001 trial, the number of patients who stopped study treatment due to an AE was 33 (28.0%) patients in the calaspargase pegol group and 23 (19.3%) patients in the pegaspargase group. WDAEs in the calaspargase pegol group compared with pegaspargase were due to hypersensitivity (8.5% versus ||||); lipase, increased (6.8% versus ||||); pancreatitis (5.9% in both groups); drug hypersensitivity (5.1% versus ||||); amylase, increased (4.2% versus ||||); and anaphylactic reaction (1.7% versus ||||).

Mortality

|| ||| |||||||| || ||| ||| ||||||||||| | |||||| |||||||| || ||| |||||||||||| ||||| ||||| || ||||||| ||| ||| ||||||| |||||||| ||||||||||| || |||||| | |||||| |||| ||| || ||||||||| |||||||||| ||||||| |||| ||| ||||||||| | ||| || ||||| ||||||| ||| |||||| |||||||| || ||| |||||||||||| |||||| || |||||| | |||| ||| || |||||||||| ||||||| ||| ||| ||||||||| | |||| ||| || ||||| ||||||. Table 16 reports the number of patients who died in the FAS population.

|| |||| ||||||| | |||||| ||| | |||||| |||||| |||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||| ||||| |||||| || ||| |||||||||||| ||||| |||||| | ||| ||| || ||||||| ||||||| |||||||| ||| ||||| | |||| ||||||||| ||||||| ||| | ||| || ||||||||| |||||| ||| |||||| || ||| |||||||||||| ||||| |||| ||| || |||||||| ||| |||||||||| ||||||| ||| ||| |||||||||| || ||| |||||||||||| ||||| ||||| ||| ||| ||| ||||||| |||| ||||| |||| |||| ||||||||||| |||| |||||| ||| |||||.

Notable Harms

Hypersensitivity Reactions

In the COG AALL07P4 trial, | |||||| patients in the calaspargase pegol group and | |||||| patients in the pegaspargase group experienced hypersensitivity events | || |||||||| || |||||| ||||||||| ||||| |||| |||||||||||||||| ||||||||| |||| |||||||| ||| ||||||||||||| ||||||||| || |||||||| ||||||||||||||||.

In the DFCI 11-001 trial, || ||||||| patients in the calaspargase pegol group and || ||||||| patients in the pegaspargase group experienced hypersensitivity events. ||| ||||||| |||||||| ||| | |||||| ||||||| |||||| |||||||| ||| ||||||||| |||||| |||||||| |||||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||| ||||| ||||||| ||| | ||||||| |||||||| || ||| |||||||||||| ||||| ||| |||||||||||| |||||| ||||||||||||| ||| ||| |||| |||||||| ||||||||||||||||||.

Anaphylactic Reactions

In the COG AALL07P4 study, 11 (25.6%) patients in the calaspargase pegol group and 10 (19.2%) patients in the pegaspargase group experienced anaphylactic reactions.

In the DFCI 11-001 study, | |||||| patients in each treatment group experienced anaphylactic reactions.

Silent Inactivation

Silent inactivation was not reported by any patient in the COG AALL07P4 trial. In the DFCI 11-001 trial, 2 (1.7%) patients in the calaspargase pegol group experienced silent inactivation and were switched to Erwinia asparaginase treatment.

Pancreatitis

In the COG AALL07P4 trial, 8 (18.6%) patients in the calaspargase pegol group and 4 (7.7%) patients in the pegaspargase group experienced pancreatitis.

In the DFCI 11-001 trial, 14 (11.9%) patients in the calaspargase pegol group and 20 (16.8%) patients in the pegaspargase group experienced pancreatitis.

Venous Thrombosis

In the COG AALL07P4 study, venous thrombosis was ||| |||||||| || ||| |||||||.

In the DFCI 11-001 study, | |||||| patients in the calaspargase pegol group and | |||||| patients in the pegaspargase group experienced venous thrombosis.

Hemorrhage

|| |||||||| || |||||| ||||||||| ||||| experienced hemorrhage in the COG AALL07P4 study or the DFCI 11-001 study.

Hepatotoxicity

In the COG AALL07P4 study, the number of patients in the calaspargase pegol group and pegaspargase group, respectively, who experienced increased blood bilirubin were 27 (62.8%) patients and 26 (50.0%) patients. There were 15 (34.9%) patients and 20 (38.5%) patients who experienced increased alanine aminotransferase in the calaspargase pegol group and pegaspargase group, respectively.

In the DFCI 11-001 study, 54 (45.8%) patients and 52 (43.7%) patients experienced increased blood bilirubin in the calaspargase pegol group and pegaspargase group, respectively. There were 93 (78.8%) patients and 92 (77.3%) patients who experienced increased alanine aminotransferase in the calaspargase pegol group and pegaspargase group, respectively. ||| ||||||| || ||| |||||||||||| ||||| ||||| ||||||||||| ||||||| |||||||.

Critical Appraisal

Internal Validity

COG AALL07P4 Study

The COG AALL07P4 study was a phase II, randomized, open-label RCT. Methods of randomization appeared to be adequate. In the COG AALL07P4 study, patients were randomized 2:1 to calaspargase pegol or pegaspargase based on permuted blocks (of 6) using an electronic remote data entry system. Treatment groups were generally balanced for baseline characteristics including prognostic factors and medical history, indicating that randomization was likely appropriate, and risk of selection bias was likely low. The open-label study design may have biased outcomes with subjective assessments for measurement of harms due to knowledge of the assigned treatment, although the direction of potential bias is unclear. AEs highlighted by the clinical experts consulted by CADTH to be especially relevant for the management of patients in clinical practice included hypersensitivity reactions, anaphylactic reactions, silent inactivation, and WDAEs. The open-label study design may have biased WDAEs due to knowledge of assigned treatment, although the direction of potential bias is unclear.

The COG AALL07P4 trial (N = 97) was not designed or powered to formally assess comparative efficacy outcomes (i.e., day 29 end-of-induction MRD, CR, EFS, DFS from the attainment of CR, and OS), making assessments of relative therapeutic efficacy of pegaspargase challenging. The protocol did not prespecify a degree of difference from which to formally conclude noninferiority or similarity between calaspargase pegol and pegaspargase. Point estimates with 95% CIs were reported to estimate the magnitude of treatment effect and end points were not adjusted for multiple comparisons. The sample size of 97 patients was relatively small and the magnitude of the treatment effect estimates observed in a small study sample may not be replicable in a larger study sample. The clinical experts consulted by CADTH did not anticipate clinically meaningful differences in efficacy between calaspargase pegol and pegaspargase due to the products’ similar mechanisms of action and use of the same asparagine-specific enzyme (i.e., derived from E. coli).

There was no imputation for missing outcome data. However, there were few patients missing in the calaspargase pegol group and the pegaspargase group, respectively, for CR at the end of induction day 29 (1 and 0) and MRD at the end of induction day 29 (up to 3 and 5), and the proportion of patients who were censored for survival outcomes appeared to be balanced between groups.

The comparator used in the COG AALL07P4 study was appropriate as pegaspargase is a pegylated formulation of asparaginase (calaspargase pegol uses the same mechanism of action as pegaspargase) and has been a component of current SOC. Calaspargase pegol is intended to substitute for pegaspargase and would be used for patients who would have otherwise received a pegaspargase-containing MDC. In addition to asparaginase, the MDC components that were included in the study protocol (cytarabine, vincristine, daunorubicin, mercaptopurine, thioguanine, and doxorubicin) were concomitant therapy and reported to be similarly dosed between treatment groups.

At the time of the data cut-off date, December 31, 2015, and at a median follow-up time of 62.6 months, median survival estimates (OS, DFS from the attainment of CR, and EFS) had not yet been reached in either treatment group, which is not unexpected for a patient population with 5-year OS rates of 89% for children and 89% for AYAs (15 years to 39 years).² The timing of assessments for CR and MRD at day 29 appears to be appropriate to capture the presence or absence of disease at the end of remission induction. Among treatment response assessments, MRD was measured using flow cytometry employed in the COG AALL07P4 study, which was reported in published guidelines as a valid method to detect disease.³⁴

DFCI 11-001 Study

The DFCI 11-001 study was a phase II, randomized, open-label RCT. Treatment groups appeared to be balanced overall for baseline characteristics and the risk of bias arising from issues related to randomization or allocation concealment is likely low. The open-label study design may have biased outcomes with subjective assessments for the measurement of harms due to knowledge of the assigned treatment, although the direction of potential bias is unclear. AEs highlighted by the clinical experts consulted by CADTH that were especially relevant for the management of patients in clinical practice included hypersensitivity reactions, anaphylactic reactions, silent inactivation, and WDAEs. The open-label study design may have biased WDAEs due to knowledge of the assigned treatment, although the direction of potential bias is unclear.

The DFCI 11-001 trial was not designed or powered to formally assess comparative efficacy (i.e., SAA, day 29 end-of-induction MRD, CR, EFS, DFS from the attainment of CR, and OS), making assessments of the relative therapeutic benefit of pegaspargase challenging. The protocol did not prespecify a degree of difference from which to formally conclude noninferiority or similarity between calaspargase pegol and pegaspargase. Point estimates with 95% CIs were reported to estimate the magnitude of treatment effect and end points were not adjusted for multiple comparison. The clinical experts consulted by CADTH did not anticipate clinically meaningful differences in efficacy between calaspargase pegol and pegaspargase due to the products’ similar mechanisms of action and use of the same asparagine-specific enzyme (i.e., derived from E. coli).

SAA measured after a single dose was 1 of the primary end points and used the established therapeutic threshold of at least 0.1 IU/mL, which was previously set as an important limit of clinical significance and is considered a valid surrogate for complete asparagine depletion.^34,51 The FDA has approved previous asparaginase products in combination with chemotherapy, including calaspargase pegol for the present target population, on the basis of accepting evidence of asparaginase activity as a “valid surrogate for clinical efficacy.”^46,51 SAA levels were measured during induction in the DFCI 11-001 trial to assess calaspargase pegol’s ability to maintain an SAA level of 0.1 UI/mL or greater 3 weeks to 4 weeks after a single dose and to assess its half-life duration compared to pegaspargase. The mechanism of action of calaspargase pegol is the same as that of the established SOC pegaspargase; however, calaspargase pegol was developed with greater biological stability than pegaspargase. The clinical experts consulted by CADTH agreed that this end point serves to support calaspargase pegol’s ability to maintain asparagine suppression in plasma, its half-life duration, and its ability to be administered with less dosing frequency than pegaspargase (i.e., a schedule of every 3 weeks versus every 2 weeks).

The assessments of SAA every 3 weeks for 30 consecutive weeks during postinduction therapy in the DFCI 11-001 trial was another primary end point, with the objective of further determining how best to dose calaspargase pegol during postinduction therapy.⁴⁴ As noted earlier in this report, this outcome to determine an appropriate dose was not assessed in this report as it was not identified as being 1 of the most important outcomes to guide treatment selection in clinical practice by the clinical experts consulted by CADTH. The FDA in its assessment of calaspargase pegol for this indication noted that a large amount of PK data to assess asparaginase activity in the DFCI 11-001 trial was not evaluable. Therefore, the FDA used an imputation method based on the population PK modelling and simulation that included patients with valid PK observations from the COG AALL07P4 and DFCI 11-001 trials, which indicated sufficient levels of asparaginase activity at steady state during postinduction to support the proposed dosing of every 3 weeks for calaspargase pegol.^50,51

There were balanced between-group proportions of patients who were censored for survival outcomes and a low number of patients missing in the calaspargase pegol and pegaspargase groups, respectively, for CR at the end of induction day 32 (5 and 4), MRD at the end of induction at day 32 (5 and 4), and SAA levels (up to 8 and 11); overall, missing outcome data were unlikely to substantially impact findings despite the lack of imputation.

At the time of the data cut-off date, October 5, 2016, and at a median follow-up time of 26.6 months, median survival estimates (OS, DFS from the attainment of CR, and EFS) had not yet been reached in either treatment group. At the time of the updated data cut-off date of June 12, 2017, with a median follow-up time of ||||| months for the calaspargase pegol group and ||||| months for the pegaspargase group, median survival estimates had also not been reached yet in either treatment group, which is not unexpected for a patient population with 5-year OS rates of 89% for children and 89% for AYAs (15 years to 39 years).²

The timing of assessments for CR and MRD at day 32 appears to be appropriate to capture the presence or absence of disease at the end of remission induction.

In both the COG AALL07P4 study and the DFCI 11-001 study, the FAS data were used for survival outcomes, CR at the end of induction, and MRD at the end of induction. While it is preferable to rely on ITT analyses to ensure patients are included in statistical analyses according to the group they were randomized to, rather than according to the treatment they received, there were minimal differences between the FAS and ITT populations, and the analyses based on FAS or ITT were minimally different.

CR and MRD assessments using flow cytometry in the COG AALL07P4 study and a PCR assay in the DFCI 11-001 study were reported by the clinical experts to be appropriate and in line with observations in clinical practice. The time points of assessment for CR and MRD on day 29 (the COG AALL07P4 study) and day 32 (the DFCI 11 to 011 study) of the end of induction were appropriate according to the clinical experts, given the differences in duration, frequency, and phases among available treatment protocols.

Outcomes identified as important by patients and clinical experts consulted by CADTH that were not assessed included HRQoL (the COG AALL07P4 and DFCI 11-001 trials) and silent inactivation (the COG AALL07P4 trial).

External Validity

There were notable limitations for generalizability in the COG AALL07P4 and DFCI 11-001 studies. Both were phase II trials with small samples of patients with ALL enrolled. The clinical experts consulted by CADTH remarked that given the disease area and a relatively small patient population therein, a phase III RCT would neither be feasible due to challenges in accruing a sufficient sample nor ethical due to pegaspargase-asparaginase as current front-line treatment for ALL.

While patients in both trials were representative of patients with ALL, subpopulations of patients were missing in each trial. The clinical experts consulted by CADTH considered the results from the COG AALL07P4 and DFCI 11-001 studies to be generalizable to patients younger than 1 year (excluded from the COG AALL07P4 and DFCI 11-001 trials) and patients older than 21 years (excluded from the DFCI 11-001 trial) or 30 years (excluded from the COG AALL07P4 trial). According to the clinical experts consulted by CADTH, patients with T-cell immunophenotype (excluded from the COG AALL07P4 trial) would also be expected to benefit from treatment with calaspargase pegol, provided there was no known prior hypersensitivity to asparaginase. While the trials only enrolled patients with newly diagnosed ALL, the clinical experts consulted by CADTH felt that it would be reasonable to generalize the results of the COG AALL07P4 and DFCI 11-001 studies to patients with relapse or refractory disease and noted an emerging consensus treatment protocol for first relapse among pediatric patients with B-lineage ALL.^2,55 Similarly, the clinical experts consulted by CADTH considered the results of the COG AALL07P4 and DFCI 11-001 studies to be generalizable to pediatric patients with Ph-positive status who were excluded from these trials. The clinical expert treating pediatric patients who was consulted by CADTH reported no concerns with using asparaginase-based treatment in pediatric patients who are given tyrosine kinase inhibitors, should current treatment protocols for ALL be expanded to include patients with Ph-positive status. However, the clinical expert consulted by CADTH who was treating adults reported avoidance of asparaginase concurrently with tyrosine kinase inhibitors due to the potential for greater toxicities. Overall, the clinical experts consulted by CADTH indicated that there was a lack of data from prospective clinical trials to inform optimal treatment for subgroups of patients and, therefore, it is anticipated that patients may benefit from treatment with calaspargase pegol based on its similarity to and extrapolation of findings for pegaspargase. In general, the populations enrolled in the COG AALL07P4 and DFCI 11-001 trials were considered by the clinical experts consulted by CADTH to be representative of patients with ALL. The clinical experts consulted by CADTH anticipated that calaspargase pegol would be used in patients who would otherwise receive a pegaspargase-containing MAC.

Different backbone therapies were employed, with an intermittent asparagine depletion versus continuous asparagine depletion protocol for the COG AALL07P4 study versus the DFCI 11-001 study, respectively. Differences in treatment protocols between the trials were echoed by the clinical experts consulted by CADTH to be observed in clinical practice, acknowledging that ALL is the most common malignancy in pediatrics with commonly adopted protocols but lacking formal established national standards. The clinical expert consulted by CADTH treating pediatric patients with ALL reported that COG-based protocols are employed by institutions across Canada except in Quebec, where DFCI-based protocols are used. A modified DFCI protocol was reported by the clinical expert consulted by CADTH treating adults with ALL to be used at a centre in Alberta. The clinical experts consulted by CADTH agreed that they expected outcomes to be similar across all treatment protocols for ALL.

Outcomes reported in the COG AALL07P4 and DFCI 11-001 trials appeared to be aligned with outcomes of interest for patients with ALL according to the clinical experts consulted by CADTH. In the COG AALL07P4 trial, attaining M1 bone marrow status (fewer than 5% malignant lymphoblasts) was used to define CR at the end of induction. In the DFCI 11-001 trial, fewer than 1% malignant lymphoblasts was used to define CR at the end of induction. According to the clinical experts consulted, an M1 bone marrow status is used to determine clinically meaningful remission among children and adults with ALL. As such, the use of 1% as a cut-off for disease detection appears to be conservative when compared with a 5% detection cut-off. The clinical experts consulted by CADTH reported that the total duration of MAC treatment for ALL is approximately 2.5 years to 3.5 years for patients who respond, with asparaginase being used within the first year of treatment. Therefore, survival outcomes assessed at 1 year are likely insufficient for follow-up. There was an absence of established MIDs for all outcomes, and the clinical experts consulted by CADTH did not provide expert opinion–based MIDs for most outcomes. According to the clinical experts consulted by CADTH, any decrease in DFS from the attainment of CR is clinically important. With respect to CR at the end of induction, the clinical experts consulted by CADTH reported a 5% difference between groups to be clinically meaningful. Evaluations of SAA levels were not reported by the clinical experts consulted by CADTH to be mandated in practice, with variable adoption across centres. The clinical experts highlighted the importance of SAA levels in TDM for both efficacy (i.e., adequate asparagine depletion and sustained SAA levels of 0.10 IU/mL or greater) and safety (e.g., hypersensitivity reactions including silent inactivation).

In general, the clinical experts consulted by CADTH commented that they did not anticipate clinically meaningful differences in efficacy between calaspargase pegol and pegaspargase.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^10,11

• “High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word ‘likely’ for evidence of moderate certainty (e.g., ‘X intervention likely results in Y outcome’).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word ‘may’ for evidence of low certainty (e.g., ‘X intervention may result in Y outcome’).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as ‘very uncertain.’”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and/or publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of a clinically important effect for CR at the end of induction based on a threshold informed by the clinical experts consulted by CADTH for this review. The target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for survival rates (OS, DFS from CR, EFS), MRD at the end of induction, SAA during induction, and harms.

For the GRADE assessments, findings from the COG AALL07P4 and DFCI 11-001 studies were assessed individually because the trials enrolled different patient populations (patients with high-risk B-cell ALL in the COG AALL07P4 study and patients with ALL and LL in the DFCI 11-001 study) and employed different treatment protocols (intermittent asparagine depletion in the COG AALL07P4 study and continuous asparagine depletion in the DFCI 11-001 study).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for calaspargase pegol versus pegaspargase in patients with high-risk B-cell ALL in the COG AALL07P4 trial. Table 3 presents the GRADE summary of findings for calaspargase pegol versus pegaspargase in patients with ALL in the DFCI 11-001 trial.

Discussion

Summary of Available Evidence

Two phase II, multicentre, randomized, open-label trials assessed the efficacy and safety of calaspargase pegol 2,500 IU/m² compared with pegaspargase 2,500 IU/m². The COG AALL07P4 trial enrolled 166 patients aged 1 year to 30 years in 23 study sites, all located in the US, with newly diagnosed high-risk B-cell ALL. The primary objective of the COG AALL07P4 trial was to determine the PK comparability (asparaginase activity) of the interventions during induction and consolidation while patients were receiving augmented Berlin-Frankfurt-Münster therapy. Secondary objectives of the COG AALL07P4 study included PD parameters during induction and consolidation, MRD (day 29), CR rate (day 29), survival (EFS, DFS of CR, and OS), and TEAEs. The DFCI 11-001 study enrolled 239 patients aged 1 year to 21 years in the US (in 6 sites) and Canada (in 3 sites) with newly diagnosed ALL or LL. The primary objective of the DFCI 11-001 study was to determine the PK comparability of the interventions during remission induction and postinduction (i.e., determine SAA levels and assess toxicity). Secondary objectives of the DFCI 11-001 study included MRD (day 32), CR rate (day 32), EFS, DFS from the attainment of CR, and OS.

In the COG AALL07P4 trial, most patients were older than 10 years (66.3%), male (50.9%), and white (82.2%). In the DFCI 11-001 trial, most patients were younger than 10 years (75%), male (61.6%), and white (70.5%). Across both the COG AALL07P4 trial and the DFCI 11-001 trial, there were notable similarities and differences in baseline demographics. All patients in the COG AALL07P4 trial and nearly all patients in the DFCI 11-001 trial (96%) had ALL. Most patients in the DFCI 11-001 study had B-cell ALL (87%), including patients with T-cell ALL (13%), whereas the COG AALL07P4 study was limited to patients with B-cell immunophenotype. Most patients had a CNS status of 1 in both trials with a minority of patients designated as CNS3 in the COG AALL07P4 study (fewer than 10%) and the DFCI 11-001 study (fewer than 2%). Most patients did not have steroid therapy before study treatment in the COG AALL07P4 trial (93%) or the DFCI 11-001 trial (84%). While the majority of patients were older than 10 years in the COG AALL07P4 trial (median = 11 years), most were younger than 10 years in the DFCI 11-001 trial (median = 4 years to 5 years). Approximately 62% of patients were diagnosed when they were 10 years or older in the COG AALL07P4 study, whereas nearly 75% of patients were diagnosed younger than 10 years in the DFCI 11-001 study. Patients in the COG AALL07P4 study were distributed equally across combined age and WBC categories, whereas more than 70% of patients in the DFCI 11-001 study were younger than 10 years with a WBC count below 50 × 10⁹/L.

Interpretation of Results

Efficacy

All outcomes in the COG AALL07P4 trial and most outcomes in the DFCI 11-001 trial were secondary end points without adjustment for multiplicity, and therefore considered as supportive evidence for assessments of certainty in effect estimates. Additionally, the relatively small samples of patients enrolled in these phase II trials resulted in wide CIs across most outcome effect estimates.

As the aim of treatment for patients with ALL is curative, survival was highlighted as an important outcome by patients, the clinical experts consulted by CADTH, and clinicians. Prevention of or delayed disease progression was also identified as important to patients. As such, the survival outcomes of OS, DFS from CR, and EFS appear appropriate and were captured in both the COG AALL07P4 trial and the DFCI 11-001 trial. However, the duration of follow-up for OS, DFS from CR, and EFS at 1 year was insufficient to adequately capture the full impact of treatment on patients. While asparaginase is incorporated into the first phases of MAC treatment over the first year, the clinical experts consulted by CADTH estimated that the total duration of MAC treatment for patients with ALL who respond is approximately 2.5 years to 3.5 years. |||||| ||||||||| || |||||||| ||| |||||| || | ||||| || |||| |||||| ||| | ||||| || ||| |||||||| ||| ||| ||||||| |||||| ||| ||| |||| ||| || ||| || ||| ||||| |||||| According to a publication by Vrooman et al. (2021),⁴² 5-year OS was estimated at 94.0% (standard error = 2.2) for calaspargase pegol compared with 95.8% (standard error = 1.9) for pegaspargase (P value for difference between groups = 0.72); however, there was significant uncertainty for these findings, which lacked numerical values for the number of OS events and a date for data cut-off.⁴² The review team was unable to rigorously assess the conduct and reporting of the 5-year OS analyses, due to the limited data available in the publication.

CR and MRD assessments using flow cytometry in the COG AALL07P4 study and a PCR assay in the DFCI 11-001 study were reported to be appropriate by the clinical experts consulted by CADTH and in line with observations in clinical practice. The time points of assessment for CR and MRD on day 29 (the COG AALL07P4 study) and day 32 (the DFCI 11 to 011 study) of the end of induction were appropriate according to the clinical experts consulted by CADTH, given the differences in duration, frequency, and phases among available treatment protocols.

SAA measurements are considered to be a surrogate for the efficacy of asparaginase formulations.⁴⁶ The use of 0.10 IU/mL as a marker of therapeutic asparaginase activity (levels above 0.10 IU/mL have been shown to be associated with complete asparagine depletion and therefore, therapeutic benefit) aligns with consensus expert recommendations³⁴ and input from clinical experts consulted by CADTH. The consensus panel noted that increased access to real-time validated asparaginase measurements (e.g., via regulatory-approved assays) has enabled more reliable asparaginase activity monitoring in clinical practice, highlighting SAA assessment as important in detecting allergic reactions, silent inactivation, and the potential for modifying dosing of asparaginase treatment.³⁴

The results of calaspargase pegol compared with pegaspargase appeared generally similar for survival, including OS, DFS from CR, EFS, and MRD at the end of induction. The findings suggested that calaspargase pegol may result in an increase in CR at the end of induction compared with pegaspargase. There was uncertainty in the effect estimates for which the majority of outcomes suggested little to no difference between treatment groups because estimates were based on small sample sizes and few events, and CIs that suggested the possibility of benefit, harm, or both. There was a potential risk of bias arising from patient-reported and assessor-reported WDAEs due to the subjective nature of assessments and knowledge of treatment assignment in the open-label study design.

An MRD level of 0.1% has been accepted by the FDA to identify patients with ALL with a high risk of relapse.⁴⁶ The clinical experts consulted by CADTH agreed that the end of induction MRD is 1 of the most clinically meaningful predictors of outcomes in ALL and is used as part of standard-risk stratification strategies for patients with ALL. The clinical experts consulted by CADTH considered the results for the end of induction MRD to be relevant and indicative of calaspargase pegol resulting in no decline in the percentage of patients who attain an early response compared with pegaspargase.

In the COG AALL07P4 trial, PAA levels were measured (measured on day 4, day 15, day 22, day 29, and day 43 of induction; this included the proportion of patients with a PAA level of 0.10 IU/mL or greater [and the proportion of patients with a PAA level of 0.40 IU/mL or greater] for each study group). PAA results were displayed in ||||| || in Appendix 1. According to the clinical experts consulted by CADTH, PAA is not currently measured in clinical practice and not used to make treatment selection in clinical practice. Generally, it is not feasible to accurately measure PAA outside the context of a clinical trial. Therefore, a surrogate measure, SAA, has been developed, which is an accepted and valid therapeutic drug assay. PAA is the most direct way to determine if a patient attained an adequate response to asparaginase therapy and as such, may also serve to assess a drug’s ability to maintain asparagine suppression in plasma.¹⁴ In the COG AALL07P4 study, the majority of patients in each treatment group had PAA of 0.1 IU/mL or greater through 18 days following the induction dose. By 25 days following the induction dose, there was a slight decrease in the proportion of patients with PAA of 0.1 IU/mL or greater for calaspargase pegol ||||||| and a larger decrease for patients in the pegaspargase ||||||| group. The results appear in line with the SAA results in the DFCI 11-001 study, which are supportive of calaspargase pegol’s ability to maintain asparaginase activity above 0.1 IU/mL with a longer half-life compared to pegaspargase.

The effects of calaspargase pegol were similar to pegaspargase for OS, DFS from CR, EFS, CR at the end of induction, MRD at the end of induction, and SAA levels. SAA levels at day 32 during induction suggested that calaspargase pegol likely resulted in a greater proportion of patients with an SAA level of at least 0.10 IU/mL compared to pegaspargase. Overall, there was uncertainty in the effect estimates for which the majority of outcomes suggested little to no difference between treatment groups, based on small sample sizes and few events, and CIs that suggested the possibility of benefit, harm, or both.

The clinical experts consulted by CADTH considered the results for SAA measured during induction to be relevant and indicative of calaspargase pegol’s greater biological stability compared with pegaspargase, calaspargase pegol’s ability to maintain asparagine suppression in plasma, its longer half-life duration compared to pegaspargase, and its ability to be administered with less dosing frequency than pegaspargase (i.e., a schedule of every 3 weeks versus every 2 weeks).

Though the DFCI 11-001 study was not designed to formally assess comparative treatment effects in SAA levels between calaspargase pegol and pegaspargase, the mechanism of action of calaspargase pegol is equivalent to that of pegaspargase, in addition to calaspargase pegol being designed with greater biological stability, which supports the plausibility of the link between the drug and the outcome.

In the DFCI 11-001 study, the results for MRD at the end of induction for 0.01 or greater were supportive of calaspargase pegol resulting in no decline in the percentage of patients who attain an early response compared with pegaspargase. In addition, the results for high end-of-induction MRD (defined as ≥ 0.001 by PCR assay) and low end-of-induction MRD (defined as < 0.001) are included in Table 18 in Appendix 1 as they were not identified by the clinical experts as being 1 of the most important end points. The results of the proportion of patients who attained low end-of-induction MRD further support the findings observed for MRD at the end of induction in the COG AALL07P4 trial that calaspargase pegol does not result in a decline in the proportion of patients who attain an early response compared with pegaspargase. The proportion of participants in the FAS with evaluable MRD was similar between the calaspargase pegol and pegaspargase groups: ||||| |||||| ||||| ||| ||| ||||| |||||| ||||| |||||

The clinical experts consulted by CADTH noted the similarities between calaspargase pegol and pegaspargase in moiety and within the context of COG-based treatment protocols; they did not anticipate a clinically meaningful difference in efficacy outcomes overall between the asparaginase drugs. Given that the body of evidence across the COG AALL07P4 study and the DFCI 11-001 study demonstrated similarities in outcomes between treatment groups, the clinical experts consulted by CADTH agreed that there is potential for a more consistent supply of asparaginase (due to the increased shelf life of calaspargase pegol) and reduced frequency of drug administration, which was identified as important to patients.

It is challenging to adequately interpret the findings considering the differences in patient populations and backbone treatment protocols, where findings presented in the COG AALL07P4 trial and the DFCI 11-001 trial were mainly applicable to patients aged 1 year to 30 years with high-risk B-cell ALL with augmented Berlin-Frankfurt-Münster treatment and to patients aged 1 year to 21 years with ALL with an intermittent asparagine depletion treatment protocol, respectively. Findings from the COG AALL07P4 and DFCI 11-001 trials may be generalized to patients with ALL of all ages, patients with relapsed or refractory ALL, patients with T-cell immunophenotype, and patients with LL based on input from clinical experts consulted by CADTH. However, according to the clinical experts consulted by CADTH for the review, there is uncertainty in whether specific subgroups of patients may derive greater benefit from treatment with calaspargase pegol in the absence of data.

HRQoL was identified as an important outcome by patients and clinical experts consulted by CADTH but was not assessed in the COG AALL07P4 study or the DFCI 11-001 study. Input from patients who experienced a drug shortage at some point during their ALL treatment highlighted poor HRQoL and financial impacts arising from the requirement to pay for alternative therapies and products to help them cope. According to patients, having alternative treatments available to ensure continued treatment was important to patients and their caregivers during an already difficult and challenging time. The clinical experts consulted by CADTH agreed that they did not expect significant differences between calaspargase pegol and pegaspargase in terms of HRQoL outcomes.

Harms

The safety profile of calaspargase pegol and pegaspargase showed similar proportions of patients with TEAEs, SAEs including grade 3 or grade 4 SAEs, and deaths among patients aged 1 year to 30 years with high-risk B-cell ALL in the COG AALL07P4 study and among patients aged 1 year to 21 years with ALL in the DFCI 11-001 study. While the number of patients who stopped study treatment due to an AE was similar between treatment groups in the COG AALL07P4 trial, there was a higher rate of WDAEs in the calaspargase pegol group compared with pegaspargase in the DFCI 11-001 trial (28.0% versus 19.3%). WDAEs were due to higher rates of hypersensitivity, increased amylase, and anaphylactic reactions in the calaspargase pegol group, whereas higher rates of increased lipase and drug hypersensitivity led to withdrawals by patients in the pegaspargase group. AESIs included hypersensitivity reactions, anaphylactic reactions, silent inactivation, pancreatitis, venous thrombosis, hemorrhage, and hepatotoxicity. The frequency of hypersensitivity reactions for calaspargase pegol compared with pegaspargase was lower in the COG AALL07P4 study ||||| |||||| |||||| and similar between groups in the DFCI 11-001 study |||||| |||||| ||||||| Anaphylactic reactions were reported by more patients in the COG AALL07P4 trial (25.6% versus 19.2%) but with equal frequency in the DFCI 11-001 trial (|||| ||| |||| ||||||) in the calaspargase pegol group and the pegaspargase group, respectively. Silent inactivation was not reported by any patient in the COG AALL07P4 study but was reported by 2 patients (1.7%) in the calaspargase pegol group and 0 patient in the pegaspargase group in the DFCI 11-001 study. Pancreatitis was reported by more patients in the COG AALL07P4 study (18.6% versus 7.7%) but by fewer patients in the DFCI 11-001 study (11.9% versus 16.8%) in the calaspargase pegol group and the pegaspargase group, respectively. With respect to thrombosis events, there were higher rates of increased blood bilirubin in both the COG AALL07P4 trial (62.8% versus 50.0%) and the DFCI 11-001 trial (45.8% versus 43.7%), and increased alanine aminotransferase in both the COG AALL07P4 trial (34.9% versus 38.5%) and the DFCI 11-001 trial (78.8% versus 77.3%) in the calaspargase pegol group and the pegaspargase group, respectively. | |||||| ||||||| ||||||||||| ||||||| ||||||| || |||| |||||| || ||| |||||||||||| ||||| |||||||||||.

The draft product monograph for calaspargase pegol included serious warnings and precautions for hypersensitivity, pancreatitis, thrombosis, hemorrhage, and hepatotoxicity;³⁶ these were therefore included as AESIs in the review. No patient experienced venous thrombosis in the COG AALL07P4 trial or hemorrhage in the COG AALL07P4 trial or the DFCI 11-001 trial.

Patients expressed side effects as 1 of the factors that was important to them when evaluating new treatments for ALL. Overall, there were small sample sizes of enrolled patients in the COG AALL07P4 and DFCI 11-001 studies with similar rates of TEAEs overall and differing rates of notable harms between groups and across studies. The clinical experts consulted by CADTH noted that since asparaginase is given as part of an MAC protocol, it is challenging to attribute differences in AEs observed in small numbers of patients to a single treatment protocol component. The clinical experts consulted by CADTH acknowledged that several AEs captured by the COG AALL07P4 and DFCI 11-001 studies were not specific to asparaginase and may be attributed to an intensive (versus intermittent) treatment strategy (e.g., hypoalbuminemia), a specific MAC component (e.g., stomatitis may be attributed to anthracycline treatment), or to the disease itself (e.g., febrile neutropenia is commonly experienced by patients with ALL). According to the clinical experts consulted by CADTH, hyperglycemia during induction and late hyperbilirubinemia were the only AEs that occurred at a higher rate with calaspargase pegol; these were AEs that were expected to occur with asparaginase preparations and were considered to be manageable. Overall, the clinical experts consulted by CADTH did not anticipate significant differences in harms between calaspargase pegol and pegaspargase. The FDA assessment report for calaspargase pegol in combination with chemotherapy for ALL did not identify any unexpected or unacceptable safety issues.⁵¹

Conclusion

Evidence from a randomized phase II, open-label trial (the COG AALL07P4 study) in patients aged 1 year to 30 years with high-risk B-cell ALL suggested that calaspargase pegol likely results in little to no difference in DFS rates from the attainment of CR at 4 years (moderate certainty) and may result in an increase in CR at the end of induction (low certainty) compared with pegaspargase. Furthermore, the COG AALL07P4 trial suggested that compared with pegaspargase, calaspargase pegol may result in little to no difference in OS rates at 1 year and 4 years, DFS rates from the attainment of CR at 1 year, EFS rates at 1 year and 4 years, and MRD at the end of induction (low certainty).

Evidence from a randomized phase II, open-label trial (the DFCI 11-001 trial) in patients aged 1 year to 21 years with ALL suggested that calaspargase pegol likely results in a greater proportion of patients with SAA during the induction phase of at least 0.10 IU/mL at day 32 (moderate certainty) when compared with pegaspargase and likely results in little to no difference in OS rates at 1 year, in DFS rates from the attainment of CR at 2 years, EFS rates at 2 years, and CR at the end of induction (moderate certainty) compared with pegaspargase. Furthermore, the DFCI 11-001 study suggested that compared with pegaspargase, calaspargase pegol may result in little to no difference in OS at 2 years, DFS from the attainment of CR at 1 year, EFS at 1 year, and MRD at the end of induction (low certainty).

SAA is an established surrogate measure of asparagine depletion. SAA levels above 0.10 IU/mL have been shown to be associated with complete asparagine depletion and therefore, therapeutic benefit. The clinical experts consulted by CADTH considered the results for SAA measured during induction to be supportive of calaspargase pegol’s greater biological stability compared with pegaspargase, calaspargase pegol’s ability to maintain asparagine suppression in plasma, its longer half-life duration compared to pegaspargase, and its ability to be administered with less dosing frequency than pegaspargase (i.e., a schedule of every 3 weeks versus every 2 weeks).

No unexpected safety signals were identified with treatment of calaspargase pegol in the COG AALL07P4 trial or the DFCI 11-001 trial. The clinical experts consulted by CADTH noted that asparaginase is given as part of an MAC protocol and it is challenging to attribute differences in AEs observed in small numbers of patients to a single treatment protocol component. The COG AALL07P4 and DFCI 11-001 studies did not report data on HRQoL.

Confidence in the effect estimates from the COG AALL07P4 and DFCI 11-001 studies was limited, primarily due to both studies not being designed to assess comparative efficacy between calaspargase pegol and pegaspargase, relatively small sample sizes, and the open-label design, which may have biased subjective outcomes such as harms.

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Appendix 1: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Figure 10: Treatment Protocol for the COG AALL07P4 Study

Sources: The sponsor’s Summary of Clinical Evidence¹² and Angiolillo et al. (2014).⁴⁰ Reproduced with permission from Wolters Kluwer Health, Inc.: Anne L. Angiolillo, Reuven J. Schore, Meenakshi Devidas, Michael J. Borowitz, Andrew J. Carroll, Julie M. Gastier-Foster, Nyla A. Heerema, Taha Keilani, Ashley R. Lane, Mignon L. Loh, Gregory H. Reaman, Peter C. Adamson, Brent Wood, Charlotte Wood, Hao W. Zheng, Elizabeth A. Raetz, Naomi J. Winick, William L. Carroll, and Stephen P. Hunger. Pharmacokinetic and Pharmacodynamic Properties of Calaspargase Pegol Escherichia coli L-Asparaginase in the Treatment of Patients With Acute Lymphoblastic Leukemia: Results From Children’s Oncology Group Study AALL07P4, Journal of Clinical Oncology, Volume 32, Issue 34, page 3874 to 3882. Available at: https://ascopubs.org/doi/10.1200/JCO.2014.55.5763

Figure 11: Treatment Protocol for the DFCI 11-001 Study

6-MP = 6-mercaptopurine; ALL = acute lymphoblastic leukemia; ASP = asparaginase, calaspargase, or calaspargase pegol; CR = complete remission; DEX = dexamethasone; DFCI = Dana-Farber Cancer Institute; DOX = doxorubicin; HD-MTX = high-dose methotrexate; HR = high risk; IM = intramuscular; IT = intrathecal; IT-M = IT methotrexate; IT-MAH = IT methotrexate/cytarabine/hydrocortisone; MTX = methotrexate; PO = orally; SR = standard risk; VCR = vincristine; VHR = very high risk.

^a Patients with CNS leukemia at diagnosis (CNS-2 and CNS-3) received intrathecal cytarabine 2 times per week until CSF was clear of malignant cells on 3 consecutive examinations.

^b Not administered if high-dose methotrexate started within 72 hours of intrathecal methotrexate given on day 32 of induction.

^c According to random assignment: calaspargase pegol 2,500 IU/m²/dose IV every 3 weeks (10 total doses) or pegaspargase 2,500 IU/m²/dose IV every 2 weeks (15 total doses). Continued at designated interval across treatment phases through consolidation phase II once started (within CNS therapy phase for SR and HR patients, within consolidation IC for VHR patients).

^d IT methotrexate/cytarabine/hydrocortisone administered every 18 weeks in consolidation phase II and continuation phases for those who received previous cranial radiation.

Sources: The sponsor’s Summary of Clinical Evidence¹² and Vrooman et al. (2021).⁴² Reproduced with permission from Wolters Kluwer Health, Inc.: Lynda M. Vrooman, Traci M. Blonquist, Kristen E. Stevenson, Jeffrey G. Supko, Sarah K. Hunt, Sarah M. Cronholm, Victoria Koch, Samantha Kay-Green, Uma H. Athale, Luis A. Clavell, Peter D. Cole, Marian H. Harris, Kara M. Kelly, Caroline Laverdiere, Jean-Marie Leclerc, Bruno Michon, Andrew E. Place, Marshall A. Schorin, Jennifer J. G. Welch, Donna S. Neuberg, Stephen E. Sallan, and Lewis B. Silverman. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001, Journal of Clinical Oncology, Volume 39, Issue 31, page 3496 to 3505. Available at: https://ascopubs.org/doi/full/10.1200/JCO.20.03692

Prior Therapy for Determining Patient Eligibility and Risk Stratification

In the COG AALL07P4 study, prior steroid therapy determined eligibility and risk stratification in the following manner:

For patients receiving steroids within the week preceding diagnosis:

• Patients who had received oral or IV steroids for less than 48 hours during the week immediately before diagnosis were eligible for classification and randomization if the results of a complete blood count (CBC) obtained before the initiation of steroid therapy (≤ 72 hours before steroids) were available, and the necessary fluorescence in situ hybridization, cytogenetic, and molecular test results were interpretable. The presteroid CBC and age of the patient were used to determine National Cancer Institute-Rome risk classification (standard-risk versus high-risk ALL).

• If a patient had received oral or IV steroids for 48 hours or more during the week immediately before diagnosis (and the results of a presteroid CBC were available to assign National Cancer Institute risk group), the patient was treated as a slow early responder and was nonrandomly assigned to the augmented regimen (early response as judged by day 8 or day 15 marrow may be influenced by the steroid pre-treatment).

• In the absence of a presteroid CBC, patients who had received less than 48 hours of steroids were assigned to the high-risk protocol because the presenting WBC count may have been influenced by steroid pretreatment. These patients were eligible for randomization in the high-risk study. As expected, patients with a slow early response were assigned to the full augmented BFM treatment group.

• In the absence of a presteroid CBC, patients who had received more than 48 hours of steroids were treated as a slow early responder on the high-risk study and were assigned to the full augmented group.

• Inhalational steroids were not considered pre-treatment.

• Patients receiving steroids within 1 month of diagnosis (e.g., week –4 to week –1):

• Patients who received less than 48 hours of steroids did not have their risk assignment changed.

• Patients who received more than 48 hours of steroids in week –4 to week –1 were assigned to the high-risk protocol and were eligible for randomization.

Table 17: Summary of Key Efficacy Results From the Studies Included in the Systematic Review

ALL = acute lymphoblastic leukemia; CI = confidence interval; COG = Children’s Oncology Group; CR = complete remission; DCO = data cut-off; DFCI = Dana-Farber Cancer Institute; DFS = disease-free survival; EFS = event-free survival; HR = hazard ratio; ITT = intention-to-treat; MRD = minimal residual disease; OR = odds ratio; OS = overall survival; PKAS = pharmacokinetic analysis set.