Reimbursement Review

Acalabrutinib (Calquence)

Sponsor: AstraZeneca Canada Inc.

Therapeutic area: Previously untreated chronic lymphocytic leukemia

What Is Chronic Lymphocytic Leukemia?

• Chronic lymphocytic leukemia (CLL) is a slow-growing, long-lasting, and incurable blood cancer. It happens when the body makes too many abnormal B cells, which build up in the blood, bone marrow, lymph nodes, and spleen. In the patient input received, patients identified emotional distress, loss of independence, disruption to work and family life, and a decline in quality of life as key negative impacts of CLL.

• In Canada, CLL is the most common type of leukemia in adults, making up about 44% of all leukemia cases. In 2019, around 1,700 people were diagnosed with CLL, and in 2022, 555 people living in Canada died from the disease.

What Are the Treatment Goals and Current Treatment Options for CLL?

• The treatment goals for CLL include delaying disease progression, controlling the disease, improving quality of life, and reducing side effects and hospital visits. Patients with CLL emphasized the need for more effective, easy to take treatments — like pills instead of infusions and shorter treatment periods — that reduce hospital visits and help them stay independent.

• The patient group input identified the following outcomes as important: delaying the disease from getting worse, living longer, managing disease symptoms, experiencing fewer side effects, experiencing improved quality of life, and having a choice of treatment. Other important outcomes identified through clinician input included easing symptoms, improving blood counts, and helping patients return to normal daily activities.

• The current treatment options for previously untreated CLL include Bruton tyrosine kinase (BTK) inhibitors (like ibrutinib, acalabrutinib, and zanubrutinib); a fixed-duration treatment with venetoclax-obinutuzumab or with ibrutinib-venetoclax; and chemotherapy combined with immunotherapy (like fludarabine-cyclophosphamide-rituximab [FCR]) in some patients who are younger and have good performance status.

What Are Calquence and Venclexta and Why Did Canada’s Drug Agency Conduct This Review?

• Calquence is a drug that is available as an oral tablet. Health Canada has approved Calquence, in combination with Venclexta, for the treatment of patients with previously untreated CLL.

• Canada’s Drug Agency (CDA-AMC) reviewed Calquence, in combination with Venclexta, to inform a recommendation to the participating public drug programs on whether it should be reimbursed for the treatment of patients with previously untreated CLL.

How Did CDA-AMC Evaluate Calquence and Venclexta?

• CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects, as well as the economic evidence, of Calquence plus Venclexta versus other treatments used in Canada for previously untreated CLL. BTK inhibitors (ibrutinib, zanubrutinib, acalabrutinib), ibrutinib-venetoclax, venetoclax-obinutuzumab, and chemoimmunotherapy were considered as relevant treatments to compare with Calquence plus Venclexta when reviewing the clinical evidence.

• CDA-AMC identified equity and ethical considerations relevant to Calquence plus Venclexta and previously untreated CLL.

• The review was informed by materials submitted by the sponsor, which included clinical and economic evidence.

• The review was also informed by 1 patient group submission and 3 clinician group submissions in response to the CDA-AMC call for input and by input from the participating public drug programs around issues that may impact their ability to implement a recommendation.

• Two hematologists with expertise in the diagnosis and management of CLL with representation from Ontario and British Columbia were consulted as part of the review process.

What Were the Findings?

Clinical Evidence

• CDA-AMC reviewed the following clinical evidence:

  • One randomized, multicentre, open-label, phase III study (AMPLIFY) evaluating the efficacy and safety of Calquence in combination with Venclexta compared to chemoimmunotherapy (FCR or bendamustine-rituximab [BR]) in 581 patients with previously untreated CLL.

• For the comparison of Calquence plus Venclexta versus FCR or BR:

  • Calquence plus Venclexta likely results in an increase in the probability of being alive and progression-free at 48 months compared with FCR or BR. The certainty of the evidence is moderate, due to imprecision.

  • Calquence plus Venclexta may result in an increase in the probability of remaining in response at 48 months when compared with FCR or BR. The certainty of the evidence is low, due to imprecision and indirectness.

  • Calquence plus Venclexta likely results in an increase in the probability of not receiving subsequent anti-CLL therapy at 48 months when compared with FCR or BR. The certainty of the evidence is moderate, due to indirectness.

  • Calquence plus Venclexta may result in an increase in the overall survival probability at 48 months when compared with FCR or BR. The certainty of the evidence is moderate, due to risk of bias and indirectness.

  • Calquence plus Venclexta may result in little to no difference in health-related quality of life up to 6 months when compared with FCR or BR. However, the certainty of evidence is very low (due to risk of bias and imprecision) about the effect of Calquence plus Venclexta on health-related quality of life at 1-year and 2-years posttreatment when compared with FCR plus BR.

  • Calquence plus Venclexta may result in a decrease in the proportion of patients with serious adverse events when compared with FCR plus BR. The certainty of the evidence is moderate, due to imprecision.

• There was no evidence to inform how Calquence plus Venclexta compares with nonchemoimmunotherapy drugs, including BTK inhibitors (ibrutinib, zanubrutinib, or acalabrutinib monotherapy), ibrutinib-venetoclax, or venetoclax-obinutuzumab.

Economic Evidence

• Calquence is available as oral tablets (100 mg). At the submitted price of $142.77 per tablet, the cost of Calquence per 28-day cycle is expected to be $7,995 per patient, based on the Health Canada–recommended dosage. In combination with Venclexta, the cost per 28-day cycle is expected to be $9,829 on cycle 3 and $15,925 on subsequent cycles for a total of 14 cycles.

• Clinical efficacy in the economic analysis for Calquence plus Venclexta versus FCR or BR was derived from the AMPLIFY trial. Evidence submitted by the sponsor indicates that Calquence plus Venclexta likely results in an improvement in the probability of being progression-free at 48 months compared with FCR or BR, with a moderate level of certainty, among patients with previously untreated CLL. Calquence plus Venclexta may result in an increase in the probability of remaining in response and an increase in overall survival at 48 months compared with FCR or BR, with low certainty. The impact of Calquence plus Venclexta on health-related quality of life was very uncertain due to missing data, imprecision in the effect estimates, and the open-label design of the AMPLIFY study. The generalizability of the AMPLIFY trial is limited by the inclusion of a relatively young trial population, considered lower risk, and by the choice of a comparator that does not adequately reflect current clinical practice.

• No indirect treatment comparison was submitted by the sponsor for this review because of the lack of feasibility of conducting a robust comparison. As a result, there is currently no direct or indirect evidence to assess the relative efficacy and safety of Calquence plus Venclexta against nonchemoimmunotherapy comparators (i.e., ibrutinib-venetoclax; venetoclax-obinutuzumab; and acalabrutinib, ibrutinib, and zanubrutinib monotherapy). The sponsor therefore assumed equal clinical efficacy for Calquence plus Venclexta compared to ibrutinib-venetoclax, venetoclax-obinutuzumab, or BTK inhibitor monotherapy (i.e., acalabrutinib, ibrutinib, or zanubrutinib).

• CDA-AMC estimates that the budget impact of reimbursing Calquence plus Venclexta for the treatment of previously untreated CLL will be approximately $29.4 million over the first 3 years of reimbursement compared to the amount currently spent on comparators. The expenditure on Calquence over this period is predicted to be $86.6 million (Calquence plus Venclexta = $155.0 million). The actual budget impact of reimbursing Calquence plus Venclexta will depend on the uptake of Calquence plus Venclexta and the time to treatment discontinuation of BTK inhibitor monotherapies.

• Based on the evidence reviewed in this review, there is no robust evidence to suggest that Calquence plus Venclexta provides a greater health benefit than any of the comparators apart from FCR or BR. However, based on clinical expert feedback and data presented by the sponsor, the use of FCR or BR for this indication is anticipated to be small (around 1% of patients) and is unlikely to be impacted should Calquence plus Venclexta become available. Therefore, FCR or BR may not be considered a relevant comparator, and the cost-effectiveness versus this comparator is likely not relevant for decision-makers. If it is anticipated that there are no differences in health outcomes between Calquence plus Venclexta versus ibrutinib-venetoclax, venetoclax-obinutuzumab, or BTK inhibitor monotherapies, then the cost of Calquence plus Venclexta should not exceed that of comparators for the treatment of adult patients with previously untreated CLL.

Background

Introduction

The objectives of this report are as follows:

• Review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of acalabrutinib at a dose of 100 mg in combination with venetoclax in the treatment of previously untreated chronic lymphocytic leukemia (CLL). The focus will be placed on comparing acalabrutinib-venetoclax to relevant comparators in clinical practice in Canada — including Bruton tyrosine kinase (BTK) inhibitors (acalabrutinib, ibrutinib, and zanubrutinib); ibrutinib-venetoclax; venetoclax-obinutuzumab; bendamustine-rituximab (BR); and fludarabine-cyclophosphamide-rituximab (FCR) — and identifying gaps in the current evidence, which are detailed in Table 1.

• Review and critically appraise the economic information submitted by the sponsor, including a cost-effectiveness analysis and a budget impact analysis. The focus of the economic review is aligned with the scope of the Clinical Review, unless otherwise stated. For most reviews, a Canada’s Drug Agency (CDA-AMC) base case is developed, informed by clinical expert input, available clinical evidence, and the best interpretation of the economic evidence based on the information provided by the sponsor.

Table 1: Information on the Application Submitted for Review and on the CDA-AMC Review

AE = adverse event; BTK = Bruton tyrosine kinase; CDA-AMC = Canada’s Drug Agency; CLL = chronic lymphocytic leukemia; DOR = duration of response; EFS = event-free survival; HRQoL = health-related quality of life; MRD = minimal residual disease; NOC = Notice of Compliance; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; SAE = serious adverse event; TTNT = time to next treatment.

Submission History for the Drug Under Review

CDA-AMC previously reviewed acalabrutinib through the reimbursement review process as monotherapy for previously untreated CLL for which a fludarabine-based regimen is inappropriate and issued recommendations to reimburse with clinical criteria and/or conditions. Additionally, CDA-AMC previously reviewed acalabrutinib for the treatment of patients with relapsed or refractory CLL who have received at least 1 prior therapy and issued recommendations to reimburse with clinical criteria and/or conditions. Acalabrutinib-bendamustine-rituximab was recently reviewed by CDA-AMC for previously untreated mantle cell lymphoma and received a final positive recommendation with conditions.

Sources of Information

The contents of the Reimbursement Review report are informed by materials submitted by the sponsor, input received from interested parties (patient groups, clinician groups, and drug programs), and input from the clinical experts consulted for this review. Calls for patient group and clinician group input are issued for each Reimbursement Review. One patient group submission from Lymphoma Canada and 3 clinician group submissions from the Leukemia & Lymphoma Society of Canada Nurse Practitioners Network (LLSC NPN), Lymphoma Canada, and the Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee (OH [CCO] HCDAC) were received. Information for the Lymphoma Canada patient group submission was gathered through an online survey of 261 patients with CLL, conducted between May 30, 2025, and July 5, 2025. The survey included responses from 9 patients who had been treated with a combination of acalabrutinib-venetoclax. Input from the LLSC NPN was provided by 2 clinicians, and input from Lymphoma Canada was provided by 6 clinicians. Information for the OH (CCO) HCDAC was gathered by email and included input from 2 clinicians. The full submissions received are available on the project landing page in the consolidated input document. The drug programs provide input on each drug being reviewed through the reimbursement review process by identifying issues that may impact their ability to implement a recommendation. Input from patient and clinician groups is considered throughout the review, including in the selection of outcomes to include in the Clinical Review and in the interpretation of the clinical and economic evidence. Relevant patient and clinician group input is summarized in the Disease Background, Current Management, and Unmet Needs and Existing Challenges sections. Each review team includes at least 1 clinical expert with expertise in 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. Two clinical experts with expertise in the diagnosis and management of CLL participated as part of the review team, with representation from Ontario and British Columbia.

Disease Background

CLL is a slowly progressing, chronic, and incurable B-cell malignancy. It is classified as a lymphoid neoplasm and is characterized by the abnormal clonal proliferation and progressive accumulation of mature, functionally impaired, CD5-positive B lymphocytes in the blood, bone marrow, lymph nodes, and spleen.¹ The pathologic and immunophenotypic features of the malignant cells are identical in CLL and small lymphocytic lymphoma (SLL). If the disease primarily presents in the blood, then the term CLL is used. If the disease primarily involves the lymph nodes, then the term SLL is used. According to the CLL Society, more than 90% of patients are classified as having CLL rather than SLL at diagnosis; most individuals initially diagnosed with SLL eventually progress to CLL.² CLL often presents insidiously, with more than 80% of patients diagnosed at an asymptomatic, early stage.^3,4 As the disease progresses, the most common features include generalized lymphadenopathy, fatigue, fever, recurrent disease-related infections, anemia, and weight loss.^1,5 A diagnosis of CLL is based on the criteria established by the International Workshop on CLL.^6,7 To distinguish a diagnosis of CLL from other lymphoproliferative disease, a blood smear or lymph node biopsy, immunophenotype, and sometimes the genetics of a patient’s circulating lymphoid cells must be evaluated.^6,7

In Canada, CLL is the most common adult leukemia, accounting for approximately 44.1% of all leukemia cases.⁸ In 2019, an estimated 1,700 new cases of CLL were reported in Canada (1,095 males and 605 females), and in 2022, 555 people living in Canada died from the disease (358 males and 197 females).^9-12 The disease predominantly affects males and older adults, with a median age at diagnosis between 66 and 70 years.^9,10,13,14 CLL is considered an incurable disease, with an estimated 5-year net survival rate of approximately 83%.¹² Patients with CLL who have high-risk features such as unmutated IGHV, complex karyotype (i.e., > 3 cytogenetic aberrations), or very high-risk abnormalities including 17p deletion and TP53 mutations, tend to have poor outcomes.^14-18 The Rai and Binet systems both stage CLL by disease severity, with advanced stages marked by anemia and/or thrombocytopenia.⁵

According to the Lymphoma Canada patient group, patients with CLL commonly experience fatigue, anxiety, frequent infections, and limitations in daily activities, which substantially affect their quality of life and overall well-being. These challenges often extend to family members, contributing to emotional and financial burden.

Current Management

Treatment Goals

Patient input: Based on input from the Lymphoma Canada patient group, patients with CLL identified key treatment goals as prolonged remission, improved disease and symptom control, prolongation of survival, improved quality of life, and minimization of treatment-related side effects. The patients emphasized the need for additional effective treatment options that offer greater choice. They emphasized a preference for convenient routes of administration, such as oral tablets instead of infusions, and fixed treatment durations rather than continuous therapy. Such treatment options would reduce the need for hospital visits while promoting daily functioning and enhancing independence.

Clinical experts consulted for this review: Key treatment goals identified by the clinical experts include achieving sustained remission; minimizing treatment-related toxicities, including cumulative cardiac complications; and decreasing the frequency of visits to cancer centres.

Clinician group input: Additional treatment goals noted by the clinician groups (OH [CCO] HCDAC, LLSC NPN, and Lymphoma Canada) include delaying disease progression, improving quality of life, supporting patient independence and minimizing caregiver burden, and reducing the need for frequent clinic visits or intensive monitoring — particularly for older adults with comorbidities and age-related functional limitations.

Current Treatment Options

Several molecular and cytogenetic abnormalities serve as key prognostic factors in CLL, helping guide treatment decisions.¹⁹ The updated 2022 guidelines for clinical practice in Canada,³ along with guidelines from the European Society for Medical Oncology²⁰ and the Cancer Care Alberta clinical practice guidelines²¹ for the frontline treatment of CLL recommend active surveillance for asymptomatic early-stage CLL, as early treatment does not confer a survival benefit. According to available guidelines,^3,21,22 in symptomatic, young patients without TP53 aberrations and good performance status, FCR is preferred for IGHV-mutated CLL. For unmutated IGHV, BTK inhibitors are preferred over FCR. In older patients without 17p deletion and/or TP53 mutations and fewer comorbidities, continuous BTK inhibitor therapy (e.g., ibrutinib, acalabrutinib) is recommended,^3,20,21 while venetoclax-obinutuzumab offers a fixed-duration treatment alternative. Another fixed-duration treatment option currently available in Canada is the combination of ibrutinib-venetoclax for patients with previously untreated CLL, which is the only currently reimbursed all-oral targeted regimen with a fixed duration. Zanubrutinib, a second-generation BTK inhibitor, is funded in select jurisdictions for patients with mutated IGHV who are not candidates for FCR.²³ Of note, the 2018 evidence-based guideline from Canada²⁴ recommended BR in preference to FCR for patients aged 65 years and older with previously untreated CLL who are better able to tolerate treatment and who do not have 17p deletion or TP53 aberrations, due to there being fewer toxicity concerns. For patients who were symptomatic with previously untreated CLL and 17p deletion and/or TP53 mutation, the guidelines^3,20,21 recommend continuous therapy with a BTK inhibitor such as ibrutinib or acalabrutinib.

According to the clinical experts consulted by CDA-AMC for this review, current first-line treatment options for CLL include BTK inhibitors and fixed-duration regimens, such as venetoclax-obinutuzumab, and ibrutinib-venetoclax, while chemoimmunotherapy (FCR) is rarely used in younger patients with favourable cytogenetic features (e.g., 13q deletion). Historically used lower-intensity regimens, such as chlorambucil or bendamustine-based combinations, have now been largely replaced. The clinical experts noted that for patients with unmutated IGHV, venetocla-obinutuzumab, ibrutinib-venetoclax, and BTK inhibitor monotherapy are preferred over FCR. According to the clinical experts, in older patients without 17p deletion and/or TP53 mutations who are better able to tolerate treatment, continuous therapy with a second-generation BTK inhibitor (e.g., acalabrutinib, zanubrutinib) may be recommended, while venetoclax-obinutuzumab or ibrutinib-venetoclax offer fixed-duration treatment alternatives. The clinical experts indicated that for patients with 17p deletion or TP53 mutation, available treatment options include second-generation BTK inhibitor monotherapy (e.g., acalabrutinib, zanubrutinib), ibrutinib-venetoclax, or venetoclax-obinutuzumab. The clinical experts noted that first-generation BTK inhibitors like ibrutinib are now being replaced by second-generation regimens (e.g., zanubrutinib, acalabrutinib) with improved cardiac safety.

The key characteristics of acalabrutinib-venetoclax are summarized with other treatments available for previously untreated CLL in Table 1 Key Characteristics in Appendix 1 in the Supplemental Material.

Unmet Needs and Existing Challenges

Patient input: The Lymphoma Canada patient group indicated that despite the availability of effective therapies, patients highlighted ongoing unmet needs, including the burden of long treatment durations, treatment-related toxicities, and logistical challenges such as travel and associated costs. There remains a strong preference for more convenient, better-tolerated treatment options that minimize disruption to everyday life. Patients with CLL often face persistent fatigue, anxiety, and stress, which can limit daily activities such as work, travel, and social engagement. Caregivers and families may also experience emotional stress and financial pressure due to reduced patient income and travel requirements.

Clinical experts consulted for this review: The clinical experts emphasized the need for therapies that can achieve sustained remissions, particularly in patients with high-risk genetic features such as TP53 mutations or deletions and unmutated IGHV. The clinical experts highlighted the importance of safer treatment options with lower toxicity profiles, especially for older adults who are at increased risk of cardiac complications, such as atrial fibrillation and hypertension, associated with continuous BTK inhibitor therapy. The clinical experts further indicated that an all-oral, fixed-duration regimen reduces the need for frequent visits to cancer centres and offers the convenience and benefits of time-limited therapy — an approach often preferred by patients. The clinical experts noted that frequent visits to cancer centres can impose a substantial treatment burden and that reducing visit frequency may enhance the overall patient experience and improve adherence to therapy.

The clinical experts noted that CLL predominantly affects older adults, who are at greater risk of treatment-related complications and may face substantial barriers to accessing care due to mobility limitations, comorbidities, and transportation challenges. For example, the intensive monitoring required during venetoclax initiation may limit its accessibility for patients living outside major cancer centres. Initiation of venetoclax requires monitoring for tumour lysis syndrome (TLS), particularly in patients who are considered to be at high risk. However, most can safely undergo a 5-week ramp-up phase in an outpatient setting. Inpatient administration may be necessary for individuals with elevated risks or complications needing closer monitoring.

Clinician group input: According to the clinicians from OH (CCO) HCDAC, LLSC NPN, and Lymphoma Canada, several persistent challenges in CLL care were identified by clinicians, including treatment-related disruption to work and daily activities, the cumulative toxicity of long-term regimens, limited options for older adults and patients with comorbidities, and uncertainty surrounding treatment sequencing and resistance. The clinicians identified a need for a safer, fixed-duration, all oral regimen that offers prolonged remission, reduces the cardiac risks associated with ibrutinib, eliminates the need for IV infusions, supports better adherence, and lowers the risk of treatment discontinuation due to adverse events (AEs).

Considerations for Using the Drug Under Review

The contents within this section have been informed by input from the clinical experts consulted for the purpose of this review and from clinician groups, as well as the reimbursement conditions proposed by the sponsor (refer to Table 2 Initiation, Renewal, Discontinuation, and Prescribing Conditions Proposed by the Sponsor in Appendix 1 in the Supplemental Material). The implementation questions from the public drug programs and the corresponding responses from the clinical experts consulted for this review are summarized in Table 3 Summary of Drug Program Input and Clinical Expert Responses in Appendix 1 in the Supplemental Material. The following has been summarized by the review team.

Place in Therapy

Clinical experts consulted for this review: The clinical experts indicated that the combination of acalabrutinib-venetoclax is an effective treatment for patients newly diagnosed with CLL. The clinical experts noted that acalabrutinib-venetoclax could serve as a viable alternative to ibrutinib-venetoclax in clinical practice in Canada. The clinical experts further noted that while continuous BTK inhibitor therapy can lead to durable remissions in patients with high-risk CLL, it requires indefinite administration and is associated with cumulative toxicities, including cardiac events, bleeding, and secondary malignancies, and with development of resistance. In contrast, fixed-duration regimens offer defined treatment periods and allow for treatment-free intervals, although they may be associated with shorter remission durations. The clinical experts noted that, given most patients’ preference for time-limited therapy, the acalabrutinib-venetoclax combination provides a promising option that may achieve durable remissions while lowering the risk of drug resistance and cumulative toxicity associated with continuous BTK inhibitor use.

Clinician group input: The clinicians from OH (CCO) HCDAC, LLSC NPN, and Lymphoma Canada generally agreed with the clinical experts consulted for this review. The clinicians consider acalabrutinib-venetoclax appropriate for both younger patients with CLL who have good performance status and older adults with comorbidities, particularly those at higher risk of cardiac events or with high-risk genetic features. The clinicians noted that the time-limited approach of acalabrutinib-venetoclax improves tolerability and adherence and reduces treatment burden.

Patient Population

Clinical experts consulted for this review: The clinical experts indicated that the combination of acalabrutinib-venetoclax may offer meaningful value to a broad population of patients with newly diagnosed CLL, particularly those at risk of substantial cardiac toxicities. The clinical experts emphasized that the patients most likely to benefit include those for whom cumulative cardiac toxicity is a concern — especially older individuals with a higher burden of comorbidities, such as pre-existing hypertension or cardiac arrhythmias, or those receiving anticoagulation therapy. However, the clinical experts noted that the real-world tolerability of this combination in older populations with more comorbidities remains uncertain.

Regarding the initiation conditions proposed by the sponsor, the clinical experts indicated they are standard and reasonable.

Clinician group input: The clinicians from OH (CCO) HCDAC, LLSC NPN, and Lymphoma Canada noted that acalabrutinib-venetoclax is best suited for patients with newly diagnosed CLL who require treatment, including those with symptomatic or progressive disease, high-risk cytogenetic features, or a preference for a fixed-duration regimen aimed at achieving deep remission. The clinical groups indicated that the patients least suitable for this combination include patients with substantial comorbidities that contraindicate the use of BTK inhibitors or B-cell lymphoma-2 antagonists, such as patients with severe cardiac conditions, substantial bleeding risk or disorders, or substantial drug-drug interactions. The clinicians further noted that patients with impaired renal function or high risk for TLS require careful assessment before initiating therapy. The clinicians indicated that this combination is most likely to benefit patients with favourable or intermediate cytogenetics who have not yet been treated for CLL and offers a well-tolerated alternative to continuous BTK inhibitor monotherapy, with fewer cardiac events and no reported cases of sudden cardiac death.

Assessing the Response to Treatment

Clinical experts consulted for this review: The clinical experts indicated that treatment response in CLL is primarily assessed through routine blood tests, physical examination, and symptom resolution, with imaging used selectively for nodal assessment. Monitoring typically occurs every 2 to 3 months, with more frequent assessments early in treatment, especially when tumour lysis risk is a concern. The clinical experts noted that a clinically meaningful response is generally defined by symptom improvement and stable or improved blood counts in patients who were asymptomatic.

Clinician group input: Clinicians from OH (CCO) HCDAC, LLSC NPN, and Lymphoma Canada generally agreed with the clinical experts consulted for this review. The clinicians further emphasized the importance of achieving deep remission, enhancing quality of life, and supporting functional recovery, which in some cases is confirmed by the absence of detectable disease through flow cytometry or imaging. The clinicians noted that while trial end points such as progression-free survival (PFS) and overall response rate are relevant, greater emphasis is placed in routine practice on symptom improvement and functional recovery — outcomes that are highly valued by patients.

Discontinuing Treatment

Clinical experts consulted for this review: The clinical experts indicated that treatment should be discontinued upon completion of the planned fixed-duration regimen, in the event of disease progression, or if unacceptable toxicity occurs.

The clinical experts agreed with the discontinuation conditions proposed by the sponsor.

Clinician group input: Additional discontinuation criteria identified by clinician groups (OH [CCO] HCDAC, LLSC NPN, and Lymphoma Canada) included the development of new medical conditions or changes in the patient’s overall health status that would substantially increase the risks of continuing therapy, such as major organ dysfunction or the emergence of contraindications to BTK or B-cell lymphoma-2 inhibitors.

Prescribing Considerations

Clinical experts consulted for this review: The clinical experts indicated that acalabrutinib-venetoclax should be prescribed and managed by hematologists or oncologists experienced in treating CLL. The clinical experts further noted that venetoclax initiation requires specialist supervision to ensure close monitoring for TLS and timely access to appropriate laboratory and supportive care resources, especially in patients at high risk for TLS, with high lymphocyte counts, or impaired renal function. According to the clinical experts, most patients are suitable for the 5-week venetoclax ramp-up on an outpatient basis, while inpatient administration may be considered for patients at high risk of TLS or other complications requiring closer monitoring.

The clinical experts agreed with the prescribing conditions proposed by the sponsor.

Clinician group input: Clinicians from OH (CCO) HCDAC, LLSC NPN, and Lymphoma Canada generally agreed with the clinical experts consulted for this review.

Clinical Review

Methods

The review team considered studies in the sponsor’s systematic review (pivotal studies and randomized controlled trials) and an indirect treatment feasibility assessment report. The sponsor did not submit long-term extensions, indirect treatment comparisons (ITCs), or studies addressing gaps in the evidence for inclusion in this review. Eligible studies for the systematic review included published and unpublished pivotal studies and phase III and IV randomized controlled trials. Relevant patients and interventions were defined by the reimbursement request and the recommended dosage in the product monograph. Relevant comparators were drugs used in clinical practice in Canada to treat patients described in the indication under review, including those considered relevant in the economic review. These included BTK inhibitors (acalabrutinib, ibrutinib, zanubrutinib), ibrutinib-venetoclax, venetoclax-obinutuzumab, FCR, and BR. The following subgroups were considered potentially important for informing the reimbursement recommendation: patients aged older than 65 years versus those aged 65 years or younger, patients with mutated versus unmutated IGHV, patients with high-risk Rai stage disease (stage III or higher) versus non–high-risk disease (stage 0 to II), patients with an Eastern Cooperative Oncology Group Performance Status of 2 versus 1 and below, and patients with complex karyotype versus without.

The review team selected outcomes (and follow-up times) for review based on the sponsor’s summary of clinical evidence, clinical expert input, and patient and clinician group input. The included outcomes are those considered relevant to expert committee deliberations, and they were selected in consultation with committee members. Evidence from the systematic review for the most important outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach:

• PFS by blinded independent review committee (IRC) at 48 months

• time to next treatment (TTNT) at 48 months

• duration of response at 48 months

• overall survival (OS) at 48 months

• change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) score at 6 months, 1-year, and 2-years posttreatment

• serious AEs.

PFS, TTNT, OS, duration of response, and EORTC QLQ-C30 were selected because they address the main treatment goals for the disease (prolonging life, achieving longer disease remission, controlling disease symptoms, and improving quality of life).

A description of the methods used for data extraction, risk of bias appraisal, and certainty of evidence assessment is available in Appendix 2 in the Supplemental Material.

Clinical Evidence

In this report, the following source of evidence submitted by the sponsor was reviewed and appraised:

• 1 pivotal study included in the systematic review, the AMPLIFY study.

Systematic Review

Description of Studies

Study Characteristics

The characteristics of the included study are summarized in Table 2. Details pertaining to the eligibility criteria, interventions and comparators, and relevant outcome measures are in Appendix 3 in the Supplemental Material.

The AMPLIFY study is an ongoing, randomized, multicentre, open-label, phase III study evaluating the efficacy and safety of acalabrutinib-venetoclax, with and without obinutuzumab, compared to chemoimmunotherapy (FCR or BR) in patients with previously untreated CLL without 17p deletion or TP53 mutation. Patients were randomized in a 1:1:1 ratio using block stratified randomization into 1 of 3 treatment groups: arm A, acalabrutinib-venetoclax (N = 291); arm B, acalabrutinib-venetoclax-obinutuzumab (N = 286); or arm C, chemoimmunotherapy (FCR or BR) (N = 290). This report presents evidence comparing the all‑oral combination of acalabrutinib-venetoclax to chemoimmunotherapy. The results for arm B (acalabrutinib-venetoclax-obinutuzumab) were not presented or assessed by the CDA-AMC review team because the sponsor’s reimbursement request was limited to the combination of acalabrutinib-venetoclax. Randomization was stratified by age (older than 65 years or 65 years or younger), IGHV mutational status, Rai stage (stage III or higher versus less than stage III), and geographic region (North America, Europe, or other). Patients were enrolled globally across 133 study sites in 27 countries in North America (including 8 sites in Canada), Europe, Asia-Pacific, and South America.

Acalabrutinib 100 mg was administered orally at a fixed dose of 100 mg twice daily starting in cycle 1 (28-day cycles) and continued for 14 cycles (392 days). Venetoclax oral dosing was initiated in cycle 3 (28-day cycles) using a 5-week dose-titration schedule, starting at 20 mg once daily and escalating weekly to a final dose of 400 mg once daily by cycle 4, day 8, continuing through to cycle 14. FCR or BR were administered intravenously from cycle 1 to cycle 6 (168 days) according to standard dosing protocols²⁵ (refer to Appendix 3 in the Supplemental Material). Posttreatment follow-up visits were scheduled approximately every 12 weeks for 3 years and then every 24 weeks until disease progression.

Only data from prespecified interim analyses of the AMPLIFY trial were submitted for this Reimbursement Review, with a data cut-off date of April 30, 2024. The median duration of follow-up was 41.3 months (range, 0 to 59 months) in the acalabrutinib-venetoclax group and 38.4 months (range, 0 to 57 months) in the FCR or BR group. The median duration of follow-up after treatment completion was 28.3 months in the acalabrutinib-venetoclax group.

Table 2: Characteristics of the AMPLIFY Study

AE = adverse event; ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate transferase; BR = bendamustine-rituximab; CIRS-G = Cumulative Illness Rating Scale–Geriatric; CLL = chronic lymphocytic leukemia; CNS = central nervous system; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FCR = fludarabine-cyclophosphamide-rituximab; HRQoL = health-related quality of life; IRC = independent review committee; iwCLL = International Workshop on Chronic Lymphocytic Leukemia; MRD = minimal residual disease; OS = overall survival; PFS = progression-free survival; SAE = serious adverse event; TTNT = time to next treatment; ULN = upper limit of normal.

^aIncludes patients from 2 treatment groups: the acalabrutinib-venetoclax group and the FCR or BR group. The third treatment group, consisting of the combination of agents acalabrutinib, venetoclax, and obinutuzumab, was excluded from the table as it falls outside the scope of this review.

^b2018 iwCLL criteria for active disease that requires treatment:

Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia hemoglobin less than 10 g/dL and/or thrombocytopenia (platelets less than 100,000/μL): (massive [i.e., at least 6 cm below the left costal margin], or progressive, or symptomatic splenomegaly; or massive nodes [i.e., at least 10 cm in the longest diameter] or progressive or symptomatic lymphadenopathy).

Progressive lymphocytosis with an increase of at least 50% over a 2-month period or a lymphocyte doubling time of less than 6 months. Lymphocyte doubling time may be obtained by linear regression extrapolation of ALC obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of less than 30 × 10⁹/L (30,000/μL), lymphocyte doubling time should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.

Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids.

Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, spine).

Symptoms documented in the patient’s chart with supportive objective measures, as appropriate, defined as at least 1 of the following disease-related symptoms or signs: unintentional weight loss of at least 10% within the 6 months before screening; significant fatigue (Eastern Cooperative Oncology Group Performance Status 2 or higher; inability to work or perform usual activities); fevers higher than 100.5°F or 38.0°C for at least 2 weeks before screening without evidence of infection; or night sweats for at least 1 month before screening without evidence of infection.

^cMeet the following laboratory parameters:

Adequate bone marrow function independent of growth factor or transfusion support within 1 week of screening, as follows: ANC of at least 750 cells/μL (0.75 × 10⁹/L); ANC of at least 500 cells/μL (0.50 × 10⁹/L) in patients with documented bone marrow involvement of CLL; and platelet count of at least 50,000 cells/μL (50x10⁹/L); platelet count of at least 30,000 cells/μL (30x10⁹/L) in patients with documented bone marrow involvement of CLL.

Serum AST and ALT less than or equal to 2.5 × ULN.

Total bilirubin less than or equal to 2 × ULN, unless directly attributable to Gilbert syndrome.

Estimated creatinine clearance of at least 50 mL/min, calculated using the Cockcroft and Gault equation (if male, [140 – age] × mass [kg] / [72 × creatinine mg/dL]; multiply by 0.85 if female); estimated creatinine clearance of at least 70 mL/min for patients selected by investigator to receive FCR in chemoimmunotherapy arm.

^dDefined by the New York Heart Association Functional Classification at screening.

Source: AMPLIFY Clinical Study Report (interim analysis).²⁶ Details included in the table are from the sponsor’s summary of clinical evidence.

Statistical Testing and Analysis Populations

The sample size of approximately 260 patients per treatment group was calculated to provide around 90% power to detect a hazard ratio (HR) of 0.62²⁷ for PFS at a 2-sided significance level of 0.05, based on 188 events at the time of final analysis. This corresponds to an anticipated 61% improvement in median PFS, from 44.7 months with FCR or BR to 72.1 months with acalabrutinib-venetoclax. The AMPLIFY study was powered at more than 99% to detect a 24% absolute difference in minimal residual disease (MRD) negativity rates between the treatment groups. The study was not powered to detect a statistically significant difference in OS between the treatment groups, given the limited sample size and the low number of OS events observed. One interim and a final analysis were prespecified for the primary end point of IRC-assessed PFS comparing acalabrutinib-venetoclax with FCR or BR.

To control the overall 2-sided type I error at the 0.05 level, a Lan-DeMets alpha-spending function with O’Brien-Fleming boundaries was used to allocate the alpha between the interim and final analyses of IRC-assessed PFS. Alpha-spending between the interim and final analyses for OS was controlled using the Haybittle-Peto approach. The following end points comparing acalabrutinib-venetoclax with FCR or BR were controlled for multiplicity using a fixed sequential hierarchical approach: IRC-assessed PFS (primary end point arm A versus arm C), IRC-assessed PFS (arm B versus arm C), MRD negativity (arm A versus arm C), MRD negativity (arm B versus arm C), OS (arm A versus arm C), and OS (arm B versus arm C). The results of arm B are out of the scope of the sponsor’s reimbursement request and not discussed in this review. All efficacy analyses were conducted using the full analysis set, based on treatment as randomized. All safety analyses were conducted using the safety analysis set, which included all patients who received at least 1 dose of the study drug.

Patient Disposition

Patient disposition for the AMPLIFY study is summarized in Appendix 4 in the Supplemental Material.

Of the 1,141 patients screened, 867 were randomized into 3 treatment groups. Of these, 291 patients were randomized to the acalabrutinib-venetoclax group and 290 were randomized to the FCR or BR group. All patients in the acalabrutinib-venetoclax group received at least 1 dose of the treatment, while 31 patients in the FCR or BR group received no treatment, with 28 (90%) withdrawing consent. Thirty-three patients (11.3%) in the acalabrutinib-venetoclax group and 51 (19.7%) in the FCR or BR group discontinued treatment, primarily due to AEs (7.9% versus 11.6%, respectively), followed by investigator decision (1.0% versus 4.6%, respectively) and patient decision (0.7% versus 1.2%, respectively).

As of the April 30, 2024, data cut-off, 22.7% of patients in the acalabrutinib-venetoclax group and 24.8% of patients in the FCR or BR group had at least 1 major protocol deviation, with deviations generally balanced between groups. The most common protocol deviations were related to eligibility criteria and study procedures (3.4% versus 2.0%, and 3.8% versus 5.9% in the acalabrutinib-venetoclax group versus the FCR or BR group).

Baseline Characteristics

Table 3: Summary of Baseline Characteristics From the AMPLIFY Study: FAS

BR = bendamustine-rituximab; CIRS-G = Cumulative Illness Rating Scale–Geriatric; ECOG = Eastern Cooperative Oncology Group; FAS = full analysis set; FCR = fludarabine-cyclophosphamide-rituximab; SD = standard deviation.

Notes: Data cut-off date: April 30, 2024.

Racial categories used in the table are as reported in the source and may not align with Canada's Drug Agency inclusive language guidelines.

Source: Clinical Study Report for AMPLIFY (interim analysis).²⁶ Details included in the table are from the sponsor’s summary of clinical evidence.

Treatment Exposure and Concomitant Medications

Details of patients’ treatment exposure and use of concomitant medications and subsequent treatments in the AMPLIFY study are in Appendix 4 in the Supplemental Material. As of the April 30, 2024, data cut-off, the median duration of exposure in the acalabrutinib-venetoclax group was 12.9 months (range, 1 month to 18 months) for acalabrutinib and 11.1 months (range, 2 months to 14 months) for venetoclax. In the FCR or BR group, 122 patients (47.1%) received FCR and 137 patients (52.9%) received BR. The median duration of exposure to the individual treatment components (e.g., fludarabine, cyclophosphamide, rituximab, or bendamustine) ranged from 5.5 months to 5.6 months.

Following randomization, the majority of patients in the AMPLIFY study (████%) received at least 1 concomitant medication, including ███ patients (████%) in the acalabrutinib-venetoclax group and ███ patients (████%) in the FCR or BR group. The most common concomitant mediations were ███████████████ ███████████ ███████████████ ███ ████████ ████ ███ ██████████ ███ ████████ ███ (████% versus ████%, ████% versus ████%, ████% versus ████%, and ████% versus ████% in the acalabrutinib-venetoclax and FCR or BR groups, respectively).

As of the April 30, 2024, data cut-off, subsequent anti-CLL therapy was reported for ██ patients (████%) in the acalabrutinib-venetoclax group and ██ patients (████%) in the FCR or BR group. The most common subsequent treatments were ██████████ (████ in both groups), █████████████ (███% versus ███% in the acalabrutinib-venetoclax and FCR or BR groups, respectively), and █████████ (███% versus ███% in the acalabrutinib-venetoclax and FCR or BR groups, respectively).

Critical Appraisal

Internal Validity

Randomization was conducted using an appropriate methodology with adequate allocation concealment, and stratification factors were prespecified, reducing the risk of bias. No clinically important differences in baseline characteristics between groups were observed, which supports the success of randomization and strengthens confidence in the low risk of bias associated with the randomization process. The open-label design may introduce performance and detection biases in PFS, objective response rate, and duration of response assessments; however, this risk of bias was mitigated by blinded IRC disease evaluation. Physicians’ knowledge of their patients’ assigned treatment may have influenced clinical management decisions, and patients’ awareness of their assigned treatment may have affected their willingness to remain in the study. Notably, while all patients randomized to the acalabrutinib-venetoclax group received at least 1 dose of the study treatment, 31 patients in the FCR or BR group did not initiate treatment. The majority of these patients withdrew consent but were still included in the analysis. However, no sensitivity analyses were conducted to assess the potential impact of this differential treatment initiation, which may introduce bias and limit the interpretability and generalizability of the results. The proportion of protocol deviations was comparable between groups and identified before database lock.

Primary and key secondary outcomes were analyzed using the full analysis set population, preserving randomization and minimizing bias by comparing groups with similar prognostic factors. Based on the enrolled sample size, the study was adequately powered (90% statistical power at a 2-sided significance level of 0.05) to detect differences in the primary end point (PFS) and the MRD negativity rate, 1 of the key secondary end points. A hierarchical testing strategy to sequentially test the primary and key secondary outcomes was used to reduce the risk of type I error across these analyses. The subgroup analyses were exploratory and not designed to detect differences between groups. In the AMPLIFY study, no information was available regarding the testing of proportionality assumptions, although such testing was planned as part of the statistical analysis plan. Visual inspection of the Kaplan-Meier (KM) plots for PFS and OS by CDA-AMC showed no obvious violations of the proportional hazards assumption; however, formal statistical testing and sensitivity analyses using alternative methods are recommended to confirm this assumption. The interim analysis was planned a priori. Because the study outcomes are based on interim analyses, there is a risk that the effect of acalabrutinib-venetoclax compared with FCR or BR is overestimated; the existence and extent of any overestimation remains uncertain.^28-30 However, the interim analysis was conducted after 98% of the prespecified PFS events had occurred, nearly reaching the target for the final analysis. Additionally, the observed P value for the between-group comparison in PFS was below the interim analysis boundary, suggesting a low risk of bias from early stopping.

In the PFS analysis, a higher proportion of patients in the FCR or BR group were censored at day 1 (11.4% versus 0.3% in the acalabrutinib-venetoclax group) due to missing baseline or postbaseline response assessments, which may have masked progression events in that group and affected the reliability of between-group comparisons. Most of the censoring reasons were addressed in sensitivity analyses without censoring, and the PFS results remained robust across these analyses. A composite strategy was used for COVID-19–related deaths, treating them as PFS events to avoid informative censoring. However, this may confound PFS interpretation by mixing true progression with unrelated mortality, especially if the death is not cancer related or treatment related. Sensitivity analyses for all identified intercurrent events showed consistent results with the primary PFS findings. PFS is a well-established end point in oncology trials and is considered by the FDA and other regulators as a potential surrogate for accelerated drug approval. The AMPLIFY trial did not demonstrate that benefits in PFS translate into OS benefits, and the correlation between PFS and OS remains uncertain due to the lack of long-term data.^31,32 The correlation between PFS and OS in first-line CLL trials was evaluated using source data from 12 front-line trials conducted by the German CLL Study Group.³² While a patient-level correlation was confirmed in the context of targeted therapies, the correlation of treatment effects between PFS and OS remains uncertain.³²

The OS data were informed by a small information fraction (10%) at the time of the interim analysis, and the reported median OS for the acalabrutinib-venetoclax group is considered unstable due to the low number of events and patients at risk, which limits the accuracy, precision, and reliability of the estimate. Higher rates of early study discontinuation were observed in the FCR or BR group (12.8% versus 1.4% in the acalabrutinib-venetoclax group), which could underestimate survival events in this group, potentially overstating the relative benefit of acalabrutinib-venetoclax. A treatment policy strategy was applied in cases of treatment discontinuation, whereby all observed data — including data collected after discontinuation — were included in the analysis. However, this approach may introduce bias as the treatment discontinuation rates differed between treatment groups (11.3% in the acalabrutinib-venetoclax group versus 19.7% in the FCR or BR group). In particular, the higher discontinuation rate in the FCR or BR group could mean that patients who dropped out were more likely to experience a poor response or more severe side effects, which may lead to an inaccurate estimation of the treatment effect. The AMPLIFY study was not powered to detect a statistically significant difference in OS between the treatment groups, given the limited sample size and the low number of OS events observed. In the AMPLIFY trial, patients could receive subsequent anti-CLL therapy, which may affect OS assessment (██% in the acalabrutinib-venetoclax group and ████% in the FCR or BR group). Dropouts due to the initiation of new anti-CLL therapy were treated as intercurrent events within the study estimands and were typically classified as nonresponse for the primary and key secondary end points, which was deemed appropriate in most cases. The available OS results are preliminary and may not reflect the true long-term OS benefit or differences between groups; any interpretation should acknowledge the high level of uncertainty and the potential for substantial changes as more events accrue.

MRD negativity was assessed in the peripheral blood by flow cytometry (10^-4). According to the clinical experts consulted, MRD assessment in bone marrow is considered more clinically meaningful,³³ but peripheral blood testing is less invasive and allows for more frequent monitoring. In addition to the potential for performance bias related to the open-label design, health-related quality of life (HRQoL) findings may be biased due to incomplete reporting, missing data (████% versus ████% and ████% versus ████% for the acalabrutinib-venetoclax and FCR or BR groups at the 1-year and 2-year posttreatment follow-up, respectively), and reliance on evaluable data, which could affect validity and generalizability. For example, patients who drop out or are excluded due to missing data or other factors may differ substantially from those who remain in the study, potentially skewing the results.

External Validity

According to the clinical experts consulted, the AMPLIFY trial population was generally representative of patients with previously untreated CLL living in Canada who are eligible for acalabrutinib-venetoclax, with some exceptions. The clinical experts noted that trial exclusions based on low neutrophil or platelet counts may reflect risks associated with FCR but saw no biologically plausible reasons why such patients would not benefit from acalabrutinib-venetoclax in clinical practice. Similarly, patients with creatinine clearance below 50 mL/min were excluded, but the clinical experts indicated that patients with clearance as low as 30 mL/min may safely receive treatment. The clinical experts indicated that, although patients with 17p deletion or TP53 mutations were excluded from the AMPLIFY trial for ethical reasons related to poor efficacy of chemoimmunotherapy in patients with these genetic variations, such patients could potentially benefit from the acalabrutinib-venetoclax combination in clinical practice. Patients aged older than 65 years with a Cumulative Illness Rating Scale–Geriatric score of greater than 6 were excluded from the trial. The median age of the study population was 61 years; however, the clinical experts indicated that in real-world practice, patients with untreated CLL are typically older, with a median age around 70 years. They further noted that older patients or patients with a more medically complex profile would remain a key part of their target population for acalabrutinib-venetoclax, representing a substantial proportion of patients in clinical practice. Although patients with substantial cardiovascular disease were excluded from the trial, the clinical experts indicated they would be eligible for treatment in clinical practice, as acalabrutinib-venetoclax is considered by clinicians to have lower toxicity than alternative regimens, particularly with respect to cardiac events. The clinical experts indicated that clinical practice in Canada includes a more heterogeneous population of patients with CLL, compared with the predominantly white population enrolled in the AMPLIFY trial. Although the clinical experts indicated that patients from Asia and other regions may benefit from acalabrutinib-venetoclax in clinical practice, the lack of trial data limits the ability to generalize the results to these populations.

The clinical experts felt that it would be reasonable to extend eligibility for acalabrutinib-venetoclax to patients with SLL. The experts noted that CLL and SLL are treated the same in clinical practice in Canada. SLL is a rare condition with no BTK inhibitor treatments or venetoclax-based regimens specifically approved for use in treating this disease in Canada. Acalabrutinib-venetoclax has received approval from Health Canda for treating patients with CLL; the indication does not include SLL. Patients with SLL were not included in the AMPLIFY trial. In 2 recommendations — the 2023 final CDA-AMC recommendation for ibrutinib-venetoclax for the treatment of adult patients with previously untreated CLL, including those with 17p deletion, and the 2024 final CDA-AMC recommendation for venetoclax-obinutuzumab for the treatment of patients with previously untreated CLL — the pan-Canadian Oncology Drug Review Expert Review Committee noted that jurisdictions may consider extending reimbursement to include patients with SLL.

The AMPLIFY trial used chemoimmunotherapy (FCR or BR) as the control treatment. The clinical experts commented that FCR or BR may not be the most appropriate comparators for acalabrutinib-venetoclax because these regimens have limited use in current practice for treating patients with CLL and are primarily reserved for young patients who are better able to tolerate treatment. The clinical experts estimated that approximately 1% to 2% of their current patient population with CLL would be treated with FCR or BR. More commonly used treatments include acalabrutinib monotherapy, zanubrutinib monotherapy, venetoclax-obinutuzumab, or — more recently — ibrutinib-venetoclax, which has begun receiving funding in select provinces. This potentially limits the generalizability of the results and introduces uncertainty in estimating the treatment effect in the clinical context in Canada. Lack of randomized controlled trial evidence comparing acalabrutinib-venetoclax to reimbursed treatments other than chemoimmunotherapy is an important limitation of the submitted evidence. Based on the information provided by the sponsor, a feasibility assessment determined that an ITC was not feasible due to substantial clinical, methodological, and statistical heterogeneity across studies, which was deemed to preclude the assumptions necessary for a valid and reliable analysis (refer to Appendix 6 in the Supplemental Material). Based on the results of the sponsor-provided feasibility assessment, the CDA-AMC review team acknowledged that neither network meta-analysis nor alternative methods of matching-adjusted indirect comparison were likely to provide unbiased treatment effect estimates for the comparison of acalabrutinib-venetoclax to nonchemoimmunotherapy. The review team considered the sponsor’s conclusion as plausible; however, no independent feasibility assessment was conducted to verify this. The comparative efficacy and safety of acalabrutinib-venetoclax versus currently relevant comparators, other than chemoimmunotherapy, remains unknown.

Although maintaining HRQoL is a key priority for patients, the difference in HRQoL outcomes between the groups was not formally tested in the AMPLIFY trial and was only analyzed in the HRQoL-evaluable population. These limitations affect the generalizability of the results. Including only evaluable patients in the model can introduce selection bias because this group may not be representative of the broader patient population. For example, these patients may represent a subgroup with different clinical profiles (e.g., older in age, having more comorbidities), and their exclusion reduces the applicability of the findings to the general CLL population.

Results

The key efficacy and harms results and findings from the GRADE assessment are presented in this section. Detailed efficacy and harms results can be found in Appendix 4 in the Supplemental Material. The results reflect the April 30, 2024, data cut-off.

Efficacy

Key results include the following:

• PFS per IRC assessment: The median follow-up duration for PFS was 41.3 months (range, 0 to 59 months) and 38.4 months (range, 0 to 57 months) in the acalabrutinib-venetoclax group and the FCR or BR group, respectively. An IRC-assessed PFS event was reported in 30.6% of patients in the acalabrutinib-venetoclax group and 32.8% of patients in the FCR or BR group. The median IRC-assessed PFS for the acalabrutinib-venetoclax group was not reached, while the median PFS for the FCR or BR group was 47.6 months (95% confidence interval [CI], 43.3 months to not estimable); the HR was 0.65 (95% CI, 0.49 to 0.87; P = 0.0038). Disease progression was reported in 26.5% and 22.8% of patients in the acalabrutinib-venetoclax and FCR or BR groups, respectively. Additionally, 4.1% of patients in the acalabrutinib-venetoclax group and 10.0% of patients in the FCR or BR group died without experiencing disease progression. The KM-estimated between-group differences in the probabilities of being alive or progression-free at 24 months and 48 months were 8.6% (95% CI, ███% to ████%) and 15.2% (95% CI, ███% to ████%), respectively, in favour of acalabrutinib-venetoclax. The PFS results were consistent across the prespecified sensitivity analyses. Findings in key subgroups generally aligned with those observed in the overall population, with HRs favouring acalabrutinib-venetoclax. However, estimates for certain subgroups — including patients aged 65 years or younger (HR = 0.80; 95% CI, 0.56 to 1.13), patients with mutated IGHV (HR = 0.67; 95% CI, 0.39 to 1.14), patients with high-risk Rai stages (HR = 0.66; 95% CI, 0.44 to 1.00) and low-risk Rai stages (HR = 0.67; 95% CI, 0.44 to 1.00), patients with an Eastern Cooperative Oncology Group Performance Status score of 2 (HR = 0.55; 95% CI, 0.23 to 1.31), and patients with complex karyotype (HR = 0.50; 95% CI, 0.22 to 1.15) versus those without (HR = 0.77; 95% CI, 0.56 to 1.07) — were less precise, with CIs touching or crossing unity. Refer to Appendix 4 in the Supplemental Material, for the PFS KM curves in the full analysis set population.

• OS per IRC assessment: There were 18 deaths (6.2% of patients) in the acalabrutinib-venetoclax group and 42 deaths (14.5% of patients) in the FCR or BR group. The median OS in the acalabrutinib-venetoclax group was 57.8 months (95% CI, 57.8 months to not estimable), while the median OS in the FCR or BR group was not reached (HR = 0.33; 95% CI, 0.18 to 0.56). The KM-estimated between-group differences in the probabilities of being alive at 24 months and 48 months were 7.2% (95% CI, ███% to ████%) and 12.7% (95% CI, ███% to ████%), respectively. Refer to Appendix 4 in the Supplemental Material, for the OS KM curves in the full analysis set population.

• Duration of response: The median duration of response was 50.4 months (95% CI, 48.5 months to not estimable) in the acalabrutinib-venetoclax group and 47.6 months (95% CI, 44.0 months to not estimable) in the FCR or BR group. The KM-estimated between-group differences in the probabilities of remaining in response at 24 months and 48 months were 6.3% (95% CI, ████% to ████%) and 15.2% (95% CI, ███% to ████%), respectively.

• Time to next treatment: ███ ██████ ████ ███ ███ ███████ ██ ███ █████████████ ████ ██████████ ██████ █████ ██ ███ ████ ██████ ████ ███ ████ ██████ ██ ███ ██████████ ██ ███ ███ ██ ██ █████ ███ █ █████ ███ ███ ████ ██ ██████ The KM-estimated between-group differences in the probabilities of not receiving subsequent anti-CLL therapy at 24 months and 48 months were ████% (95% CI, ███% to ████%) and ████% (95% CI, ███% to ████%), respectively.

• Health-related quality of life: The between-group difference in the mean change from baseline in the EORTC QLQ-C30 global health status scale or quality of life scale was ████ points (95% CI, █████ to ████) at 6 months, ████ points (95% CI, █████ to ████) at the 1-year posttreatment follow-up, and ████ points (95% CI, █████ to ████) at the 2-year posttreatment follow-up.

• The MRD negativity rate in peripheral blood, measured by flow cytometry (10^-4), for the acalabrutinib-venetoclax group at cycle 9 was 26.8% and for the FCR or BR group at 12 weeks after the start of cycle 6 was 51.0% (risk difference = █████%; 95% CI, █████% to █████%; P < 0.0001), in favour of FCR or BR.

• Event-free survival: ███ ██████ ███ ███ ███ ███████ ██ ███ █████████████ ████ ██████████ ██████ █████ ██ ███ ████ ██████ ████ ███ ████ ██████ ██ ███ ██████████ ██ ███ ███ ██ ██ █████ ███ █ █████ ███ ███ ████ ██ ██████ The KM-estimated between-group differences in the probabilities of being event-free at 24 months and 48 months in the acalabrutinib-venetoclax and FCR or BR groups, respectively, were ████% (95% CI, ████% to ████%) versus ████% (95% CI, ████% to ████%) and ████% (95% CI, ████% to ████%) versus ████% (95% CI, ████% to ████%).

• Overall response rate: The proportion of patients with overall response per IRC assessment was 92.8% in the acalabrutinib-venetoclax group and 75.2% in the FCR or BR group (estimated risk difference = 17.6%; 95% CI, 11.5% to 23.6%).

Harms

Key results include the following (as of the April 30, 2024, data cut-off).

Treatment-emergent AEs (TEAEs) were reported in 92.8% of patients (270 of 291) in the acalabrutinib-venetoclax group and 91.1% of patients (236 of 259) in the FCR or BR group. TEAEs of grade 3 or higher occurred in 53.6% of patients receiving acalabrutinib-venetoclax and in 60.6% of those treated with FCR or BR. The most frequently reported grade 3 or greater TEAEs in the acalabrutinib-venetoclax group, as compared to the FCR or BR group, were neutropenia (26.8% versus 32.4%), COVID-19 pneumonia (5.5% versus 2.7%), decreased neutrophil count (5.5% versus 8.5%), and anemia (3.8% versus 6.6%). Serious AEs were reported in 24.7% of patients in the acalabrutinib-venetoclax group and 27.4% of patients in the FCR or BR group. The most common serious AEs in the acalabrutinib-venetoclax group, as compared to the FCR or BR group, were COVID-19 pneumonia (5.8% versus 2.3%), followed by COVID-19 (3.1% versus 1.5%), and febrile neutropenia (1.7% versus 8.1%). A total of 3.4% of patients in the acalabrutinib-venetoclax group and 3.5% in the FCR or BR group died due to AEs. COVID-19 pneumonia was the only AE with death as an outcome that occurred in 2% of patients or more (2.1% in the acalabrutinib-venetoclax group).

The study treatment was discontinued due to AEs in 7.9% of patients in the acalabrutinib-venetoclax group, compared with 10.8% in the FCR or BR group. In the acalabrutinib-venetoclax group, 22 patients (7.6%) discontinued acalabrutinib and 18 patients (6.2%) discontinued venetoclax due to TEAEs. Cardiac events of any grade were reported in 9.3% of patients in the acalabrutinib-venetoclax group and 3.5% in the FCR or BR group. Leukopenia occurred in 37.5% of patients in the acalabrutinib-venetoclax group versus 54.1% in the FCR or BR group. A higher proportion of patients in the acalabrutinib-venetoclax group experienced hemorrhage events and infections compared to those in the FCR or BR group (hemorrhage: 32.3% versus 4.2%; infections: 50.9% versus 31.7%). Hypertension was reported in 4.1% of patients in the acalabrutinib-venetoclax group compared with 2.7% of patients in the FCR or BR group.

Summary of Findings and Certainty of the Evidence

A literature-based minimal important difference (MID) estimate was used as the threshold for the EORTC QLQ-C30 global health status score in the GRADE certainty of evidence assessment (MID: 5 to 10 points for both improvement and deterioration) (refer to the Summary of Outcome Measures and Minimal Important Differences Table in Appendix 3 in the Supplemental Material). In the absence of literature-based MID estimates, the thresholds suggested by the clinical experts were used for the following outcomes: PFS (threshold: 10% at 48 months), OS (threshold: 5% at 48 months), duration of response (threshold: 10% at 48 months), and TTNT (threshold: 10% at 48 months). For serious AEs, where no empirically estimated or expert opinion-based threshold was available, the certainty was assessed based on the presence of a non-null effect.

Table 4: Summary of Findings for Acalabrutinib-Venetoclax vs. FCR or BR for Patients With Previously Untreated CLL

BR = bendamustine-rituximab; CI = confidence interval; CLL = chronic lymphocytic leukemia; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; FCR = fludarabine-cyclophosphamide-rituximab; HRQoL = health-related quality of life; LSM = least squares mean; MID = minimal important difference; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, 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.

^aAn empirically derived MID was not identified for the between-group difference for this outcome. A difference of 10% between the groups was identified by the clinical expert consulted by Canada’s Drug Agency as a threshold of clinical importance for this outcome.

^bRated down 1 level for serious imprecision. Based on the MID identified by the clinical experts (10% between-group difference), the point estimate suggests a clinically important benefit, while the lower boundary of the 95% CI suggests the possibility of no clinically important benefit. Certainty was not rated down for indirectness. The trial population was younger and at lower risk than the broader first-line population of patients with CLL, limiting representativeness. However, the clinical experts considered the results to be broadly applicable. Certainty was not rated down for risk of bias. The subpopulation exclusions also raised concern that the enrolled population may have had a more favourable baseline prognosis, which could overestimate treatment effects for PFS. Given that the 95% CI for the risk difference is wide and captures a possible range of effects, this concern was not judged sufficient to rate down the certainty of evidence. Additionally, although the results were based on an interim analysis and the median PFS was not reached in the acalabrutinib-venetoclax group, the certainty of evidence was not rated down for risk of bias related to overestimation of treatment effect because 98% of the prespecified PFS events for the final analysis had already occurred at the time of the interim analysis, reducing concern that the 48-month Kaplan-Meier estimate materially overestimates the effect.

^cRated down 1 level for serious imprecision. Based on the MID identified by the clinical experts (a difference of 10%), the point estimate suggests a clinically important benefit, while the lower boundary of the 95% CI suggests the possibility of no clinically important benefit. Rated down 1 level for indirectness. Duration of response is conditional on the patients experiencing response, and the trial population was younger and at lower risk than the broader first-line population with CLL. The results are from an interim analysis, and frequent censoring beyond 48 months limits the reliability of longer-term evaluation of duration of response. The evidence at 48 months may change to an important degree with further follow-up.

^dThis analysis was not part of the statistical analysis plan and was requested from the sponsor by Canada’s Drug Agency to facilitate the Grading of Recommendations Assessment, Development and Evaluation assessment.

^eStatistical testing for this outcome was not adjusted for multiplicity. The results are considered as supportive evidence.

^fImprecision was not rated down. Based on the MID identified by the clinical experts (a difference of 10%), the point estimate suggests a clinically important benefit, and the lower bound of the 95% CI was only slightly (██ ███ ████) below the expert opinion-based threshold. Rated down 1 level in total for indirectness and risk of bias. Use of subsequent anti-CLL therapy was lower in the FCR or BR group than would be expected in clinical practice according to the clinical experts. The imbalance between groups and the results being based on interim analyses increased the risk of bias and may lead to an overestimation of the treatment effect.

^gAn empirically derived MID was not identified for the between-group difference for this outcome. A difference of 5% between the groups was identified by the clinical expert consulted by Canada’s Drug Agency as a threshold of clinical importance for this outcome.

^hRated down 1 level for indirectness and 1 level for risk of bias. The AMPLIFY trial was not powered to assess OS between-group difference, given the limited sample size and the low number of OS events observed. The OS data were informed by a small information fraction (only 10%) at the time of the interim analysis. The median OS was not reached in the FCR or BR group. The subsequent anti-CLL therapy was imbalanced across treatment groups and was lower in the FCR or BR group than would be expected in clinical practice. The trial population was younger and at lower risk than the broader first-line population of patients with CLL. The results are from an interim analysis, and the observed benefit remains uncertain and may change with additional follow-up, given the frequent censoring, particularly beyond 48 months.

ⁱRated down 2 levels for serious risk of bias due to potential for bias arising from the open-label nature of the study, the subjective nature of the outcome, and missing data.

^jRated down 2 levels for serious risk of bias due to missing data, because the proportion of patients available for assessment substantively diminished over time, and due to assessor knowledge of treatment assignment. Rated down 1 level for imprecision. Based on the MID identified in the literature (5 points), the point estimate suggested little to no difference, while the upper bound of the 95% CI suggested an increase compared to FCR or BR. The wide CI limits the certainty of this finding.

^kRated down 2 levels for serious imprecision. An empirically derived MID was not identified for the between-group difference for this outcome, and an expert opinion-based threshold was not available. With the null specified as the threshold of importance, the point estimate suggested a decrease in the proportion of patients with serious adverse events with acalabrutinib-venetoclax compared with FCR or BR. However, the 95% CI around the point estimate contains the potential for a decrease as well as an increase in serious adverse events. Differences in treatment discontinuation rates between study groups may influence the interpretation of harms outcomes as a potential risk of bias, but certainty was not further rated down given that the wide CIs may include a possible range of effects.

Source: Clinical Study Report for AMPLIFY (interim analysis).²⁶ Details included in the table are from the sponsor’s summary of clinical evidence.

Long-Term Extension Studies

No long-term extension study was available for this review.

Indirect Evidence

No ITC was available for this review.

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps in the systematic review evidence were available for this review.

Discussion

Efficacy

This report summarizes evidence from an interim analysis of the phase III AMPLIFY trial comparing acalabrutinib-venetoclax to chemoimmunotherapy (FCR or BR) for previously untreated CLL without 17p deletion or TP53 mutations. The results for arm B (the triplet regimen of acalabrutinib, venetoclax, and obinutuzumab) in the AMPLIFY trial were not presented or evaluated in this review because they were outside the scope of the approved Health Canada indication and the sponsor’s reimbursement request. The clinical experts consulted for this review, along with the clinician groups providing input, emphasized that the acalabrutinib-venetoclax regimen offers a convenient, all-oral, fixed-duration treatment option that is increasingly preferred in clinical practice to minimize long-term toxicity. The clinical experts indicated that this combination represents an important addition to the treatment landscape in Canada. Patient input revealed that, despite effective therapies, unmet needs persist, particularly the burdens of long treatment durations, treatment-related toxicities, and logistical challenges such as travel and costs. Based on expert opinion and results from head-to-head trials comparing ibrutinib versus acalabrutinib monotherapy in the relapsed or refractory CLL setting, the clinical experts suggested that acalabrutinib may have a more favourable safety profile, particularly lower rates of atrial fibrillation, hypertension, and sudden cardiac death.³⁴ Therefore, acalabrutinib-venetoclax may be a viable alternative to ibrutinib-venetoclax in the present patient target population, potentially offering improved cardiac safety. However, in the absence of head-to-head clinical trials directly comparing these combinations in the indicated population, this potential safety benefit remains theoretical.

According to the clinical experts consulted, the AMPLIFY trial likely included a subset of patients with a more favourable prognosis, which may not fully represent the broader population of individuals with previously untreated CLL. In clinical practice, the clinical experts emphasized that a higher proportion of patients are older, have comorbidities (Cumulative Illness Rating Scale–Geriatric score > 6), and present with poorer performance status (Eastern Cooperative Oncology Group Performance Status score of 2) compared to those included in the trial. Additionally, the AMPLIFY trial population had a higher proportion of patients with favourable prognostic factors, including Rai stages I to III and the absence of 11q deletions or complex karyotypes, although over one-half had unmutated IGHV. The clinical experts consulted by CDA-AMC noted that older patients or patients with a more medically complex profile make up a substantial portion of those seen in routine clinical practice and would remain part of the target population for acalabrutinib-venetoclax. While patients with 17p deletion or TP53 mutations were excluded from the trial due to ethical concerns regarding chemoimmunotherapy comparators, the clinical experts suggested that these patients may still benefit from acalabrutinib-venetoclax in clinical practice. However, the effects of acalabrutinib-venetoclax remain uncertain in older patients, those with multiple or severe comorbidities, and individuals with 17p deletion and TP53 mutations. The clinical experts felt it would be reasonable to extend eligibility for acalabrutinib-venetoclax to patients with SLL, noting that CLL and SLL are considered 2 manifestations of the same disease and are treated similarly in clinical practice in Canada.

The AMPLIFY trial used chemoimmunotherapy (FCR or BR) as the comparator, which the clinical experts consulted by CDA-AMC noted may limit the relevance of the findings given that these regimens are now used in only 1% to 2% of patients in their practice. However, the clinical experts noted that chemoimmunotherapy was standard of care and commonly funded when the AMPLIFY trial was initiated. There are no head-to-head comparisons between acalabrutinib-venetoclax and available comparator treatments. Based on the information provided by the sponsor, a feasibility assessment determined that an ITC was not feasible due to substantial clinical, methodological, and statistical heterogeneity across studies, which were deemed to preclude the assumptions necessary for a valid and reliable analysis. As a result, the comparative efficacy and safety of acalabrutinib-venetoclax against nonchemoimmunotherapy comparators, including BTK inhibitors, ibrutinib-venetoclax, and venetoclax-obinutuzumab, remains unknown.

Most patients identified fear of disease progression as an important factor impacting their daily lives and HRQoL. The clinical experts consulted for this review considered PFS an important end point for patients with untreated CLL, particularly given the variable and often indolent natural history of this disease. Based on a 10% clinical importance threshold suggested by the clinical experts consulted by CDA-AMC, acalabrutinib-venetoclax likely results in an increase in PFS at 48 months when compared with FCR or BR. However, there is imprecision in the between-group difference due to relatively wide 95% CIs and the lower limit including the possibility of a nonmeaningful benefit in PFS. The median PFS for the acalabrutinib-venetoclax group was not reached, while the median PFS for the FCR or BR group was 47.6 months. The proportion of patients with disease progression was slightly higher in the acalabrutinib-venetoclax group (26.5%, versus 22.8% in the FCR or BR group). The KM curves for PFS began to separate at approximately 6 months, with clearer divergence by 9 to 12 months, which was maintained thereafter, consistently favouring acalabrutinib-venetoclax, indicating a delayed but durable benefit compared with FCR or BR. Additionally, the lower rate of disease progression observed in the FCR or BR group may be due to higher censoring in the acalabrutinib-venetoclax group (27.2%, versus 7.6% in the FCR or BR group) and a shorter median duration of follow-up in the FCR or BR group (38.4 months, versus 41.3 months in the acalabrutinib-venetoclax group). Many patients in the FCR or BR group may have left the trial early or were followed for a shorter period, potentially masking true progression rates in that group. As a result, a higher cumulative number of disease progression events was observed in the acalabrutinib-venetoclax group, despite the longer time to progression. The clinical experts consulted by the review team noted that the observed delayed PFS benefit was consistent with expectations for this regimen, given its fixed treatment duration of approximately 13 months. Although the duration of the trial was not long enough to observe the median PFS, the clinical experts considered that the 48-month PFS estimates would not change to a meaningful degree with additional follow-up because of the relatively indolent nature of the disease. The PFS results were consistent across prespecified sensitivity analyses. The sample sizes for the prespecified subgroup analyses were small and were not powered to detect differences between subgroups. PFS was used as a surrogate for OS; however, information on the validity of PFS as a surrogate for OS in this population for the treatment under review was unavailable. It remains unclear whether the PFS results will translate into improved OS.^31,32

The AMPLIFY study showed that acalabrutinib-venetoclax may result in an improvement in OS probability at 48 months compared with FCR or BR. Given that the study population primarily comprised a relatively favourable subset of patients — characterized by younger age, good overall health, and predominantly low cytogenetic risk — the overall mortality risk during the follow-up period was assessed as lower across all treatment groups than would be expected in the broader population of patients with untreated CLL. The clinical experts consulted for this review agreed with this assessment. The AMPLIFY trial was not designed to detect a statistically significant difference in OS, given the limited sample size and the low number of OS events observed. The available follow-up was insufficient to reflect the potential impact on OS at longer time points because the current results are based on a limited information fraction (approximately 10% of the final analysis). As such, the findings may not truly reflect the long-term survival benefits or differences between groups. Any interpretation should consider the uncertainty of these findings and the potential for substantial changes as more events accrue. In the AMPLIFY study, patients were allowed to receive posttreatment anticancer medications after discontinuing the study treatment, which could influence the assessment of OS. The subsequent treatments were not balanced between groups. The clinical experts noted that the rate of subsequent BTK inhibitor-based therapy in the FCR or BR group was lower than would be expected in clinical practice.

The AMPLIFY study suggests that acalabrutinib-venetoclax may result in an increase in the probability of remaining in response at 48 months when compared with FCR or BR. In the AMPLIFY trial, as described, the population consisted of younger patients considered at lower risk, and the results are based on an interim analysis. Given that duration of response is conditional on the patients experiencing response, the trial’s exclusion of older patients and those with less favourable prognosis may lead to a bias in favour of a longer response. Frequent censoring beyond 48 months limits the reliability of longer-term outcomes, and the 48-month evidence may change with additional follow-up. Although the absolute difference in the probability of remaining in response at 48 months was higher than the expert-provided threshold of 10%, the 95% CIs for the difference were wide and included no meaningful benefit, indicating imprecision and low certainty in the evidence. It was the clinical experts’ opinion that the difference in median duration of response between the acalabrutinib-venetoclax group (50.4 months) and the FCR or BR group (47.6 months) was unlikely to be clinically meaningful. The AMPLIFY study showed that acalabrutinib-venetoclax likely results in an improvement in the probability of not receiving subsequent anti-CLL therapy at 48 months compared with FCR or BR. ███ ███████ ██ ███ ████ ██████████ ████ ███ ███ ████████ ████ ███ ██████ ███ ███ ███████ ███ █████████████ ████ ██████████ ████████ ████ ████ ██████ ███ ███ ██ ██.

MRD negativity results appeared to favour FCR or BR over acalabrutinib-venetoclax in the AMPLIFY trial. MRD was assessed in peripheral blood at 9 months — corresponding to cycle 9 for the acalabrutinib-venetoclax group and 12 weeks after the start of cycle 6 for the FCR or BR group. The clinical experts consulted for this review noted that, given the 14-month treatment duration for acalabrutinib-venetoclax, the timing of MRD assessment may have been premature to fully capture the potential MRD benefit of this regimen. While MRD outcomes are fully integrated into treatment management protocols in other diseases, such as multiple myeloma, treatment decisions for the patient target population are not currently guided by MRD status. Further research is needed to clarify the relationship between undetectable MRD and clinical outcomes, such as PFS and other long-term outcomes, across different treatment regimens.

HRQoL was highlighted as an outcome of importance to patients and was assessed in the trial using the EORTC QLQ-C30 global health status and quality of life score. The AMPLIFY study showed that acalabrutinib-venetoclax may result in little to no clinically important difference in HRQoL compared with FCR or BR at 6 months. Although scores on the EORTC QLQ-C30 improved by 1 year, the between-group mean difference was still █████ than the MID and the certainty of the evidence was rated down further to very low, primarily due to the open-label study design, incomplete reporting, lack of appropriate account of missing data (particularly with the potential of data missing not at random), and reliance on evaluable data only. These points increase uncertainty and compromise the validity and generalizability of the results. The proportion of missing data in the acalabrutinib-venetoclax and FCR or BR groups was ████% and ████% at the 1-year posttreatment follow-up and ████% and ████% at the 2-year posttreatment follow-up, respectively. Including only evaluable patients in the model can introduce selection bias, and this group may not be representative of the overall population of patients with CLL.

Harms

According to the clinical experts consulted for this review, the safety profile of acalabrutinib-venetoclax was consistent with the known class effects of BTK inhibitors and venetoclax. In the AMPLIFY study, more than 90% of patients experienced at least 1 TEAE. The AMPLIFY trial showed, with low certainty, that acalabrutinib-venetoclax may result in a decrease in serious AEs compared with FCR or BR. The most frequently reported TEAEs were headache and diarrhea (which are typically associated with BTK inhibitors) as well as neutropenia, which is commonly observed with both chemotherapy and venetoclax. Compared with FCR or BR, acalabrutinib-venetoclax had lower rates of treatment discontinuation; however, treatment modifications, including dose interruptions and reductions, were more frequent with acalabrutinib-venetoclax. The clinical experts consulted noted that this was largely due to the longer treatment duration of acalabrutinib-venetoclax compared with FCR or BR. The clinical experts identified infections, cardiac toxicity, hypertension, and bleeding events as notable harms. While they noted that chemoimmunotherapy is traditionally known to cause more serious infections, including viral and fungal infections, the incidence of infections, including COVID-19, was numerically higher in the acalabrutinib-venetoclax group. According to the clinical experts, this likely reflects both the early-pandemic context and the immunosuppressive effects of treatment because BTK inhibitors can predispose patients to atypical and viral infections. Additionally, during the AMPLIFY study, the FCR or BR group used antibacterials, antivirals, and corticosteroids for systemic use more often than the acalabrutinib-venetoclax group. This likely reflects a greater need for infection prevention in the FCR or BR group. Hemorrhagic events and cardiac events, such as atrial fibrillation and hypertension, were noted by the clinical experts as anticipated risks with BTK inhibition. TLS, a known risk during venetoclax initiation, was uncommon in the study and was primarily mitigated through established ramp-up protocols. The clinical experts consulted indicated that acalabrutinib-venetoclax offers a more favourable and predictable safety profile than FCR or BR, with manageable toxicities and lower death rates. According to the clinical experts, the safety findings of the AMPLIFY study suggest that acalabrutinib-venetoclax provides a tolerable, fixed-duration alternative to continuous BTK inhibitor therapy or fixed-duration ibrutinib-venetoclax in previously untreated CLL. The clinical experts further noted that the combination of acalabrutinib-venetoclax has the potential for improved cardiac safety compared to ibrutinib-venetoclax. However, in the absence of head-to-head clinical trials directly comparing these combinations, this potential advantage remains theoretical.

Ethics and Equity Considerations

The clinical experts consulted for this review indicated that older adults are disproportionately impacted by this disease and its treatment due to a combination of clinical and logistical challenges. These patients are more likely to experience treatment-related complications and often face substantial barriers to accessing care, including difficulty travelling to appointments, limited mobility, lack of personal support, and out of pocket costs such as parking fees. As a result, they are particularly vulnerable to delays or interruptions in treatment. The clinical experts emphasized the importance of ongoing monitoring for all patients — regardless of the risk of disease relapse — to assess the long-term efficacy of fixed-duration therapies. Regular blood monitoring and clinical assessments every 3 months is essential for detecting disease relapses and informing future treatment decisions. The initiation of venetoclax requires careful monitoring for TLS, including multiple weekly blood draws and supportive care. For patients in rural or remote areas, limited access to cancer centres creates substantial logistical and emotional challenges, disrupting daily life. Many patients face transportation challenges, particularly during winter months, which can complicate their ability to access timely care. Caregivers and families may also experience emotional stress and financial pressure due to reduced patient income and travel requirements.

According to the clinical experts consulted, access-related challenges within the current funding and delivery landscape further contribute to disparities, particularly for treatments such as a combination of ibrutinib-venetoclax. As a result, health care providers must often rely on compassionate access programs offered by pharmaceutical companies, which can create administrative hurdles that may limit how quickly patients can start treatment. The clinical experts noted that when differences in efficacy between treatments are minimal or not well established, clinicians tend to choose options that are more accessible and less administratively complex. The clinical experts further noted that MRD testing is not typically covered by funding and is not widely available outside of major centres, with next-generation sequencing methods being too expensive. The clinical experts consulted emphasized the need for a national, cost-effective strategy to support equitable access to MRD testing across Canada.

Conclusion

Patients and clinicians highlighted the need for new, effective, and better-tolerated time-limited oral therapies for CLL that minimize side effects, prolong disease remission, improve quality of life, reduce reliance on hospital-based care, and support greater patient independence. The ongoing phase III, open-label, multicentre AMPLIFY study comparing the efficacy and safety of acalabrutinib-venetoclax versus FCR or BR in patients with previously untreated CLL without 17p deletion and/or TP35 mutations was included in this review. Results from the AMPLIFY study demonstrated that, compared with FCR or BR, the combination of acalabrutinib-venetoclax likely improves PFS and TTNT. The AMPLIFY study also demonstrated with low certainty that acalabrutinib-venetoclax may result in an improvement in OS and duration of response when compared with FCR or BR. However, the results of the AMPLIFY study are based on an interim analysis in a relatively young patient subgroup, considered lower risk. The extent to which these results translate into long-term benefits, including improved OS, remains unclear and represents a gap in the evidence. The impact of acalabrutinib-venetoclax on HRQoL was very uncertain due to missing data, imprecision in the effect estimates, and the open-label design of the AMPLIFY study. No new harms events were identified with acalabrutinib-venetoclax, and the clinical experts consulted by CDA-AMC considered the safety profile of the acalabrutinib-venetoclax combination to be consistent with expectations and manageable in clinical practice. The comparative efficacy and safety of acalabrutinib-venetoclax versus nonchemoimmunotherapy comparators, including BTK inhibitors, ibrutinib-venetoclax, or venetoclax-obinutuzumab, remains unknown.

Economic Review

Methods

The review team appraised the pharmacoeconomic evidence submitted by the sponsor on the cost-effectiveness and budget impact of acalabrutinib-venetoclax compared to chemoimmunotherapy (FCR or BR), ibrutinib-venetoclax, venetoclax-obinutuzumab, acalabrutinib monotherapy, ibrutinib monotherapy, and zanubrutinib monotherapy for previously untreated CLL.

Summary of the Submitted Economic Evaluation

The sponsor submitted a cost-utility analysis to estimate the cost-effectiveness of acalabrutinib-venetoclax from the perspective of a public health care payer in Canada over a lifetime horizon (40 years). The modelled population comprised adult patients with previously untreated CLL, which is aligned with the Health Canada indication. The sponsor’s base-case analysis included costs related to drug acquisition and administration, subsequent treatment, disease management, AEs, and terminal care.

In the sponsor’s base case, 3 alternatives were identified on the efficiency frontier: FCR or BR, venetoclax-obinutuzumab, and acalabrutinib-venetoclax. Among these comparators, acalabrutinib-venetoclax was the more costly and most effective, and the incremental cost-effectiveness ratio relative to venetoclax-obinutuzumab was $1,221,115 per quality-adjusted life-year gained (incremental costs = $36,294; incremental quality-adjusted life-years = 0.03). Acalabrutinib-venetoclax was dominant over venetoclax-ibrutinib, acalabrutinib monotherapy, ibrutinib monotherapy, and zanubrutinib monotherapy. Of the incremental benefit compared to FCR or BR (6.27 incremental quality-adjusted life-years), approximately 99% of the benefit was predicted to be accrued after the treatment duration of the AMPLIFY trial (maximum follow-up = 59 months). Additional information about the sponsor’s submission is summarized in Appendix 10 in the Supplemental Material.

CDA-AMC identified several key issues with the sponsor’s analysis (refer to Table 5; full details are provided in Appendix 11 in the Supplemental Material).

Table 5: Key Issues With the Sponsor’s Economic Submission

AE = adverse event; BR = bendamustine-rituximab; BTK = Bruton tyrosine kinase; CDA-AMC = Canada’s Drug Agency; FCR = fludarabine-cyclophosphamide-rituximab; HRQoL = health-related quality of life.

Note: Full details of the issues identified by CDA-AMC are provided in Appendix 11 in the Supplemental Material.

CDA-AMC Assessment of Cost-Effectiveness

In the absence of head-to-head trials comparing acalabrutinib-venetoclax versus other fixed-duration regimens (i.e., ibrutinib-venetoclax and venetoclax-obinutuzumab) and BTK inhibitor monotherapies (i.e., acalabrutinib, ibrutinib, zanubrutinib), the sponsor conducted a feasibility assessment and concluded that performing a robust ITC was not feasible. As part of the Clinical Review, the CDA-AMC review team acknowledged that neither network meta-analysis nor alternative methods of matching-adjusted indirect comparison were likely to provide unbiased treatment effect estimates for the comparison of acalabrutinib-venetoclax to nonchemoimmunotherapy. The clinical review team considered the sponsor’s conclusion as plausible; however, no independent feasibility assessment was conducted to verify the sponsor’s conclusion. In the cost-utility analysis, the sponsor assumed equivalent efficacy between acalabrutinib-venetoclax and nonchemoimmunotherapy comparators; however, there is no evidence to assess the relative efficacy and safety of acalabrutinib-venetoclax against nonchemoimmunotherapy comparators. The comparative efficacy and safety of acalabrutinib-venetoclax against FCR or BR was derived from the AMPLIFY trial. The clinical experts consulted during this review highlighted that FCR or BR are rarely used in clinical practice in Canada, which was supported by data in the sponsor-submitted budget impact analysis, which showed that only around 1% of patients receive FCR or BR.

CDA-AMC noted several limitations that add uncertainty to the sponsor’s base case, including the lack of comparative clinical evidence, uncertainty in the magnitude of postprogression benefit against FCR or BR, and uncertainty in subsequent treatment costs. These limitations could not be addressed through reanalysis due to lack of supporting clinical evidence. As such, no reanalyses were performed.

Summary of the Budget Impact

The sponsor submitted a budget impact analysis to estimate the 3-year (fourth quarter 2026 to third quarter 2029) budget impact of reimbursing acalabrutinib-venetoclax for the treatment of patients with previously untreated CLL. The sponsor assumed that the payer would be CDA-AMC–participating public drug plans and derived the size of the eligible population using an epidemiologic approach. The price of acalabrutinib was aligned with the price included in the sponsor’s economic evaluation, while the prices of comparators were based on the publicly available list prices. Additional information pertaining to the sponsor’s submission is provided in Appendix 12 in the Supplemental Material.

CDA-AMC identified a number of issues with the sponsor’s estimated budget impact that could not be addressed. Although the sponsor estimated that the budget impact of reimbursing acalabrutinib-venetoclax for use in the reimbursement population will be approximately $29.4 million over the first 3 years (estimated expenditure on acalabrutinib: $86.6 million; estimated expenditure on acalabrutinib-venetoclax: $155.0 million), the impact of reimbursing acalabrutinib-venetoclax is highly uncertain. The actual budget impact of reimbursing acalabrutinib-venetoclax for use in previously untreated CLL will depend on the uptake of acalabrutinib-venetoclax and the time to treatment discontinuation of BTK inhibitor monotherapies.

Conclusion

Based on the Clinical Review, when compared with FCR or BR, acalabrutinib-venetoclax likely improves the probability of being progression-free at 48 months, with moderate certainty, among patients with previously untreated CLL. The AMPLIFY study also demonstrated, with low certainty, that acalabrutinib-venetoclax may result in an improvement in OS and duration of response when compared with FCR or BR. The cost-effectiveness of acalabrutinib-venetoclax versus FCR or BR is highly uncertain due to limitations with the submitted analysis. In addition, based on feedback from the clinical experts and data presented by the sponsor, the use of FCR or BR for this indication is anticipated to be small (around 1% of patients), and FCR or BR would not be impacted should acalabrutinib-venetoclax become available. Therefore, FCR or BR may not be considered a relevant comparator for this analysis, and the cost-effectiveness versus this comparator is likely not relevant for decision-makers.

The sponsor submitted an ITC feasibility assessment concluding that ITC was unlikely to provide unbiased treatment effect estimates for the comparison of acalabrutinib-venetoclax versus nonchemoimmunotherapy (i.e., ibrutinib-venetoclax; venetoclax-obinutuzumab; and acalabrutinib, ibrutinib, or zanubrutinib monotherapy). The CDA-AMC clinical review team considered the sponsor’s conclusion as plausible; however, no independent feasibility assessment was conducted to verify the sponsor’s conclusions. Given the lack of direct or indirect evidence, the comparative efficacy and safety of acalabrutinib-venetoclax versus currently relevant comparators, other than FCR or BR, remains unknown. In addition, conclusions about the comparative harms and impact on HRQoL, which were deemed important by patient and clinician groups, could not be made as these outcomes were not assessed. Given the lack of comparative clinical evidence, there is insufficient evidence to determine whether acalabrutinib-venetoclax provides greater health benefit than nonchemoimmunotherapy comparators. If it is anticipated that there are no differences in health outcomes between acalabrutinib-venetoclax versus ibrutinib-venetoclax, venetoclax-obinutuzumab, and BTK inhibitor monotherapies, then the cost of acalabrutinib-venetoclax should not exceed that of those comparators for the treatment of adult patients with previously untreated CLL.

The budget impact of reimbursing acalabrutinib-venetoclax to the public drug plans in the first 3 years is estimated to be approximately $29.4 million. The 3-year expenditure on acalabrutinib (i.e., not accounting for current expenditure on comparators) is estimated to be $86.6 million (acalabrutinib-venetoclax = $155.0 million). The estimated budget impact is uncertain due to uncertainty in the uptake of acalabrutinib-venetoclax and in the time to treatment discontinuation of BTK inhibitor monotherapies.

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