CADTH Reimbursement Review

Venetoclax (Venclexta)

Sponsor: AbbVie Corporation

Therapeutic area: Acute myeloid leukemia

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

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

Introduction

Acute myeloid leukemia (AML) is a hematopoietic neoplasm that is characterized by an abnormal proliferation of immature blast cells from the bone marrow, which do not differentiate into red blood cells, platelets, and granulocytes, ultimately resulting in a variety of cytopenias. WHO defines AML as having more than 20% blast cells in peripheral blood or bone marrow. It is the second-most common form of leukemia in adults, with most cases occurring in older adults; the median age of onset is 67 years. In 2016, 1,090 Canadians were diagnosed with AML.¹ According to statistics from the Canadian Cancer Society, approximately 65% to 70% of patients achieve complete remission after induction therapy. However, the prognosis for AML appears to be poorer in those older than 60 years compared to younger patients; only 25% to 40% of those older than age 60 are expected to survive 3 years or longer. If an allogeneic stem cell transplant (SCT) is performed during the first remission, the 5-year disease-free survival rate is 30% to 50%. If there has been no recurrence by 2 years post-transplant, patients have about an 80% chance of staying in complete remission for a long period of time.¹

Standard treatment for patients who are medically fit consists of cytotoxic remission induction therapy with cytarabine combined with an anthracycline. Induction therapy is followed by high-intensity consolidation therapy. This may be accompanied by targeted therapy for specific clinical situations or genetic mutations. The determination of eligibility for intensive chemotherapy is based on patient age, fitness, and preference, and the presence of comorbidities. In general, intensive therapy is poorly tolerated by older patients. According to the 2017 Canadian consensus guidelines for the treatment of older patients with AML, induction therapy shows a survival benefit for patients up to age 80, with the exception of those who have major comorbidities or those with adverse risk cytogenetics who were not candidates for hematopoietic SCT. For patients who are not eligible for induction therapy, azacytidine (AZA) is recommended for those with adverse risk cytogenetics or transformed from myelodysplastic syndrome (MDS), while either hypomethylating agent (HMA) or low-dose cytarabine (LDAC) could be used for others.

The B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) is administered at a dose of 600 mg orally when combined with LDAC. The indication under review is VEN in combination with AZA or LDAC for the treatment of patients with newly diagnosed AML who are 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy. The sponsor’s reimbursement request is consistent with that of the indication. A concurrent CADTH review of VEN in combination with AZA is ongoing.

The objective of the current review is to perform a systematic review of the beneficial and harmful effects of VEN in combination with LDAC (VEN-LDAC) for the treatment of patients with newly diagnosed AML who are 75 years or older or who have comorbidities that preclude the use of intensive induction therapy.

Stakeholder Perspectives

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

Patient Input

• One patient group, the Leukemia & Lymphoma Society of Canada (LLSC), provided input for this review. The LLSC used an online survey, conducted between December 7, 2020, and January 24, 2021, to gather input. There were 29 patient respondents, ranging in age from 25 years to 84 years.

• Patients noted the impact that symptoms such as fatigue, suddenness of symptom development, anxiety, and fear of relapse have on their quality of life. Many patients reported symptoms that affected their social and family lives, and some noted that they were unable to work due to their condition.

• With respect to outcomes of importance to patients, respondents hoped that new treatment options could maintain remission. Quality of life was mentioned repeatedly. Patients also hoped that a new therapy would have fewer associated side effects. Patients appeared to value any treatment that could be administered on an outpatient basis or close to their home.

Clinician Input

Input From Clinical Experts Consulted by CADTH

• The clinical experts noted that current treatments have low rates of complete remission (CR), and that patients’ responses are not very durable when these do occur. They also noted that treatments that are associated with higher CR rates tend to have increased toxicity and are poorly tolerated in this population.

• The clinical experts noted that VEN combinations will likely become first-line treatments for patients who are not fit for induction chemotherapy, and that this will likely change the standard of care for AML. The preferred combination will likely be VEN in combination with an HMA; VEN-LDAC will likely be the treatment of choice in patients who have had prior HMA. The ability to administer VEN-LDAC at home will be an advantage for a certain subset of patients. In patients who have not received a prior HMA, the clinical experts recommended VEN plus an HMA, and also suggested that VEN plus an HMA may even be suitable in patients with prior HMA use. One clinical expert also noted that ivosidenib plus AZA may be reasonable in patients with IDH1 mutations, if available.

• With respect to VEN-LDAC, the clinical experts believed this combination would be the first-line treatment or standard of care in patients who are unfit for induction and who had received a prior HMA; they would not prescribe VEN-LDAC in patients who were eligible for induction. It is currently not possible to identify which patients would and would not respond to treatment. The outcomes used to determine response include complete blood count (CBC) and bone marrow blasts. A clinically meaningful response would be indicated by improved survival and CR rates, decreased hospitalizations and transfusion requirements, and decreased rates of progression. Response should be assessed after cycle 1 and cycle 2, with a response expected after a maximum of 2 cycles.

• The clinical experts agreed that disease progression and intolerable adverse events (AEs) were factors in the decision to discontinue treatment. Disease progression would be indicated by worsening CBC, increased marrow blasts, or loss of transfusion independence.

Clinician Group Input

• Two clinician groups provided input: the Canadian Leukemia Study Group (CLSG) and the Ontario Health (Cancer Care Ontario) Hematology Disease Site Drug Advisory Committee (OH HDSDAC).

• Neither of the 2 clinician groups held views that differed materially from those of the clinical experts consulted by CADTH for this review.

• Both clinician groups saw VEN-LDAC as replacing LDAC monotherapy in this patient population.

Drug Program Input

The drug programs indicated that the current treatment options for patients with newly diagnosed AML who are ineligible for intensive induction chemotherapy include AZA, LDAC, and best supportive care (BSC). It was noted that some patients 75 years of age and older may be fit to tolerate induction chemotherapy. The ramp-up dosing schedule for VEN with LDAC differs significantly from the ramp-up dosing schedule already in use for chronic lymphocytic leukemia (CLL) indications, and the current packaging for VEN is designed for the CLL ramp-up dosing schedule. The drug programs indicated that this combination treatment may change the place in therapy of comparator drugs. They also identified the potential for indication creep for patients with a high risk of MDS, patients who have progressed or had an inadequate response on low-dose chemotherapy for AML, and patients who have relapsed after induction chemotherapy (who are not eligible for SCT and are then treated with LDAC). It was noted that VEN-LDAC may require increased health care resources (i.e., related to hospital admission, additional pharmacy and nursing resources if management of tumour lysis syndrome [TLS] is necessary, monitoring for drug interactions, and home care resources and training if LDAC is administered at home). Affordability was also identified as an issue, given that VEN is an add-on to an existing treatment.

Clinical experts were consulted by CADTH for questions related to implementing VEN-LDAC into current provincial drug plans. Overall, most implementation questions related to the dosing schedule and administration and the eligible patient population.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

One study met the inclusion criteria for this review. The VIALE-C study is an ongoing, sponsor-funded, phase III, double-blind, randomized controlled trial (RCT) that compared VEN-LDAC (N = 143) to placebo plus LDAC (PLA-LDAC) (N = 68) in treatment-naive patients with AML who were ineligible for intensive induction chemotherapy. The study was conducted at 76 sites in 21 countries, including Canada (10 patients). The primary outcome was overall survival (OS). The secondary outcomes included CR with complete remission with incomplete blood count recovery (CR + CRi) rate, CR with complete remission with partial hematologic recovery (CR + CRh) rate, and event-free survival (EFS).

The majority of patients in the study were male (55.5%) and White (70.6%). The median age was 76 years (range = 36 to 93). The majority of patients had de novo AML (61.6%), while the remainder had secondary AML. The majority of patients (65.2%) had intermediate cytogenetic risk, while most of the remainder (32.8%) had poor cytogenetic risk. Most patients were considered ineligible for intensive induction chemotherapy based on age (≥ 75 years), followed by Eastern Cooperative Oncology Group Performance Status (ECOG PS) in patients 18 years to 74 years of age. Approximately 40% of patients were 75 years or older and had 1 comorbidity in addition to age.

Efficacy Results

The median OS at the final analysis (after a median follow-up of 12 months) in the VEN-LDAC group was 7.2 months versus 4.1 months in the PLA-LDAC group, for a hazard ratio (HR) of 0.75 (95% confidence interval [CI], 0.52 to 1.27; P = 0.114). Thus, the VIALE-C trial failed to meet its primary outcome because it did not demonstrate a statistically significant difference in OS at the final analysis data cut-off date. Nevertheless, Health Canada granted VEN-LDAC a Notice of Compliance (NOC) because of what it described as the “totality of the evidence”; namely, a clear, consistent difference in favour of the combined therapy of VEN-LDAC when compared to LDAC alone for other outcomes, including CR + CRi, CR + CRh, median duration of CR, and transfusion independence. At a post hoc 6-month follow-up analysis (after a median follow-up of 17.5 months), the median OS was 8.4 months in the VEN-LDAC group, and it remained at 4.1 months in the PLA-LDAC group, for an HR of 0.70 (95% CI, 0.50 to 0.99). These results for OS remained the same in a 12-month post hoc follow-up analysis.²

At the final analysis, the median EFS was 4.7 months (95% CI, 3.7 to 6.4) in the VEN-LDAC group and 2.0 months (95% CI, 1.6 to 3.1) in the PLA-LDAC group, for an HR of 0.58 (95% CI, 0.42 to 0.82; P = 0.002). At the time of the 6-month post hoc follow-up analysis, the EFS in the VEN-LDAC group was 4.9 months (95% CI, 3.7 to 6.4); in the PLA-LDAC group, it was 2.1 months (95% CI, 1.5 to 3.2), indicating a limited increase in EFS from the final analysis to the 6-month post hoc follow-up, for an HR of 0.61 (95% CI, 0.44 to 0.84).

At the final analysis, per investigator assessment, the CR + CRi rate was 47.6% (95% CI, 39.1% to 56.1%) in the VEN-LDAC group and 13.2% (95% CI, 6.2% to 23.6%) in the PLA-LDAC group. At the 6-month post hoc follow-up analysis, the CR + CRi rate was 48.3% (95% CI, 39.8% to 56.8%) in the VEN-LDAC group and was unchanged from the final analysis in the PLA-LDAC group.

At the final analysis, the CR + CRh rate was 46.9% in the VEN-LDAC group (95% CI, 38.5% to 55.4%) versus 14.7% in the PLA-LDAC group (95% CI, 7.3 to 25.4). At the 6-month post hoc follow-up analysis, the CR + CRh rate for patients in the VEN-LDAC group was 48.3% (95% CI, 39.8% to 56.8%), and was unchanged in the PLA-LDAC group at 14.7% (95% CI, 7.3% to 25.4%).

At the final analysis, the median time to first remission (CR + CRi) was 1.1 months (range = 0.8 to 4.7) in the VEN-LDAC group and 3.7 months (range = 0.9 to 6.5) in the PLA-LDAC group. At the 6-month post hoc follow-up analysis, the median time to first remission (CR + CRi) was similar to the results from the final analysis.

At the final analysis, the median duration of remission (DOR) (CR + CRi) was 10.8 months in the VEN-LDAC group and 6.2 months in the PLA-LDAC group. At the 6-month post hoc follow-up analysis, the median DOR (CR + CRi) was 11.7 months in the VEN-LDAC group. It remained at 6.2 months in the PLA-LDAC group.

At the final analysis, transfusion independence (red blood cell [RBC] and platelet) was achieved by 37.1% of patients in the VEN-LDAC group and by 16.2% of patients in the PLA-LDAC group. At the 6-month post hoc follow-up analysis, transfusion independence was achieved by 39.2% of patients in the VEN-LDAC group and by 17.6% of patients in the PLA-LDAC group. Therefore, there was a slight increase in the percentage of patients who were transfusion-independent in each treatment group from the final analysis to the 6-month post hoc follow-up analysis.

Harms Results

At the time of the 6-month post hoc follow-up analysis, 99.3% of patients in the VEN-LDAC group and 98.5% of patients in the PLA-LDAC group experienced at least 1 AE. The most common AEs (VEN-LDAC versus PLA-LDAC) were neutropenia (45.8% versus 17.6%), thrombocytopenia (45.8% versus 39.7%), nausea (43.0% versus 30.9%), diarrhea (33.1% versus 17.6%), and febrile neutropenia (32.4% versus 29.4%). Grade 3 or higher AEs occurred in 97.2% of patients in the VEN-LDAC group and in 95.6% of patients in the PLA-LDAC group. The most common were neutropenia (48.6% versus 17.6%), thrombocytopenia (45.8% versus 38.2%), and febrile neutropenia (32.4% versus 29.4%).

Serious adverse events (SAEs) occurred in 66.9% of patients in the VEN-LDAC group and in 61.8% of patients in the PLA-LDAC group. The most common SAEs (VEN-LDAC versus PLA-LDAC) were febrile neutropenia (16.9% versus 17.6%) and pneumonia (14.1% versus 10.3%).

AEs leading to death occurred in 23.2% patients in the VEN-LDAC group versus 20.6% of patients in the PLA-LDAC group. The most common AE that led to death in the VEN-LDAC group was pneumonia, which occurred in 4.9% of patients treated with VEN-LDAC and in 0 patients treated with PLA-LDAC.

Notable harms included infections, which were under the broader category of infections and infestations; 64.8% of patients in the VEN-LDAC group and 60.3% of patients in the PLA-LDAC group experienced an event. Pneumonia was the most common infection, occurring in 21.8% and 16.2% of patients in the VEN-LDAC and PLA-LDAC groups, respectively. All of the following notable harms occurred more frequently in the VEN-LDAC group: second primary malignancy in 2.1% versus 0% of patients, TLS in 5.6% versus 0% of patients, and hemorrhage in 41.5% versus 30.9% of patients. Any AE of neutropenia was reported in 68.3% and 45.6% patients, respectively.

Critical Appraisal

• The VIALE-C study failed to meet its primary outcome of OS. However, it is plausible for a trial not to meet a pre-specified end point when the parameters used for statistical planning are unknown or uncertain at the time a trial is executed. Therefore, it was not surprising to see a greater difference in OS at the 6-month post hoc follow-up analysis, by which time more deaths had occurred. All of the secondary outcomes assessed in the trial consistently demonstrated improvement in favour of VEN-LDAC over PLA-LDAC.

• A large number of patients withdrew from the study, and there were numerically fewer withdrawals in the VEN-LDAC group than in the PLA-LDAC group (72.0% versus 82.4% of patients, respectively). Most of these withdrawals were due to deaths, and this also accounted for the difference between groups. This difference in withdrawals may have affected the interpretation of patient-reported outcomes and harms. The VEN-LDAC group also had longer exposure to the study drug.

• The population included in the VIALE-C study was consistent with the population one would expect to use VEN-LDAC in Canada, according to the clinical experts consulted by CADTH. Dosing of LDAC may have been different in the VIALE-C study — which used body surface area to determine dosing — than in Canada, where a flat dose tends to be used.

Indirect Comparisons

Description of Studies

A systematic review and network meta-analysis (NMA) were conducted of trials comparing VEN-LDAC, venetoclax plus azacitidine (VEN-AZA), LDAC, AZA, and BSC in adults with AML who were not eligible for standard induction chemotherapy. Data were available for OS for 4 trials in a connected network and for CR + CRi for 3 trials.

Efficacy Results

For OS, VEN-LDAC was favoured over LDAC (HR = 0.70; 95% credible interval, 0.50 to 0.99) and BSC (HR = 0.46; 95% credible interval, 0.26 to 0.81), with no difference seen between VEN-LDAC and AZA (HR = 0.82; 95% credible interval, 0.54 to 1.24) or between VEN-LDAC and VEN-AZA (HR = 1.23; 95% credible interval, 0.76 to 2.01). For CR + CRi, VEN-LDAC was favoured over LDAC (odds ratio [OR] = 6.24; credible interval, 2.98 to 14.42), AZA (OR = 5.84; credible interval, 2.39 to 15.22), and BSC (OR = 73.35; 95% credible interval, 8.05 to 2,370.88), with no difference seen between VEN-LDAC and VEN-AZA (OR = 1.16; 95% credible interval, 0.43 to 3.33).

Harms Results

No analysis of harms was included in the NMA.

Critical Appraisal

A key limitation of the NMA was the clinical heterogeneity between studies in important prognostic indicators and potential treatment-effect modifiers of blast count at baseline, prior treatment with HMAs, and cytogenetic risk. Because the network was sparse, fixed-effects models had to be used, and there was no opportunity for baseline covariate adjustments. Due to the previously described limitations, the comparative efficacy estimates may be biased, and it is not possible to quantify or identify the direction of the bias. Certain estimates, particularly for CR + CRi, were highly imprecise because of low numbers of responses in some study arms.

Conclusions

One multinational, sponsor-funded, double-blind, placebo-controlled RCT was included in this review. The VIALE-C trial evaluated the treatment effect of a combination therapy of VEN-LDAC compared to LDAC alone in patients with AML who were ineligible to receive intensive induction chemotherapy. Although results for the primary outcome, OS, were not statistically significant, there were consistent improvements in secondary outcomes, such as EFS, CR + CRi rate, CR + CRh rate, and transfusion independence in favour of VEN-LDAC versus LDAC alone. Health-related quality of life (HRQoL) and symptoms (fatigue) are deemed important outcomes by patients; however, these analyses were confounded by the large amount of attrition that occurred in both treatment groups and the early failure of the statistical testing hierarchy of outcomes. The treatment effects of VEN-LDAC and VEN-AZA may be comparable; however, comparative efficacy was based on a small indirect treatment comparison (ITC) with limitations, and only OS and CR + CRi were assessed. It remains uncertain whether VEN-LDAC is better than AZA alone, given that the ITC failed to show consistent results based on OS and CR + CRi. Neutropenia was the most common AE associated with the use of VEN-LDAC, and although there was no clear indication of more infections, there did appear to be numerically more cases of pneumonia compared to LDAC alone.

Introduction

Disease Background

AML is a hematopoietic neoplasm that is characterized by an abnormal proliferation of immature blast cells from the bone marrow that do not differentiate into red blood cells, platelets, and granulocytes, ultimately resulting in a variety of cytopenias. WHO defines AML as having greater than 20% blast cells in peripheral blood or bone marrow. Initial presentation is often a manifestation of these various cytopenias because patients may be fatigued (anemia) or suffer from an infection (neutropenia) or bleeding (thrombocytopenia). AML is the second-most common leukemia in adults, with most cases occurring in older adults; the median age of onset is 67 years. In 2016, 1,090 Canadians were diagnosed with AML.¹ According to statistics from the Canadian Cancer Society, approximately 65% to 70% of patients achieve CR after induction therapy.¹ The prognosis for AML appears to be poorer in patients over the age of 60 compared to younger patients, including those who have unfavourable cytogenetics and multidrug resistance. Approximately 25% to 40% of patients over the age of 60 are expected to survive 3 years or more. The risk of secondary AML (due to MDS or therapy for other malignancies) also appears to increase with age; this also predicts a poor prognosis.⁴ If an allogeneic SCT is performed during the first remission, the 5-year disease-free survival is 30% to 50%. If there is no recurrence by 2 years post-transplant, patients have about an 80% chance of staying in CR for a long period of time.¹

Standards of Therapy

Standard treatment for patients who are medically fit consists of cytotoxic remission induction therapy with cytarabine, administered by infusion over 7 days, combined with an anthracycline, usually daunorubicin or idarubicin, given daily for the first 3 days. Induction therapy is followed by high-intensity consolidation therapy. This may be accompanied by targeted therapy for specific clinical situations or genetic mutations: midostaurin in patients with FLT3 mutation and gemtuzumab ozogamicin (a monoclonal antibody against CD33) in patients with favourable- and intermediate-risk disease.

The determination of eligibility for intensive chemotherapy is based on patient age, fitness, and preference, and on the presence of comorbidities. In general, intensive therapy is poorly tolerated by older patients. According to the 2017 Canadian consensus guidelines for treatment of older patients with AML, induction therapy shows a survival benefit for patients up to age 80, with the exception of those patients with major comorbidities or adverse risk cytogenetics who are not candidates for hematopoietic SCT. Daunorubicin is the recommended drug for induction therapy, with midostaurin added for patients aged 70 years or younger with an FLT3 mutation, and gemtuzumab ozogamicin added for patients aged 70 years or younger with de novo AML and favourable- or intermediate-risk cytogenetics. For patients who are not eligible for induction therapy, AZA is recommended for those with adverse risk cytogenetics or transformed from MDS, while either HMA or LDAC can be used for others.

In the past decade, there has been a growing trend toward treating more elderly patients (65 years to 80 years) with AML. The elderly pose additional challenges and considerations when it comes to treatment, including toxicity and tolerability issues, and as noted previously, they have a poorer prognosis than younger patients at baseline. According to the clinical experts consulted by CADTH for this review, patients who are not eligible for induction chemotherapy can receive AZA, LDAC, BSC, or other drugs in clinical trials as first-line therapies. According to the clinical experts, approximately 10% of patients older than 75 years are eligible for induction chemotherapy (depending on their disease risk and performance status), although few patients over 80 would be eligible. VEN-AZA, which is also being reviewed by CADTH, is likely to be used ahead of VEN-LDAC, except in most patients who have had prior treatment with an HMA.

The key goals of treatment are to prolong survival, induce remission, decrease the number of hospital visits and transfusion requirements, and improve HRQoL. In AML, CR and response are considered surrogates for those outcomes. Not all patients respond to first-line therapy, and all eventually become refractory to current treatment options, with limited life expectancy. There are few effective treatment options following relapse on front-line AML therapy; many patients will receive a drug that is an alternative to the one initially given (e.g., LDAC following AZA) or off-label AZA (with or without VEN), or will participate in a clinical trial. A minority of patients with FLT3 mutations receive gilteritinib, but many patients are not well enough to tolerate further therapy; hence, they receive BSC only.

Drug

VEN is an orally administered selective inhibitor of the anti-apoptotic protein BCL-2, which is overexpressed and appears to contribute to cancer cell survival in various malignancies, including hematologic. It may also be associated with resistance to chemotherapy.

VEN was granted a Health Canada NOC on December 4, 2020. The approved indication is for VEN (Venclexta) in combination with AZA or LDAC for the treatment of patients with newly diagnosed AML who are 75 years of age or older, or who have comorbidities that preclude the use of intensive induction therapy.⁵ This indication is consistent with the reimbursement request. VEN underwent expedited review under Project Orbis.

After an initial dose ramp-up of 4 days, VEN is administered at a dose of 600 mg orally when combined with LDAC (administered at a dose of 20 mg/m² subcutaneously once daily on day 1 to day 10 of each 28-day cycle). According to the product monograph, VEN in combination with LDAC should be continued if the patient is considered to be deriving clinical benefit or until unacceptable toxicity is observed. It is recommended that patients without unacceptable toxicity be treated for a minimum of 6 cycles. VEN is also indicated for use in CLL, either alone or in combination with obinutuzumab or rituximab.⁵

Table 3 summarizes the characteristics and indications for VEN, AZA, and LDAC.

Patient Group Input

This section was prepared by CADTH staff based on the input provided by the patient group.

About the Patient Group and Information Gathered

One patient advocacy group, the LLSC, provided input on VEN-LDAC for the treatment of AML. The LLSC’s mission is to cure leukemia, lymphoma, Hodgkin’s disease, and myeloma, as well as to improve the quality of life of all Canadians affected by blood cancers. The LLSC has received funding from AbbVie.

The LLSC used an online survey to gather information for its submission. The survey was conducted from December 7, 2020 to January 24, 2021.

Respondents included 29 patients, all from Canada: 13 from Ontario, 6 from Quebec, 6 from British Columbia, and 4 from Alberta. Patients’ ages ranged from 25 years to 84 years; 2 were aged 75 years or older. There were 18 females and 10 males. One did not report gender. Information on comorbidities was not reported. All patients had been diagnosed with AML within the past 7 years. None of the respondents had experience with VEN-LDAC.

Disease Experience

According to the patients with AML who responded to the LLSC survey, the symptoms that affect their quality of life include fatigue, suddenness of symptom development, anxiety, fear of relapse (number of patients unspecified for preceding symptoms), and loss of eyesight (n = 1). One patient experienced a ruptured spleen and was in a coma for 8 days. Fatigue was the symptom mentioned most often. Fatigue and other symptoms affect social and family life. Some patients reported that these symptoms were compounded by changes related to the coronavirus 2019 (COVID-19) pandemic, leading to further social isolation. Some patients reported that they are unable to work due to their disease and associated symptoms. Many patients did not provide information about the specific symptoms they experienced but described being diagnosed with AML as a life-changing event. The following are comments from patients regarding their experiences with AML:

Pre-diagnosis, I was very, very active, holding 3 jobs that equalled a full pay cheque — librarian in the morning, massage therapist 3 afternoons, and teaching at a local university on the weekends. As I become ‘sicker,’ I could barely walk across the room. The day I was diagnosed, I was wheeled up to the cancer ward from emergency and was there for 5 months. Everything in my life stopped cold turkey — employment, social life, relationships, etc. I made a complete personal 360 degree pivot to focus on my healing and living.

Well COVID and my compromised immune system has caused me to be very socially isolated. I haven't seen some very important people in my life for almost 2 years at this point. Symptoms have also caused an impact to my physical fitness and being able to do things that I normally would.

When asked if there are any aspects or symptoms of AML that are easier to control, most patients (n = 7) indicated no, and 1 commented that there was no control with AML. Three patients indicated that exercise was helpful in alleviating some symptoms. They reported that exercise and keeping active helped, particularly with fatigue.

Two patients reported feeling no impact or felt back to normal at the time of survey.

AML affects not only those who are diagnosed, but also their caregivers. These may include a spouse, immediate family members, and friends. Patients considered the emotional support they received from caregivers as important and reported that they required assistance for medical visits and daily activities. According to the LLSC survey, patients reported that caregivers may feel multiple emotions about the patient’s AML; stress, worry, sadness, insecurity, and fear of dying were all frequently mentioned. Their companion through the disease journey was important for patients.

Experiences With Currently Available Treatments

According to the LLSC survey, the front-line treatments that patients received after diagnosis included chemotherapy (n = 24), SCT or bone marrow transplant (n = 16), drug therapy (n = 6), radiation therapy (n = 5), and chimeric antigen receptor T-cell therapy (n = 1). Two patients cited specific drugs they had received: 1 reported receiving treatment with VEN, and the other received Vyxeos (daunorubicin and cytarabine). Patients reported a wide range of side effects with current treatments. Those they considered to have a large impact on their quality of life included hair loss (n = 17), weakness (n = 15), extreme fatigue (n = 14), diarrhea (n = 10), infections (n = 8), anemia (n = 8), mouth sores (n = 8), nausea and vomiting (n = 7), fever (n = 6), low blood cell counts (n = 6), tingling sensations (n = 4), constipation (n = 2), graft-versus-host disease (n = 2), lung, heart, kidney, or nerve problems (n = 2), cough (n = 1), rashes (n = 1), shortness of breath (n = 1), and psychological distress (n = 1). Patients frequently mentioned the side effects of chemotherapy and SCT and the impact of these treatments on their quality of life. These side effects from front-line treatments affected patients in terms of physical activity (n = 15), eating challenges (n = 12), anxiety (n = 11), and problems in mental health and overall happiness (n = 11), social development (n = 6), and educational development (n = 6). Overall, the side effects from front-line therapies caused significant disturbance to daily living and quality of life. During SCT, patients were at risk of opportunistic infections and were isolated from visitors. The following are comments from patients regarding their experiences with front-line AML treatments:

• “The main challenge was the nausea and vomiting. I didn’t seem to have much control over it and had my wonderful bucket always with me. I could be fast asleep and awake and vomit.”

• “Your whole world changes when you are diagnosed with AML. Suddenly, you confront your mortality. You feel extremely weak, you have to go into hospital for months, and you don't realize you MUST go into remission to have a stem cell transplant.”

• “Extremely tired and little desire to be active. Difficulty eating and keeping it down. A few days of low hemoglobin and fluid on the lung that caused shortness of breath.”

• “The worst issue is that I have no more job and that the treatments made me lose a lot of concentration and I get exhausted easily.”

• “Had to move to Vancouver for treatment for 9 months. Two or 3 months total in hospitals. Daily outpatient care. Kinda turns your life upside-down.”

Patients who responded to the LLSC survey reported a mixture of positive and negative experiences accessing treatments. Thirteen respondents reported generally positive experiences, and some attributed their experience to the support from medical staff. Six patients reported negative experiences. Negative experiences were related to challenges with receiving care and being informed about treatment plans. Some patients needed to relocate to receive their treatment.

Improved Outcomes

• The majority of respondents to the LLSC survey indicated that the factors they considered when evaluating a new cancer treatment were physician recommendation (n = 19), possible impact on disease (n = 17), quality of life (n = 12), closeness to home (n = 9), and outpatient treatment (n = 8).

• The LLSC survey respondents also reported that they hoped new treatment options could maintain remission, be targeted and have fewer side effects, be covered by public plans, and be accessible in more geographic regions. The opportunity to have access to other supportive options, such as meditation, hypnosis, neuro-linguistic programming support, and awareness support (thoughts, emotions, and behaviours), was also mentioned.

Experience With the Drug Under Review

None of the LLSC respondents had experience with VEN-LDAC.

Companion Diagnostic Test

Not applicable.

Additional Information

Not applicable.

Clinician Input

Input From Clinical Experts Consulted by CADTH

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

Unmet Needs

Key goals of treatment include prolonging survival, inducing remission, decreasing hospitalizations and transfusion requirements, and improving HRQoL. The clinical experts indicated that current lower-intensity treatments have low rates of CR, and the CR rates that occur are not durable. Treatments with intensive chemotherapy are associated with higher CR rates but tend to have increased toxicity and are not well tolerated in the population under review.

Place in Therapy

The clinical experts indicated that VEN combinations will likely become the new standard of care for the first-line treatment of patients aged 18 years or older with AML who are not eligible for induction chemotherapy. VEN in combination with an HMA is expected to be the preferred combination, although VEN will be used in combination with LDAC in some patients who have received prior treatment with an HMA. Overall, VEN-LDAC will likely be used in a smaller number of patients than will VEN-AZA, although an advantage of VEN-LDAC will be the ability to administer the treatment at home. For patients with treatment-naive AML aged 75 years or older who are eligible for intensive chemotherapy, especially those with good- or intermediate-risk cytogenetics, there would have to be a discussion with the patient about the risks and benefits of the potential different treatment options. It should be noted there is no consistency as to the upper age limit at which an acute leukemia treatment centre would administer intensive chemotherapy. Given that VEN-LDAC is myelosuppressive, it may not be suitable for a small number of frail patients, or for those who would be unable to travel to the treating hospital for count checks. This, too, would need to be an assessment made by the treating physician in conjunction with the patient.

Patient Population

VEN-LDAC will be most suited for patients who have AML and are unfit for induction, and who have received a prior HMA. The identification of these patients will likely be based on clinical judgment and patient preference. There is also a subset of patients who may be fit for induction chemotherapy but choose VEN-LDAC based on their goals of care, toxicity profile, and lifestyle factors, such as distance from hospital. Patients should have a diagnosis of AML with greater than 20% blasts. The use of therapy will not be dependent on symptoms. At present, it is not possible to identify patients who are more or less likely to respond to VEN-LDAC.

Patients with good risk cytogenetics and patients with myeloproliferative neoplasm in blast crisis have been excluded from studies of VEN-LDAC, as have patients with isolated granulocytic sarcoma. One clinical expert indicated that clinical studies suggest that response to VEN plus an HMA in patients with prior HMA exposure is similar to the response observed with VEN-LDAC; however, there are no direct comparisons of these 2 treatments post-HMA. Patients with central nervous system (CNS) involvement by AML have been excluded from all AML studies, but this does not mean that this group of patients would not benefit from VEN-LDAC with concomitant intrathecal therapy, similar to the current practice of administering systemic intensive chemotherapy and intrathecal therapy to those patients who have CNS involvement by AML.

Assessing Response to Treatment

The outcomes used to measure response include CBC and bone marrow blasts, although 1 clinical expert noted that the strict definitions of response do not always capture responding patients. A clinically meaningful response would be indicated by improved survival, CR rate, decreased need for hospitalization and transfusion, and decreased rate of progression. One clinical expert indicated that response should be assessed using bone marrow biopsy after the first and second cycle, and a response would be expected after 2 cycles if there is going to be a response. The other clinical expert indicated that response should be assessed at minimum after 4 cycles to 6 cycles, but that most clinicians assess after the first cycle, given cost and to guide the dosing of VEN for subsequent cycles. Once a response is obtained, then CBC could be followed for evidence of progression.

Discontinuing Treatment

The experts agreed that disease progression and intolerable AEs were factors in the decision to discontinue treatment. Disease progression would be indicated by worsening CBC, increased marrow blasts, or loss of transfusion independence. The clinicians could not comment on whether VEN could be continued as a single drug if a patient stopped LDAC.

Prescribing Conditions

The clinical experts indicated that a hospital or outpatient clinic would be an appropriate setting for treatment. Because VEN-LDAC is myelosuppressive, physicians should have experience in looking after acute leukemia patients. Patients might require hospital admission for VEN dose ramp-up. The proportion of patients depends upon the population: 1 clinician indicated that the proportion would be small, and another that it could be 25% to 50%. Patients would also require pre-treatment and monitoring for TLS, which occurs in 1% to 2% of patients. A not-insignificant proportion of patients will need to be hospitalized for neutropenic fever and other complications during their cycle of therapy. Pharmacists would be involved in reviewing medications, given that a significant proportion of patients are on azoles, which interact with VEN and require dose modifications.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

Two group clinician inputs were provided for the reimbursement review of VEN-LDAC for the treatment of AML.

The CLSG is a cross-Canada collective of physicians who treat acute leukemia, representing all major leukemia centres in all Canadian provinces. CLSG notes that its mission is to “improve the diagnosis and treatment of leukemia in Canada, by identifying diagnostic and management best practices, promoting Canada-wide standards of care, fostering clinical and basic leukemia research and improving new drug access.” CLSG gathered information for this review from its board members, who are all leukemia physicians working in academic, university-based treatment settings. CLSG opinions were formulated through ongoing group discussions and polling of members. Input was also requested from other international experts, as appropriate. Written opinions were further reviewed, edited, and approved by the group.

The OH HDSDAC provided evidence-based clinical and health system guidance on drug-related issues in support of Cancer Care Ontario’s mandate, including the Provincial Drug Reimbursement Programs and Systemic Treatment Program. Information for this submission was collected through joint discussions at the Disease Advisory Committee meeting.

Unmet Needs

The CLSG noted that approximately 40% to 50% of newly diagnosed patients with AML are judged to be unfit for intensive induction chemotherapy. CLSG added that these patients are generally older than 75 years of age or younger with severe comorbidities. For these patient populations, both clinician groups noted that the current standard of care treatments include AZA and LDAC along with BSC. The CLSG added that AZA is only approved for patients with AML with 20% to 30% blasts; however, it is widely used in Canada for patients with greater than 30% blasts.

The CLSG noted that for patients with poor-risk cytogenetics or AML transformed from MDS, AZA is the current treatment of choice; however, for patients with AML arising de novo with standard-risk cytogenetics, both AZA and LDAC can be used. CLSG added that in real-world clinical practice, many Canadian patients are not able to receive AZA-based therapy because, given its instability after reconstitution, the drug needs to be given in an oncology clinic setting. The CLSG also noted that for patients who live in rural or remote areas — and for some patients in urban settings — regular travel to these clinics may be problematic because of patient frailty and difficulty obtaining suitable transportation. It was also noted that unlike AZA, LDAC is stable for up to 14 days and can be administered at home, either by self-injection or by a home care nurse; further, this regimen requires only 1 clinic visit per month to receive the medicine and is considerably less costly than AZA and well tolerated. The CLSG estimated that approximately 70% to 75% of unfit patients with AML who receive treatment will receive AZA, and about 25% to 30% will receive LDAC. The group referenced the Canadian consensus guidelines for the use of these drugs.

Both clinician groups noted that the goals of treatment for this population are to improve survival, improve or maintain quality of life, and achieve transfusion independence (including improving hematopoiesis), given that the latter is an important surrogate determination of HRQoL.

Both clinician groups noted that currently available treatments offer a short survival advantage and short duration of transfusion independence for this patient population, and that overall response rates are low, with remission rates in the range of 15% to 25%. The CLSG also noted that nearly all patients who respond will become resistant and experience disease progression, usually within months; the median OS is approximately 4 months to 7 months with LDAC and 7 months to 10 months with AZA. The CLSG emphasized that AZA treatment requires frequent clinic visits for injections, which may not be feasible for many frail, older patients, especially those who live far from cancer centres.

Both clinician groups noted that the patients with the greatest unmet needs are those with AML who are not eligible for standard 7 + 3 induction therapy. This includes patients who are older or have comorbidities, because they generally have poor response rates and outcomes with standard therapies. The CLSG added that those who live farther away from cancer centres face the greatest unmet needs and challenges; according to CLSG, VEN-LDAC would provide the greatest benefit for those patients because they would be able to receive this treatment at home.

Place in Therapy

Both clinician groups agreed that VEN-LDAC would replace LDAC monotherapy. The CLSG added that VEN-LDAC would become the treatment of choice for previously untreated, unfit patients with AML who are unable to regularly visit a clinic for treatment (due to distance from a cancer centre, patient frailty, or lack of suitable transportation). The CLSG further noted that treatment with VEN-LDAC would be suitable for patients who have progressed to AML while receiving treatment with AZA for MDS. Given that most of these patients already receive LDAC, the CLSG noted that the addition of VEN would greatly improve response rates and allow for transfusion independence, thereby improving quality of life.

Both clinician groups indicated that it would not be appropriate for patients try other treatments before initiating treatment with VEN-LDAC because the submission is for first-line treatment, and the VIALE-C trial only included previously untreated patients with AML.

Both clinician groups also noted that the combination under review will replace the current first-line treatment. The CLSG noted that if treatment with VEN-LDAC fails, patients could potentially receive AZA if they have not previously received it. The CLSG reasons that this is done frequently for LDAC failures at present.

Patient Population

Both clinician groups noted that older, frail patients, or those with considerable comorbidities, would be best suited for treatment with VEN-LDAC. The OH HDSDAC added that no companion diagnostics are required to identify the patient population best suited.

Both clinician groups indicated that the patients who are least suitable for treatment with VEN-LDAC are those who are easily able to travel to a clinic to receive AZA injections and who have not previously received AZA or decitabine treatment; these patients would be offered VEN-AZA. The groups added that VEN-LDAC may be more suitable for the very frail or very elderly. Patients who have an ECOG PS of 4 due to major comorbidities (e.g., are incapacitated due to major stroke or advanced dementia) would, in most cases, receive BSC. The OH HDSDAC added that subcutaneous LDAC can be given by home care.

The CLSG identified patients with standard-risk cytogenetics to have better OS; however, they indicated that all patients could benefit from treatment with VEN-LDAC.

Assessing Response to Treatment

Both clinician groups noted that blood counts should be monitored frequently, particularly during the initial treatment cycles, and that the indicators of response include improvement in blood counts, achievement of CR (less than 5% blasts in a cellular marrow), and transfusion independence.

Both clinician groups also agreed that an improvement in hematopoiesis would be considered a clinically meaningful response to treatment with VEN-LDAC. The CLSG added that a CR with achievement of transfusion independence would be of major clinical benefit to patients. The advantages include not having to return to clinic frequently for red cell and platelets transfusions and chemotherapy injections, improvement in fatigue, and lower risk of bleeding and infections. The CLSG noted that these advantages were demonstrated in the clinical study through sustained improvements in the fatigue and Global Health Status/Quality of Life scores compared with LDAC alone.

Both clinician groups agreed that frequent and regular CBCs should be performed to assess response to treatment because treatment delays and dose modifications may be needed. The OH HDSDAC added that bone marrow assessments should be performed as needed and based on clinical judgment. The CLSG indicated that patients should be re-evaluated for response every 4 weeks (at the start of each treatment cycle) and that bone marrow assessment may be performed after 1 to 2 cycles to assess remission status.

Discontinuing Treatment

Both clinician groups indicated that disease progression at any time (significant increase in blasts in the marrow or blood) would be considered a factor for treatment discontinuation. The CLSG added that lack of objective hematologic response after 4 treatment cycles should be considered cause for treatment discontinuation. The OH HDSDAC also indicated that treatment-related toxicities and patient preference should be considered when deciding to discontinue treatment.

Prescribing Conditions

Both clinician groups agreed that outpatient-specialized hematology or leukemia clinics, either community-based or at academic centres, are appropriate settings for treatment with VEN-LDAC. Both clinician groups indicated that patients may be admitted as inpatients due to TLS or AML complications while they continue with treatment. The CLSG noted that treatment should be administered and supervised by a hematologist with expertise in managing acute leukemia patients and experience in the use of VEN.

Additional Considerations

The OH HDSDAC added that VEN dose adjustments with co-administration of an azole are sometimes required. In the pivotal study (VIALE-C trial), the LDAC dose is lower than what is commonly used in Canadian practice. The OH HDSDAC also indicated that in patients who present with hyperleukocytosis, a longer ramp-up phase should be considered when initiating VEN.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation.

The drug programs indicated that current treatment options for patients newly diagnosed with AML who are ineligible for intensive induction chemotherapy include AZA, LDAC, and BSC. It was noted that some patients 75 years of age and older may be fit to tolerate induction chemotherapy. The ramp-up dosing schedule for VEN-LDAC differs significantly from the ramp-up dosing schedule already in use for CLL indications, and the current packaging for VEN is designed for the CLL ramp-up dosing schedule. The sponsor provided additional information related to this concern, stating that the ramp-up schedule is more gradual for CLL because the dosage starts at 20 mg per day and is increased over a period of 4 weeks, whereas the ramp-up schedule for VEN-LDAC in AML starts at 100 mg and lasts only 4 days. Therefore, for patients with AML, physicians will have the option of either ordering the appropriate number of 100 mg tablets for the ramp-up or initiating treatment with the standard bottle of 100 mg tablets. The drug programs indicated that VEN-LDAC may change the place in therapy of comparator drugs. They also identified the potential for indication creep for patients with a high risk of MDS, those who have progressed or have had an inadequate response on low-dose chemotherapy for AML, and those who have relapsed after induction chemotherapy, are not eligible for SCT, and are then treated with LDAC. It was noted that the treatment combination may require increased health care resources (i.e., hospital admission, additional pharmacy and nursing resources to manage TLS if needed and monitor for drug interactions, and home care resources and training if LDAC is administered at home). Affordability was also identified as an issue because VEN is an add-on to existing treatment.

The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Clinical Evidence

The clinical evidence included in the review of VEN-LDAC is presented in 3 sections. The first section, the Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of VEN in combination with LDAC for the treatment of patients with newly diagnosed AML who are 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5.

Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist (https://www.cadth.ca/resources/finding-evidence/press).⁸

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) through Ovid and Embase (1974‒) through Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Venclexta (venetoclax) and AML. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 1 for the detailed search strategies.

The initial search was completed on February 11, 2021. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee on June 10, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the CADTH Grey Matters: A Practical Tool for Searching Health-Related Grey Literature checklist.⁹ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 1 study was identified from the literature for inclusion in the systematic review (Figure 1).¹⁰ The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

VIALE-C

The VIALE-C study is an ongoing, sponsor-funded, phase III, double-blind RCT that compared VEN-LDAC (N = 143) versus PLA-LDAC (N = 68) in treatment-naive patients with AML who were ineligible for intensive induction chemotherapy. Randomization was stratified by AML status (secondary, de novo), age (18 years to < 75 years, ≥ 75 years), and region (US, EU, China, Japan, rest of world). The trial was conducted at 76 sites in 21 countries, including Canada (10 patients).

The primary objective of the trial was to evaluate whether VEN-LDAC improves OS versus PLA-LDAC in treatment-naive patients with AML. The secondary objectives were to evaluate whether VEN-LDAC improved CR + CRi, CR + CRh, CR + CRi by the initiation of cycle 2, CR + CRh by the initiation of cycle 2, CR, rate of transfusion independence, fatigue, HRQoL, minimal residual disease response rate, EFS, and response rates and OS in molecular subgroups like IDH1, IDH2, and FLT3. Definitions and further details of outcomes are provided in Table 8.

There was a 21-day screening period, although bone marrow samples and peripheral blasts used for AML diagnosis could be collected within 30 days of randomization. A total of 255 patients were screened, and 211 were randomized. Randomization was stratified by AML status (secondary or de novo), age (18 years to < 75 years, ≥ 75 years), and region (US, Europe, China, Japan, rest of world).

An interim analysis of OS was performed by the independent data monitoring committee based on a data cut-off date of October 1, 2018, when 100 OS events (75%) were observed. After the data were reviewed and extracted for the interim analysis, the total number of OS events included in the full analysis set by the October 1, 2018, cut-off date was 103. When making the decision to recommend termination of the study, the committee used a stopping boundary for the final analysis based on the number of accrued events (N = 133) and an efficacy stopping boundary (one-sided P value) of P = 0.022 (HR = approximately 0.690). The final analysis had a cut-off date of February 15, 2019.

The clinical study report presented efficacy data for the final analysis (data cut-off date of February 15, 2019) as well a 6-month post hoc follow-up analysis based on a data cut-off of date of August 15, 2019. Safety data were presented for patients through 6 months of follow-up.

Populations

Inclusion and Exclusion Criteria

Eligible patients had to be 18 years or older with histologically confirmed AML (WHO criteria) and be considered ineligible for intensive induction chemotherapy on the basis of age (≥ 75 years) or significant cardiac, pulmonary, renal, hepatic, or other comorbidity (refer to Table 6) that the investigator believed could make them incompatible with conventional intensive chemotherapy. Patients aged ≥ 75 years had to have an ECOG PS of 0 to 2; those aged 18 years to 74 years could have an ECOG PS of 0 to 3. Patients also had to have a projected life expectancy of greater than 12 weeks, and adequate renal and hepatic function.

Reasons for exclusion from the trial included having received any prior treatment for AML (with the exception of hydroxyurea, if patients had any antecedent myeloproliferative neoplasm, or acute promyelocytic leukemia). Patients with CNS involvement were also excluded, as were those with HIV, hepatitis B or C, or New York Heart Association disability status greater than 2.

Baseline Characteristics

The majority of patients in the study were male (55.5%) and White (70.6%); the median age was 76 years (range = 36 to 93) (Table 7). The majority of patients had de novo AML (61.6%), while the remainder had secondary AML. Most of the patients with secondary AML had MDS. The majority of patients (65.2%) had intermediate cytogenetic risk, and most of the remainder (32.8%) had poor cytogenetic risk. With respect to performance status, 48.8% of patients had an ECOG PS of 2 or more.

The majority of patients were considered ineligible for intensive chemotherapy based on age (≥ 75 years), followed by ECOG PS in patients 18 years to 74 years of age. Approximately 40% of patients 75 years or older also had 1 comorbidity in addition to age.

The treatment groups were generally well-balanced with respect to demographics and clinical characteristics at baseline; there were small numerical differences between the VEN-LDAC and PLA-LDAC groups for ECOG PS of 2 (44.1% versus 36.8%, respectively), patients with secondary AML (40.6% versus 33.8%) and those with grade 4 neutropenia (54.9% versus 44.1%).

Interventions

VEN or placebo tablets were administered by patients once daily and dosed before LDAC on days when LDAC was administered. LDAC was administered by a trained provider as a subcutaneous injection daily at a dose of 20 mg/m² on day 1 to day 10 of each 28-day cycle.

Patients continued treatment until documented (investigator-assessed) disease progression, unacceptable toxicity, withdrawn consent, or if they met protocol criteria for discontinuation. Treatments could be administered in hospital, in clinic, or at home, depending on local regulations. VEN was initiated with a 4-day ramp-up, with 100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and 600 mg on day 4 of cycle 1.

There was a protocol for dose interruptions to manage cytopenias and other AEs. In patients who achieved a CRi or morphologic leukemia-free bone marrow and experienced grade 4 neutropenia or thrombocytopenia that persisted beyond day 28, VEN was to be interrupted from day 28 until absolute neutrophil count was greater than or equal to 500 per µL to 1,000 per µL and platelet counts of greater than or equal to 25 × 10³ per µL to 100 × 10³ per µL were achieved. This approach was taken because typically, if AML persists in the bone marrow, then cytopenias would be attributable to the disease process, and VEN-LDAC may continue; however, if a patient with previous CR presents with new-onset grade 4 neutropenia or thrombocytopenia lasting longer than 1 week, unless due to underlying disease, a dose interruption would be considered, in consultation with the sponsor’s medical monitor.

For patients who continued to respond based on bone marrow assessment after cycle 2, but had persistent cytopenias, dose interruptions could be considered following a specific protocol. Patients who were on VEN 600 mg for a 28-day cycle had a week-long interruption in dosing, while patients who were on 21-day out of 28-day cycles had a 14-day interruption, and patients on a 14-day out of 28-day cycle were reduced to 400 mg daily with a 14-day interruption. Cytopenias that occurred during cycle 1 or cycle 2 were considered more likely due to the disease process rather than the study drug; therefore, dose reductions were not typically recommended during cycle 1 or 2.

With respect to LDAC, during cycle 2 and subsequent cycles, study treatments could be delayed at the discretion of the investigator if the patient experienced myelosuppression, such as febrile neutropenia, acute infection (viral, bacterial, or fungal) requiring IV anti-infectives, or extensive supportive care for hemorrhage. Myelosuppression is reversible, and LDAC dosing was interrupted in these cases; dose reductions were not recommended but were permitted in rare instances.

Outcomes

A list of efficacy end points specified in the CADTH review protocol that were assessed in the VIALE-C trial included in this review is provided in Table 8. These end points are summarized in this section. A detailed description and critical appraisal (in terms of measurement properties) of the patient-reported measures assessed in the VIALE-C trial (i.e., the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30] and Patient-Reported Outcome Measurement System Short Form v1.0 – Fatigue 7a [PROMIS F-SF]) is provided in Appendix 4.

The primary outcome of the VIALE-C trial was OS, which was defined as the number of days from randomization to death. All events of death were included in the final analysis regardless of whether the patient was still on the study drug. For patients who had not died, their data were censored at the date they were last known to be alive on, or before the cut-off date. The date which patients were last known to be alive was determined by selecting the last available date from a list of study procedures.

Disease assessments were performed using modified International Working Group (IWG) criteria. Assessments were performed at the end of cycle 1 (± 3 days), and patients with resistant disease at the end of cycle 1 had their assessments repeated at the end of cycle 2 or cycle 3 based on hematologic recovery to confirm a suspected response. Thereafter, assessments were performed every 3 cycles starting at the end of cycle 4 and continued until disease progression as defined by the European Leukemia Net, or until 2 successive disease assessments resulted in CR, CRi, or withdrawal of consent. For patients with 2 consecutive disease assessments of CR or CRi, further disease assessments consisted of laboratory and physical exam and included bone marrow evaluation if there was concern of relapse.

Disease assessments were reviewed by investigators in conjunction with hematopathologists as well as an independent review committee (IRC). The assessments by the IRC were not shared with trial sites. A charter that outlined the review process was used by the IRC. The CR + CRi rate was defined as the percentage of patients who achieved a CR + CRi at any time point during the study using the modified IWG criteria for AML. Randomized patients who had no IWG disease assessments were considered non-responders.

The CRh was derived using bone marrow blast and hematology lab values: bone marrow blasts less than 5%, a peripheral blood neutrophil count greater than 0.5 × 10³/µL, a peripheral blood platelet count of greater than 0.5 × 10⁵/µL, and a 1-week platelet transfusion-free period before the hematology lab collection. For a bone marrow sample collected during or after the last cycle of treatment, the hematology lab results collected within 14 days after the bone marrow sample collection date were used for CRh analysis. The CR + CRh rate was defined as the proportion of patients who achieved a CR or CRh at any time point during the study. Randomized patients who had no disease assessment were considered non-responders. The CR + CRh rate by initiation of cycle 2 was defined as the percentage of patients who achieved a CR or CRh by the initiation of cycle 2. For randomized patients who discontinued treatment before the initiation of cycle 2, all assessments performed before the cut-off date or the initiation of post-treatment therapy, whichever occurred earlier, were included in the analysis.

Post-baseline transfusion independence was defined as a period of at least 56 days with no transfusion after the first dose of study drug and before the last dose of study drug (plus 30 days), or before death or the initiation of post-treatment therapy, whichever was earlier. Transfusion independence was calculated for RBCs and platelets. The rate of conversion was calculated as the percentage of patients who achieved transfusion independence post-baseline compared to baseline.

The PROMIS F-SF measures the impact and experience of fatigue on patients over the past 7 days. Fatigue is measured using a 7-item instrument, with responses scored on a 5-point scale ranging from 1 (never) to 5 (always). Data were collected and reported as a least squares mean (LSM) change from baseline every 2 cycles beginning with cycle 3. The minimal important difference (MID) for this instrument ranges between 3 and 5.

Global Health Status on the EORTC QLQ-C30 was a secondary outcome of the trial. The EORTC QLQ-C30 consists of a Global Health Status/Quality of Life scale, a financial difficulties scale, 5 functional scales (cognitive, social, physical, emotional, and role functioning) and 8 symptom scales or items (fatigue, insomnia, appetite loss, pain, constipation, diarrhea, dyspnea, and nausea and vomiting). For the Global Health Status and 5 functional scales, an increase in score indicates improvement, whereas a decrease in score indicates worsening. The MID is 10 for this instrument. The EuroQol 5-Dimensions was also assessed as an exploratory outcome using a Visual Analogue Scale ranging from 100 (best imaginable health) to 0 (worst imaginable health). The MID is 7 for this scale.

EFS was defined as the number of days from randomization to date of progressive disease, relapse of CR or CRi, treatment failure (defined as failure to achieve CR, CRi, or morphologic leukemia-free state after at least 6 cycles of study treatment), or death from any cause. If a specified event did not occur, then patients were to be censored at the date of last disease assessment. Data for any patients without post-randomization disease assessments were censored at the date of randomization.

Statistical Analysis

Primary Outcome

Power Calculation

The calculation of sample size was based on the following assumptions: median OS of 6 months in the PLA-LDAC treatment group and 11 months in the VEN-LDAC group (HR = 0.545); an interim analysis of OS at 75% of the death events with an O’Brien-Fleming boundary; and a 2:1 randomization ratio of VEN-LDAC to PLA-LDAC. Based on these assumptions, 133 death events were required to provide 90% power to detect a statistically significant difference between groups at an alpha of 0.05; as a result, 210 patients were randomized into the trial, 140 patients in the VEN-LDAC group and 70 in the PLA-LDAC group.

Statistical Test or Model

For the primary outcome, the distribution of OS was estimated for each treatment group using Kaplan-Meier methodology, and the difference between groups was compared using the log rank test stratified by AML status (de novo or secondary) and age (18 years to < 75 years, ≥ 75 years). The HR between treatment groups was estimated using a Cox proportional hazards model with these same stratification factors.

Multiplicity

A hierarchical testing procedure was used to account for multiple comparison testing. The primary outcome of OS was tested first; secondary outcomes were then tested in a specified order. If the statistical test was not significant at a level of P = 0.05 for the primary outcome, then statistical significance was not to be declared for any of the secondary outcomes. The Lan-DeMets alpha spending function with O’Brien-Fleming boundary was used at the interim analysis to ensure that the false-positive rate for each primary or key secondary efficacy outcome was 0.05 or less.

Data Imputation Methods

Patients who had no disease assessment were considered non-responders for the estimation of response rates. Patients who had not experienced disease progression or death were censored at the last disease assessment date for analyses of DOR and EFS.

Sensitivity Analysis

A stepwise multivariate Cox regression was performed to identify pre-treatment factors that may be associated with survival, and included numerous baseline factors, such as treatment group, age, sex, AML status, bone marrow blast count, ECOG PS, cytogenetics risk, prior HMA use, geographic region, FLT3 mutation status, IDH mutation status, and NPM1 mutation status.

Subgroup Analyses

Preplanned subgroup analyses were performed for a variety of outcomes: OS, CR rate, CR + CRi rate, CR + CRh rate, and CR + CRi rate by the initiation of cycle 2. These analyses do not appear to have been adjusted for multiple comparisons.

Preplanned subgroup analyses were performed for the following subgroups of interest to the CADTH review protocol: age (18 years to < 65 years, 65 years to < 75 years, ≥ 75 years), AML status (de novo, secondary), baseline ECOG PS (< 2, ≥ 2), prior HMA for MDS (yes or no), cytogenetic risk (favourable, intermediate, poor), molecular markers (FLT3, IDH1, IDH2, TP53, NPM1), and bone marrow blast count (< 30%, 30% to < 50%, and ≥ 50%).

Secondary Outcomes

For the secondary outcomes of CR + CRi rate, CR + CRh rate, and transfusion independence, rates were compared between groups using the Cochran-Mantel-Haenszel test using the same stratification factors as OS. For the PROMIS F-SF and EORTC QLQ-C30, a linear mixed-effects regression model with an appropriate covariance structure was fitted to the longitudinal data to test for differences between treatment groups. For the analysis of EORTC QLQ-C30 outcomes, the model included the following factors: baseline score, stratification factors (age and AML status), treatment group, visit, and treatment group by visit interaction.

Sensitivity Analyses

The final analysis of response- or progression-related outcomes was based on investigator assessment. Sensitivity analyses were performed based on IRC assessment.

Duration of CR, CR + CRi, and CR + CRh were also assessed, including death from all causes by the cut-off date, as a sensitivity analysis.

There were 5 amendments to the VIALE-C trial protocol:

• February 17, 2017: The study was updated to include non-elderly patients with AML (18 years of age and older) to address feedback from regulatory agencies and include females of child-bearing potential. The definition of the secondary outcome of EFS and the description of the justification for the choice of VEN dose of 600 mg were updated.

• October 6, 2017: This amendment clarified the phase of the trial and the fact that patients who had previously been treated with VEN or were receiving other concurrent investigational drugs could not be enrolled.

• June 22, 2018: Evaluation of CR + CRh as a secondary outcome and evaluation of transfusion independence during any consecutive 56 days during the study treatment period were added as exploratory outcomes.

• November 29, 2018: Transfusion independence rates, minimal residual disease response rate, CR + CRh rate by initiation of cycle 2, and OS in molecular subgroups were added as secondary outcomes. It was also clarified that CR rate was an outcome to be evaluated.

• May 29, 2018: The sponsor could unblind patient treatment assignments following the final analysis results and provide investigators with this information if requested so that a decision could be made about a patient’s treatment continuation.

Analysis Populations

The full analysis set comprised the intention-to-treat (ITT) population that consisted of all patients randomized by interactive voice or web response system, while the safety analysis set included all patients who received at least 1 dose of study drug.

Results

Patient Disposition

All total of 211 patients were randomized into the trial and included in the full analysis set. The 44 screen failures were due to failure to meet inclusion or exclusion criteria (n = 27), withdrawn consent (n = 5), loss to follow-up (n = 1), and other (n = 11).

There were 210 patients who received at least 1 dose of the study drug and were included in the safety analysis set. In the VEN-LDAC group, 72.0% of patients discontinued the study, while in the PLA-LDAC group, 82.4% of patients discontinued. The most common reason for study discontinuation in both treatment groups was death.

Exposure to Study Treatments

The exposure to study treatments in the VIALE-C trial is summarized in Table 12. At the time of the final analysis, the median duration of exposure to VEN-LDAC was 3.9 months (range = 0.0 to 17.1), and the median duration of exposure to PLA-LDAC was 1.7 months (range = 0.1 to 14.2); at the 6-month follow-up post hoc analysis, the median duration of exposure was 4.1 months (range = 0.0 to 23.5) versus 1.7 months (range = 0.1 to 20.2), respectively. In the VEN-LDAC group, 20.4% of patients had 1 dose reduction, 4.2% had 2 dose reductions, and 1.4% had more than 2 dose reductions. Dose interruptions occurred at least once in approximately 91% of patients in the VEN-LDAC group and in 71% of patients in the PLA-LDAC group. Data on the use of subsequent therapies were not reported.

Efficacy

The results of the final analysis were based on a data cut-off date of February 15, 2019, and a median follow-up of 12 months. The results of the 6-month follow-up post hoc analysis were also reported by the sponsor and were based on a data cut-off date of August 15, 2019, and median follow-up of 17.5 months. A summary of the efficacy outcomes in the VIALE-C trial is provided in Table 13. The final analysis of response- or progression-related outcomes was based on investigator assessment; sensitivity analyses were performed based on IRC assessment. The results of subgroup analyses are reported for the efficacy outcomes specified in the CADTH review protocol; refer to Appendix 3 for the detailed results of these analyses.

Overall Survival

At the final analysis, the median OS in the VEN-LDAC group was 7.2 months versus 4.1 months in the PLA-LDAC group, for an HR of 0.75 (95% CI, 0.52 to 1.07; P = 0.114). Overall survival was the primary outcome; thus, the VIALE-C study failed to meet its primary outcome. At the 6-month post hoc follow-up analysis, the median OS in the VEN-LDAC group was 8.4 months, and the median remained at 4.1 months in PLA-LDAC group, for an HR of 0.70 (95% CI, 0.50 to 0.99); these results remained the same at a 12-month post hoc follow-up analysis.¹⁵ The results of a Cox regression sensitivity analysis showed 5 covariates were found to be associated with OS (treatment group, age, AML status, ECOG PS, and cytogenetic risk). Figure 2 shows the Kaplan–Meier analysis of OS over time. Most patients had died by the end of the study. The results of pre-specified subgroup analyses that were performed suggest there was heterogeneity in treatment effect based on patient subgroups (refer to Appendix 3, Table 26).

Figure 2: Kaplan-Meier Analysis of Overall Survival From the VIALE-C Study

CI = confidence interval; HR = hazard ratio; PBO + LDAC = placebo plus low-dose cytarabine; PH = proportional hazard; VEN + LDAC = venetoclax in combination with low-dose cytarabine.

Data cut-off: February 15, 2019 (median follow-up was 12 months).

Source: Clinical Study Report for VIALE-C.³

Event-Free Survival

At the final analysis, the median EFS was 4.7 months (95% CI, 3.7 to 6.4) in the VEN-LDAC group and 2.0 months (95% CI, 1.6 to 3.1) in the PLA-LDAC group, for an HR of 0.58 (95% CI, 0.42 to 0.82). Refer to Figure 3 for a Kaplan–Meier analysis of EFS. At the time of the 6-month post hoc follow-up analysis, the EFS in the VEN-LDAC group was 4.9 months (95% CI, 3.7 to 6.4); for the PLA-LDAC group, it was 2.1 months (95% CI, 1.5 to 3.2), indicating a limited increase in EFS from the final analysis to the 6-month post hoc follow-up, for an HR of 0.61 (95% CI, 0.44 to 0.84).

Figure 3: Kaplan-Meier Analysis of Event-Free Survival From the VIALE-C Study

CI = confidence interval; HR = hazard ratio; PBO + LDAC = placebo plus low-dose cytarabine; PH = proportional hazard; VEN + LDAC = venetoclax in combination with low-dose cytarabine.

Source: Clinical Study Report for VIALE-C.³

A sensitivity analysis of the final analysis of EFS based on IRC assessment was also performed; the median EFS by IRC assessment was 5.0 months in the VEN-LDAC group versus 2.2 months in the PLA-LDAC group, for an HR of 0.62 (95% CI, 0.44 to 0.88).

Complete Remission Plus Complete Remission With Incomplete Blood Count Recovery

At the final analysis, per investigator assessment, the CR + CRi rate was 47.6% (95% CI, 39.1% to 56.1%) in the VEN-LDAC group and 13.2% (95% CI, 6.2% to 23.6%) in the PLA-LDAC group. At the 6-month post hoc follow-up, the CR + CRi rate was 48.3% (95% CI, 39.8% to 56.8%) in the VEN-LDAC group and was unchanged from the final analysis in the PLA-LDAC group.

The CR + CRi rate based on IRC assessment was performed as a sensitivity analysis. The IRC-assessed CR + CRi rate was 39.9% in the VEN-LDAC group and 13.2% in the PLA-LDAC group. The sponsor attributed the difference in results between investigator and IRC assessment primarily to interpretation of RBC transfusion independence and growth factor use to support a CR, although the sponsor did not elaborate on specifically how these factors would lead to differences in results.

Complete Remission Plus Complete Remission With Partial Hematologic Recovery

At the final analysis, the CR + CRh rate was 46.9% (95% CI, 38.5% to 55.4%) in the VEN-LDAC group versus 14.7% (95% CI, 7.3% to 25.4%) in the PLA-LDAC group. At the 6-month post hoc follow-up analysis, the CR + CRh rate for patients in the VEN-LDAC group was 48.3% (95% CI, 39.8% to 56.8%), and was unchanged in the PLA-LDAC group, at 14.7% (95% CI, 7.3% to 25.4%).

Time to Remission

At the final analysis, the median time to first remission (CR + CRi) was 1.1 months (range = 0.8 to 4.7) in the VEN-LDAC group and 3.7 months (range = 0.9 to 6.5) in the PLA-LDAC group. At the 6-month post hoc follow-up analysis, the median times to first remission (CR + CRi) were similar to the final analysis.

Duration of Remission

At the final analysis, the median DOR (CR + CRi) was 10.8 months in the VEN-LDAC group and 6.2 months in the PLA-LDAC group. At the 6-month post hoc follow-up, the median DOR (CR + CRi) was 11.7 months in the VEN-LDAC group and remained at 6.2 months in the PLA-LDAC group.

DOR based on IRC assessment was performed as a sensitivity analysis. The median DOR (CR + CRi) based on IRC assessment was not reached in the VEN-LDAC group and was 8.3 months in the PLA-LDAC group.

Post-Baseline Transfusion Independence

At the final analysis, the median duration of RBC transfusion independence was 118.5 days in the VEN-LDAC group and 146.0 days in the PLA-LDAC group. At the 6-month post hoc follow-up analysis, the median duration of first RBC transfusion independence was 133.5 days in the VEN-LDAC group and 110.0 days in the PLA-LDAC group. The median duration of platelet transfusion independence was 163.5 days in the VEN-LDAC group and 112.0 days in the PLA-LDAC group. At the 6-month post hoc follow-up analysis, the median duration of platelet transfusion independence was 198.5 days in the VEN-LDAC group and 132.5 days in the PLA-LDAC group.

At the final analysis, transfusion independence (RBC and platelet) was achieved by 37.1% of patients in the VEN-LDAC group and 16.2% of patients in the PLA-LDAC group. At the 6-month post hoc follow-up analysis, transfusion independence was achieved by 39.2% of patients in the VEN-LDAC group and 17.6% in the PLA-LDAC group. Therefore, there was a slight increase in the percentage of patients who were transfusion-independent in each group from the final analysis to the 6-month post hoc follow-up.

Health-Related Quality of Life

Refer to Appendix 3, Table 27 for detailed data on HRQoL and symptoms (fatigue) outcomes. The EORTC QLQ-C30 Global Health Status/Quality of Life Scale was assessed as a secondary outcome, and subscales were assessed as exploratory outcomes. There were differences in baseline scores between the VEN-LDAC and PLA-LDAC groups, although there was no consistent pattern in the differences. There was a large amount of missing data, with assessments missing for more than 50% of the ITT population. A large portion of the missing data were missing due to attrition; however, compliance with filling out the instrument was typically around 70% to 80% across time points.¹⁶ Data were reported every 2 cycles, starting with cycle 3. By cycle 3, data were available for only 69 patients out of 127 patients in the VEN-LDAC group, and for 22 patients of 59 patients in the PLA-LDAC group; by cycle 9, data were available for 22 patients in the VEN-LDAC group and 7 patients in the PLA-LDAC group. For the EORTC QLQ-C30 Global Health Status/Quality of Life Scale, the LSM difference between the VEN-LDAC and PLA-LDAC groups based on changes from baseline after 9 cycles was 6.381 (95% CI, –8.49 to 21.28). The results for individual subscales varied widely, with some reporting improvement from baseline for VEN-LDAC and improvement over PLA-LDAC (appetite loss), while for other scales, there was a worsening (diarrhea and dyspnea) that exceeded the MID of 10 for this instrument. Diarrhea is an adverse effect associated with VEN-LDAC; therefore, a worsening on this subscale is not surprising. It is unclear why appetite might have improved and dyspnea might have worsened; however, any results must be interpreted with caution, given the large amount of missing data. The EuroQol 5-Dimensions was also assessed as an exploratory outcome. These results can be found in in Appendix 3.

Symptoms

Fatigue was assessed using the PROMIS F-SF score (Table 27). There was a significant amount of missing data, just as for the EORTC QLQ-C30 Global Health Status/Quality of Life Scale, again due mainly to attrition and also due to compliance of 70% to 80%.¹⁶ Fatigue scores decreased (improved) from baseline in the VEN-LDAC group at the end of all cycles, and this exceeded the MID of 3 starting at cycle 5. Improvements from baseline were also seen in the PLA-LDAC group beginning at cycle 7. The largest between-group difference occurred at cycle 5, with an LSM difference between VEN-LDAC and PLA-LDAC of –4.923 (95% CI, –10.03 to 0.19). Note that the large amount of missing data precludes any conclusions being drawn about the efficacy of VEN-LDAC for this outcome.

Hospital Admission

This outcome was not specifically assessed in the VIALE-C trial, although hospital admissions were reported as AEs. AEs resulted in hospitalizations for 56.3% of patients in the VEN-LDAC group and 51.5% of patients in the PLA-LDAC group at the time of the 6-month post hoc follow-up analysis.

Harms

Only the specific harms specified in the review protocol are reported in this section. Refer to Table 14 for detailed data on harms outcomes, which are based on the 6-month post hoc follow-up analysis.

Adverse Events

At the time of the 6-month post hoc follow-up analysis, 99.3% of patients in the VEN-LDAC group and 98.5% of patients in the PLA-LDAC group had experienced at least 1 AE. The most common AEs (VEN-LDAC versus PLA-LDAC) were neutropenia (45.8% versus 17.6%), thrombocytopenia (45.8% versus 39.7%), nausea (43.0% versus 30.9%), diarrhea (33.1% versus 17.6%), and febrile neutropenia (32.4% versus 29.4%). AEs of grade 3 or higher occurred in 97.2% of patients in the VEN-LDAC group and in 95.6% of patients in the PLA-LDAC group; the most common were neutropenia (48.6% versus 17.6%), thrombocytopenia (45.8% versus 38.2%), and febrile neutropenia (32.4% versus 29.4%).

Serious Adverse Events

SAEs occurred in 66.9% of patients in the VEN-LDAC group and 61.8% of patients in the PLA-LDAC group. The most common SAEs (VEN-LDAC versus PLA-LDAC) were febrile neutropenia (16.9% versus 17.6%) and pneumonia (14.1% versus10.3%).

Withdrawals Due to Adverse Events

AEs resulting in discontinuation of VEN-LDAC occurred in 26.1% of patients; AEs resulting in discontinuation of PLA-LDAC occurred in 23.5% of patients. Pneumonia was the most common reason for discontinuation in the VEN-LDAC group, occurring in 4.9% of patients versus 1.5% of patients treated with PLA-LDAC.

Mortality

AEs leading to death occurred in 23.2% of patients in the VEN-LDAC group versus 20.6% of patients in the PLA-LDAC group. The most common AE that led to death in the VEN-LDAC group was pneumonia, which occurred in 4.9% of patients treated with VEN-LDAC and in no patients treated with PLA-LDAC.

Notable Harms

Notable harms included infections, which were grouped under the broader category of infections and infestations; 64.8% of patients in the VEN-LDAC group and 60.3% of patients in the PLA-LDAC group experienced an event. Pneumonia was the most common infection, occurring in 21.8% and 16.2% of patients in the VEN-LDAC and of PLA-LDAC groups, respectively. All of the following notable harms occurred more frequently in the VEN-LDAC group: second primary malignancy in 2.1% versus zero patients, TLS in 5.6% versus zero patients, and hemorrhage in 41.5% versus 30.9% of patients (grade ≥ 3: 11.3% versus 7.4%); any AE of neutropenia was reported in 68.3% and 45.6% patients, respectively.

Critical Appraisal

Internal Validity

The VIALE-C study was a double-blind RCT, and steps were taken to maintain blinding, such as the use of a placebo that was identical in appearance to VEN. There was a large numerical imbalance in a number of AEs, including neutropenia, between the VEN-LDAC and PLA-LDAC treatment groups; this may have resulted in loss of blinding in those patients experiencing these AE, given that many are known adverse effects of VEN. However, the primary outcome of OS and those outcomes that were largely based on laboratory testing results should not have been affected.

Overall survival is a standard outcome in oncology drug investigation, with robust methods for ascertainment. Collection was likely to be complete and the timing of events was likely to be accurately determined. Standard methods for survival analysis were used, with surviving patients censored at the date they were known to be alive on or before the data cut-off date. There was minimal loss to follow-up or withdrawal and good balance between demographic and clinical characteristics at baseline; therefore, censoring is unlikely to be related to prognosis. The prognosis of recruited patients is unlikely to have changed with time because there were no changes to inclusion or exclusion criteria that were likely to affect prognosis and that recruitment took place over a relatively short time period. There was no evidence of violation of the proportional hazards assumption, and competing risks for this end point are unlikely.

A statistical hierarchy was used to account for multiplicity; however, early failure of the hierarchy (at the level of the primary outcome) meant that subsequent testing lacked control for type I error. This limits any statistical inferences that can be drawn with respect to statistical significance for any of the subsequent outcomes that were to be tested in the hierarchy after OS. Health Canada noted this limitation in its review of VEN-LDAC for this indication, but still granted a NOC based on the “totality of evidence,” citing clear numerical differences between VEN-LDAC and PLA-LDAC for outcomes like CR + CRi (19.9% difference between groups) and transfusion independence (20% difference between groups).¹²

Event-free survival is a composite end point consisting of death from any cause, confirmed morphologic relapse from CR + CRi, confirmed disease progression, and treatment failure. Treatment failure was defined as failure to reach CR, CRi, or a morphologic leukemia-free state after at least 6 cycles. EFS is an accepted end point in the development of treatments for leukemia,¹⁷ although empirical data show inconsistent correlation between EFS and OS.¹⁸ However, compared to OS, EFS provides a more direct measurement of the ability of the treatment to achieve a response and the durability of response because it is affected by trial treatment alone, whereas OS is affected by trial treatment, post-trial treatment, and supportive or palliative care.¹⁸ A time-to-event analysis of all individual end points making up the composite EFS outcome was not reported, making it difficult to fully assess for violations of the assumptions underlying the composite end point (i.e., the events were of equal importance to patients, occur with similar frequency, and have a similar sensitivity to the treatment). The proportion of patients with each individual end point was reported, and the distribution of these in each treatment group is consistent with observed results for OS and CR + CRi, which were higher in the VEN-LDAC group compared to the PLA-LDAC group. Results for the individual analyses of OS, DOR, and CR + CRi show similar directions of effect, but this does not adjust for competing events. Standard methods for survival analysis were used, with surviving patients censored at the date they were known to be alive on or before the cut-off date. There was minimal loss to follow-up or withdrawal and good balance between demographic and clinical characteristics at baseline; therefore, censoring is unlikely to be related to prognosis. The prognosis of recruited patients is unlikely to have changed with time because there were no changes to the inclusion or exclusion criteria that were likely to affect prognosis and because recruitment took place over a relatively short time period. There was also no evidence of violation of the proportional hazards assumption.

An a priori sample size calculation was performed, although the assumptions upon which the estimates used were based was not reported (i.e., median OS of 11 months with VEN-LDAC and 6 months with PLA-LDAC). These assumed estimates differed from the actual median OS observed in the trial, perhaps leading to a non-statistically significant finding for OS in the final analysis (7.2 months with VEN-LDAC and 4.1 months with PLA-LDAC). It is reasonable for a trial not to reach its pre-specified outcome when the parameters used for statistical planning were unknown or uncertain at the time of executing the trial. Therefore, it is not surprising to see a greater difference between VEN-LDAC and PLA-LDAC at the 6-month post hoc follow-up analysis, by which time more death events had occurred. The trial was relatively small, with fewer than 100 patients in the PLA-LDAC group; the small number may not have provided adequate power to assess some of the patient-reported outcomes due to the high rate of attrition in the study.

The interpretation of outcomes like fatigue and HRQoL is limited by the large amount of missing data. For example, by cycle 5, in the assessment of EORTC QLQ-C30 Global Health Status, only about 30% of the original ITT population remained in the VEN-LDAC group, while about 20% of the original ITT population remained in the PLA-LDAC group. Even after cycle 3, the earliest time point assessed, nearly 50% of the ITT population was missing from the VEN-LDAC group, and nearly two-thirds were missing from the PLA-LDAC group. The large amount of missing data was not only due to attrition because compliance with filling out these instruments was relatively low, at about 78% at cycle 3, and lower at some other later time points. A MID has been established for the EORTC QLQ C30 Global Health Status in a diverse group of patients with cancer; the PROMIS instrument has been validated in various chronic diseases. The sponsor took steps to validate PROMIS in a population reflective of the indication using data from the VIALE-C study. Using the study population under review to validate the instrument is an unusual approach to validation, and there is risk of bias in it.

There was a numerical difference in the number of patients discontinuing the study, with a lower percentage in the VEN-LDAC group than in the PLA-LDAC group (72.0% versus 82.4%). This difference between groups is accounted for by the difference in deaths between the 2 groups; thus, it can be considered informed censoring, given the primary outcome of OS. However, the difference in exposure to study drug could affect other outcomes, including patient-reported outcomes and the interpretation of harms data.

Protocol deviations occurred due to violations related to inclusion or exclusion criteria, receipt of wrong treatment or incorrect dose of study drug, demonstration of withdrawal criteria without being withdrawn, and use of prohibited concomitant medications. An assessment of deviations was performed to assess their impact on data integrity or patient safety; no protocol deviations were found to affect either.

Both CR and CR + CRi and were investigator-assessed based on laboratory and clinical findings, with an independent review assessed as sensitivity analyses. CR + CRi is an accepted end point in the development of treatments for leukemia,¹⁷ although empirical data suggest that the strength of the correlation between CR + CRi and OS maybe be population- and treatment-dependent.¹⁸ The differences in results between investigator and IRC methods of assessment were minimal. Both CR and CRi reflect bone marrow and peripheral blood improvement, with different thresholds, and the direction of effect was the same for each outcome. Randomized patients without a post-baseline disease assessment were considered non-responders. This is a conservative assumption that biases the individual estimates of response downwards, but it does account for a competing risk of death in an aged population.

It is not clear how data on transfusion independence were collected, or whether it might be susceptible to survivor bias; (i.e., if patients had to survive to a visit for transfusion since the last visit to be captured in the analysis). There is the risk of undercounting transfusion in seriously ill patients.

External Validity

Input from the clinical experts consulted by CADTH was sought to assess the generalizability of evidence for VEN-LDAC. The clinical experts believed that the population included in the VIALE-C study was representative of those who would be treated with VEN-LDAC under the indication, and that the outcomes assessed in the trial covered all the major outcomes of interest. The clinical experts noted that the dose of VEN-LDAC used (adjusted based on body surface area) was expressed differently than in Canadian practice, where a flat dose is used; this resulted in a lower dose being used in the VIALE-C study than what would typically be used in Canadian practice.

In practice, for those patients who are under 75 years old, the indication requires at least 1 criterion associated with lack of fitness for intensive induction chemotherapy be met, such as an ECOG PS of 2 to 3 or comorbidities such as cardiovascular disorders (ejection fraction ≤ 50%) requiring treatment, respiratory functions (diffusing capacity of the lungs for carbon monoxide ≤ 65% or forced expiratory volume in 1 second [FEV₁] ≤ 65%), or impaired renal functions (creatinine clearance ≥ 30 mL/minute to < 45 mL/minute). Nearly 50% of patients in the study had an ECOG PS of 0 to 1, which probably reflects the target population for which the drug could be used in clinical practice. Most of the study patients (60%) were newly diagnosed and likely without prior treatment for AML except for MDS. It is unknown whether these restricted criteria could affect the generalizability of the findings to all patients with multiple comorbidities or with prior treatment.

A concern was identified surrounding the assumption within the study inclusion criteria that patients aged 75 years or older would not be eligible for standard induction chemotherapy. In the Canadian setting, such patients would be considered for treatment if they were medically fit, especially if they had favourable- or intermediate-risk cytogenetics.

The settings for the study were predominantly urban hospitals and clinics. Therefore, the study does not necessarily address the rural or remote Canadian context, in which patients would not have access to frequent laboratory testing for monitoring of ramp-up of VEN and cytopenias and outpatient or inpatient treatment for side effects and complications.

Indirect Evidence

Description of Indirect Comparison(s)

Objectives and Methods for the Summary of Indirect Evidence

An ITC was required because of the lack of studies directly comparing VEN-LDAC with other treatments currently in use in the Canadian setting.

Search Methods

A focused literature search for NMAs dealing with VEN and AML was run in MEDLINE All (1946–) on February 11, 2021. No limits were applied.

Description of Indirect Comparison

One report including ITCs was supplied by the sponsor. It included a systematic review with an NMA comparing VEN-LDAC and VEN-AZA with AZA, LDAC, and BSC as well as 2 propensity score analyses comparing VEN-AZA with LDAC (2-way) and VEN-AZA with AZA with LDAC (i.e., a 3-way comparison).

Table 15 shows the study selection criteria and key aspects of the methods for the systematic review. The patient population of interest included treatment-naive adult patients with AML who were ineligible for intensive chemotherapy; however, the search allowed flexible wording to ensure retrieval of studies. The term “treatment-naive” was considered interchangeable with “previously untreated” or “newly diagnosed,” and “ineligible for chemotherapy” included patients described as old or elderly, unfit for intensive chemotherapy, unfit for standard chemotherapy, or unfit for high-dose chemotherapy. The initial search for articles included a broader set of comparators and included controlled clinical trials as a study design. More restricted selection criteria that were developed for a planned EUnetHTA submission were applied at the stage of full-text review; the table reflects these criteria. The reasons for selection of comparators were not given, but the overall declared intention was to select high-quality studies that might enable ITC.

Methods of the ITC

Objectives

The objective of this study was to compare the efficacy of VEN combination therapies with alternative treatments in treatment-naive patients with AML who were ineligible for intensive chemotherapy, including:

• Objective 1: Comparison of VEN-LDAC and VEN-AZA with LDAC, AZA, and BSC using NMA

• Objective 2: Comparison of VEN-AZA versus LDAC using propensity score weighting analysis

• Objective 3: Comparison of VEN-AZA versus AZA versus LDAC using 3-way propensity score weighting analysis

Study Selection Methods

To be included in the ITCs, trials retrieved by the systematic review had to meet the following criteria:

• Study design: phase III RCTs

• Population: treatment-naive adult patients with AML who were ineligible for intensive chemotherapy

• Interventions: VEN-LDAC, VEN-AZA, LDAC, AZA, and BSC (including blood transfusion, etoposide, mercaptopurine, and hydroxyurea)

• Outcomes of interest: OS, EFS, CR, CRi, CR + CRi

The decision to restrict the ITC to phase III RCTs for reasons of quality led to the exclusion of trials containing glasdegib because there was no phase III trial connected to the network containing VEN-LDAC and VEN-AZA.

ITC Analysis Methods

Three analyses were conducted: 1 NMA and 2 propensity score weighted comparisons. The propensity score weighted comparisons were not relevant to this review and will not be discussed further.

The NMA compared VEN-LDAC with VEN-AZA and comparator treatments for the available end points of OS and CR + CRi. The feasibility of pooling to create a network for analysis was pre-assessed on the basis of study and patient characteristics. The main analysis excluded patients from the VIALE-C LDAC group who would not have been eligible to enter VIALE-A because they had previously been treated with HMAs or had good cytogenetic risk. For OS, the proportional hazards assumption was assessed using log-log cumulative hazard plots, which led to the decision to model OS using proportional hazards.

The model was a Bayesian mixed treatment comparison in the generalized linear model framework, with OS modelled using the identity link and dichotomous outcomes modelled using the logit link. Due to limited data, only fixed-effects models were estimated. Prior distributions were non-informative, following a selection process that was not detailed. Posterior probabilities were modelled using Bayesian Markov chain Monte Carlo methods, with 50,000 iterations on 3 chains and a burn-in period of 50,000 iterations. Convergence was assessed by trace and density plots and Gelman-Rubin plots and diagnostics. Selection between models was made by the difference information criterion. The chosen definition of a meaningful difference in the difference information criterion was not given.

Results of the ITC

Summary of Included Studies

Following the removal of duplicates, 7,319 records were screened by title and abstract; of these, 225 were screened in full text. With the addition of the VIALE-A and VIALE-C study reports, the final selection was 7 RCTs with at least 2 arms of interest.

With the additional restriction of the comparators for the NMA inclusion criteria, removing decitabine from the comparators, 4 trials were included in the NMA: VIALE-C, VIALE-A, AZA-001, and AZA-AML-001. Table 16 shows a summary of the study characteristics for these 4 trials.

Table 17 shows a summary of patient baseline characteristics for the 4 studies included in the NMA. Only the treatment arms used in the NMA are presented. The table is in 2 panels, the first showing demographic and clinical characteristics, and the second showing the cytogenetic and mutation data. Table 18 shows an assessment of heterogeneity based on the study and patient characteristics. The most important sources of heterogeneity were in the indicators of disease severity, bone marrow blast counts, proportion of patients with poor cytogenetic risk, and baseline ECOG PS.

Table 20 shows the results of the risk of bias assessment for the 4 trials included in the ITC. The Quality Assessment Questions appear in Table 15: Study Selection Criteria and Methods for the Systematic Review. The risk of bias was low for all trials for treatment randomization, allocation concealment, and baseline balance. Trials AZA-001 and AZA-AML-001 were open-label studies; therefore, the risk of bias was high. In comparison, trials VIALE-C and VIALE-A were double-blind studies, with low risk of bias. Trial AZA-001 was at high risk of bias for imbalance in dropouts because more patients appear to have dropped out of the conventional care arm, and for selective reporting because overall AEs were not available. All trials were at unclear risk of bias for the inclusion of an ITT analysis. Where a reason was given, the concern was with lack of detail on the methods for the handling of missing data.

Trial Networks

Figure 4 shows the network for the NMA for OS. Four trials reported this end point and were included in the NMA. The network was linear, with a single branch, and included 5 treatments. There were no closed loops. AZA was the best represented treatment, with 3 trials contributing data, followed by LDAC, with 2 trials contributing data.

Figure 4: Network Diagram for the NMA for OS

BSC = best supportive care; ITC = indirect treatment comparison; LDAC = low-dose cytarabine.

Source: ITC report.²⁰

Figure 5 shows the network for the NMA for CR + CRi. Three trials reported this end point and were included in the NMA; the fourth, AZA-001, did not report data on CRi. The network was linear, with a single branch, and included 5 treatments. There were no closed loops. AZA and LDAC were the best represented treatments, with 2 contributing trials each.

Figure 5: Network Diagram for the NMA for CR + CRi

BSC = best supportive care; ITC = indirect treatment comparison; LDAC = low-dose cytarabine.

Source: ITC report.²⁰

Table 21 shows the data included in the NMAs for the end points of OS and CR + CRi. In the 2 trials comparing AZA with BSC, the HRs for OS were 0.60 (95% CI, 0.38 to 0.95) and 0.48 (95% CI, 0.24 to 0.94) for AZA-001 and AZA-AML-001, respectively. In the 2 trials comparing AZA with LDAC, the HRs for OS were 0.37 (95% CI, 0.12 to 1.13) and 0.90 (95% CI, 0.70 to 1.16) for AZA-001 and AZA-AML-001, respectively.

Results

Results of the NMA

Overall Survival: Table 22 shows the results for the NMA for OS. VEN-LDAC was favoured over comparators LDAC (HR = 0.70; 95% credible interval, 0.50 to 0.99) and BSC (HR = 0.46; 95% credible interval, 0.26 to 0.81), with no treatment favoured between VEN-LDAC and VEN-AZA (HR = 0.81; 95% credible interval, 0.50 to 1.31) and VEN-LDAC and AZA (HR = 0.82; 95% credible interval, 0.54 to 1.24).

Complete Remission Plus Complete Remission With Incomplete Blood Count Recovery: Table 23 shows the results of the NMA for OS. VEN-LDAC was favoured over comparators LDAC (OR = 6.24; 95% credible interval, 2.98 to 14.42), AZA (OR = 5.84; 95% credible interval, 2.38 to 15.22), and BSC (OR = 73.35; 95% credible interval, 8.05 to 2,370.88), with no treatment favoured between VEN-LDAC and VEN-AZA (OR = 1.16; 95% credible interval, 0.43 to 3.33).

Critical Appraisal of the ITC

The key limitations of the NMA include the small size and structure of the network (which had no closed loops), potential sources of heterogeneity across the trials related to differences in study design and patient characteristics. These limitations resulted in imprecise estimates and the potential for bias.

Critical Appraisal of the Systematic Review

The NMA was based on an systematic literature review that identified studies according to pre-specified inclusion criteria. These included a broad selection of comparators and outcomes. The literature search was last conducted in October 2000 and appeared comprehensive in terms of the databases searched and the search strategy. Two sets of selection criteria were applied: an initial broader set of criteria and, at the full-text review step, a narrowed set of criteria intended to create a high-quality dataset for meta-analysis. The selection of comparators was not justified, but those meaningful to the Canadian context were included. Lists of studies excluded at the full-text state for both sets of criteria were provided. Screening and selection were done by 2 independent reviewers, with a third reviewer involved to reconcile differences. Data extraction was also completed by 2 independent reviewers. Data were extracted to pre-designed data sheets, with any differences reconciled by a third reviewer.

Critical Appraisal of the NMA

Studies included in the NMA were selected from those identified by the systematic literature review. The criteria for inclusion were provided and are consistent with the objective. The eligible interventions were restricted further to those used in Canada for the treatment of the population of interest, which was defined as treatment-naive adult patients with AML who are ineligible for intensive chemotherapy. Only clinical efficacy outcomes were pre-specified for the NMA. Available data limited the end points further to OS and CR + CRi for the NMA. Patient-reported quality of life and safety end points were not represented.

Heterogeneity in study and patient baseline characteristics were reported and reviewed by the authors as part of the assessment of feasibility for the meta-analysis. Baseline differences were noted in the prognostic variables and in the potential treatment-effect modifiers of blast count at baseline, prior treatment with HMAs, and cytogenetic risk. The proportion of patients with 50% or greater bone marrow blasts at baseline ranged from 0% (AZA-001 trial) to 100% (AZA-AML-001) in the network for OS and from 70.8% (VIALE-A) to 100% (AZA-AML-001) in the network for CR + CRi. Patients with prior HMA treatment were excluded from the VIALE-A, AZA-001, and AZA-AML-001 studies, but not from VIALE-C, in which 19.9% were treated with HMAs. This might represent a group more refractory to treatment with AZA, affecting both OS and CR + CRi end points. Patients with poor cytogenetic risk were more represented in the AZA arm of the VIALE-A trial compared with the AZA arm of the AZA-001 trial (39% versus 26%). This difference potentially affects the NMA network for OS. The median length of study follow-up ranged from 17.5 months (VIALE-C) to 24 months (AZA-AML-001). The variability was unlikely to affect CR + CRi, as response tended to occur early, but it may affect OS because patients may be censored before OS events in studies with short follow-up times.

Four studies formed a mainly linear connected network for OS, with 3 studies for CR + CRi. The end point of CR + CRi was not reported for AZA-001. There were no closed loops in either network, meaning that inconsistency within the networks could not be statistically assessed. The dose and duration for AZA and the dose (but not duration) for LDAC was the same across trials; BSC included the same constituents, limiting heterogeneity in dosing. In studies AZA-001 and AZA-AML-001, patients were pre-selected for the comparator therapy. As a result, the comparison of AZA against LDAC was made in patients pre-selected for LDAC, while the comparison of AZA against BSC was made in patients pre-selected for BSC. These were treated as 2 separate contrasts, not a 3-armed trial.

A standard Bayesian generalized linear model was used for the meta-analysis, and the diagnostics and model selection were sufficiently described. The reviewers checked the proportional hazards assumption for OS for the contributing plots using log-log plots. The risk of violation of the proportional hazards assumption was low for the VIALE-A and VIALE-C trials and low to moderate for the AZA-AML-001 trial, in which the survival curves were largely overlapping and intermittently crossing. The model in the NMA assumed constant hazards, which was an appropriate choice, given the low to moderate risk of violation of the proportional hazards assumption and the small number of studies available.

The networks for all analyses were small. Thus, the decision was made a priori to limit the analysis to fixed-effects models. This entailed the assumption that between-study heterogeneity was 0, which was unlikely to be the case. The small number of studies led to imprecise estimates, with the risk of not detecting a difference. In the analysis of CR + CRi, low response counts (including 0, requiring a 0-cell adjustment) led to highly uncertain estimates with wide credible intervals. The small number of studies meant there was no opportunity to use statistical methods (such as meta-regression) to adjust for variability in baseline treatment-effect modifiers and correct for potential bias. Finally, non-informative prior distributions were used in the models, as is usual practice, under the assumption that the final estimates will reflect only the data. However, with a low information dataset, the prior may add to the imprecision. Consideration of alternative priors was mentioned, but not detailed.

Summary

Seven trials met the systematic review inclusion criteria. With the additional restriction of the comparators for the NMA inclusion criteria, removing decitabine from the comparators, 4 trials were included in the ITC. Data were available for OS for 4 trials in a connected network and for CR + CRi for 3 trials.

For OS, VEN-LDAC was favoured over LDAC and BSC, with no treatment favoured between VEN-LDAC and AZA or VEN-LDAC and VEN-AZA. For CR + CRi, VEN-LDAC was favoured over LDAC, AZA, and BSC, with treatment favoured between VEN-LDAC and VEN-AZA.

The systematic review was well conducted and documented. The NMA used appropriate methods to model survival, having assessed the risk of violation of the proportional hazards assumption. There was clinical heterogeneity in important prognostic indicators and potential treatment-effect modifiers of blast count at baseline, prior treatment of HMAs, and cytogenetic risk. Because the network was sparse, fixed-effects models had to be used, and there was no opportunity for baseline covariate adjustments. Due to the aforementioned limitations, the comparative efficacy estimates may be biased, and it is not possible to quantify or identify the direction of the bias. Results of the ITC must be interpreted with caution.

Discussion

Summary of Available Evidence

One multinational, sponsor-funded, double-blind RCT met the selection criteria for this review. The VIALE-C trial compared VEN-LDAC to PLA-LDAC in a population of patients who were not considered eligible for intensive induction chemotherapy. VIALE-C was an event-driven study, and the final analysis occurred once 133 deaths had occurred, corresponding to a median follow-up of 12 months. The primary outcome of the trial was OS. A hierarchical testing strategy was employed to control for multiplicity. Secondary outcomes included CR + CRi rate, CR + CRh rate, EFS, and transfusion independence. Patient-reported outcomes, such as fatigue and HRQoL, were also assessed. Due to failure of the statistical hierarchy at the level of the primary outcome, the statistical significance of the secondary outcomes remains inconclusive. The majority of patients in the study were male (55.5%) and White (70.6%); the median age was 76 years (range = 36 to 93). The majority of patients had de novo AML (61.6%), while the remainder had secondary AML. The majority (65.2%) had intermediate cytogenetic risk, and most of the remainder (32.8%) had poor cytogenetic risk. The majority of patients were considered ineligible for intensive chemotherapy based on age (≥ 75 years), followed by ECOG Performance Status in patients 18 years to 74 years of age.

The results of an ITC were also reviewed. Seven trials met the inclusion criteria for the systematic review, and 4 were included in an NMA. The NMA included VEN-LDAC, VEN-AZA, and their individual components, as well as BSC. No additional studies were found that were considered relevant to the population of interest in this review.

Interpretation of Results

Efficacy

The VIALE-C trial demonstrated a median OS of 7.2 months in the VEN-LDAC group and 4.1 months in the PLA-LDAC group at the final analysis data cut-off date that was based on a median follow-up of 12 months. The between-group difference was associated with a 25% reduction in hazard (HR = 0.75; 95% CI, 0.52 to 1.07), which was confirmed by a 30% reduction in hazard (8.4 months versus 4.1 months) by a post hoc analysis performed 6 months after the final analysis data cut-off date. Health Canada–approved the drug combination based on the “totality of evidence,” which included the consistent improvement in all other disease-specific and clinically important outcomes, such as CR + CRi rate, DOR, and transfusion independence.

The observed treatment effect was based on the administration of VEN with a 4-day ramp-up and 600 mg on day 4 of cycle 1 and beyond, along with treatment interruption or reduction. The treatment effect was nearly depleted after 12 months of follow-up, when the majority of patients had died. The add-on treatment extended median OS for 3 to 4 months in a difficult-to-treat AML patient population. The analysis of OS in patient subgroups suggested heterogeneity across some subgroups; however, interpretation of these results is limited by small sample sizes, lack of statistical comparison, and wide CIs around point estimates.

Overall, as an add-on combination therapy when comparing to LDAC alone, VEN-LDAC demonstrated a clinically significant improvement in all the relevant outcome measures except for patient-reported outcomes, such as fatigue and HRQoL, for which there is high uncertainty due to poor data quality. For example, CR was achieved in 27% of patients in the VEN-LDAC group and in 7% of patients in the PLA-LDAC group (a difference of 20% between groups), and CR + CRi was achieved in 48% versus 13% of patients (a difference of 35%), respectively. Transfusion independence (RBC and platelets) was achieved by 37% of patients in the VEN-LDAC group and by 16% of patients in the PLA-LDAC group (a difference of 21% between groups). It is clear from clinician input that transfusion independence is an important outcome for the population that falls under the indication because these are elderly patients who are often frail and find it difficult to get to transfusion centres. The importance of achieving transfusion independence is supported by patient input submitted to CADTH.

Patient-reported outcomes were also assessed. However, as previously noted, there was a significant amount of missing data due to a large number of deaths occurring in the study and the potential of unblinding due to patients’ or investigators’ awareness of treatment assignment as a result of treatment-related AEs, such as gastrointestinal events, neutropenia, blood disorders, and infections, which combined prevented the evaluation of the impact of VEN-LDAC on HRQoL and symptoms. This is an important limitation, given the importance that patients placed on symptoms — most notably fatigue — in the input they provided to CADTH.

Although the most appropriate comparator for VEN-LDAC is likely PLA-LDAC, AZA was also included as a potential comparator in the protocol for this systematic review because some patients may use an HMA as an alternative to VEN-LDAC. In the sponsor-submitted NMA, there was no difference in OS between VEN-LDAC and AZA, or between VEN-LDAC and VEN-AZA because the 95% credible interval included the null value of 1. With respect to CR + CRi rates, VEN-LDAC was favoured over LDAC, AZA, and BSC because the 95% credible interval included the null value, and there was no significant difference between VEN-LDAC and VEN-AZA. Therefore, both VEN-LDAC and VEN-AZA appear to demonstrate benefit over BSC, AZA, and LDAC with respect to CR + CRi rates. The clinical experts consulted by CADTH, as well as the clinician groups, were all clearly of the opinion that VEN-AZA, or VEN-LDAC in patients who have prior HMA use, will become the new standard of care for this indication. The ITC results may support this assertion; however, as noted earlier in this clinical review, there are limitations that should be considered when interpreting results from the NMA. Additionally, there is no comparative evidence of VEN-LDAC versus intensive induction chemotherapy, which may be an option for some patients.

Harms

Neutropenia was the most common adverse effect of VEN-LDAC therapy, and it occurred numerically more frequently with VEN-LDAC than with PLA-LDAC. All of the events of neutropenia were grade 3 or higher, occurring in 48.6% of patients in the VEN-LDAC group and in 17.6% of patients in the PLA-LDAC group. Thrombocytopenia was the next most common AE; however, there was no clear numerical difference between groups: it occurred in 45.8% of patients treated with VEN-LDAC and in 39.7% of patients treated with PLA-LDAC. Gastrointestinal AEs, most notably nausea, vomiting, and diarrhea, were also more frequent in the VEN-LDAC group than in the PLA-LDAC group. In their input to CADTH, patients expressed concern about nausea and vomiting associated with prior treatments; thus, this adverse effect may be of particular concern for some patients.

The product monograph for VEN contains black-box warnings for TLS and serious infections. TLS is a serious adverse effect seen in hematologic malignancies and is due to the release of the contents of lysed cells. The release of these cellular contents, which include electrolytes like phosphorous and potassium, as well as cytokines, can lead to significant electrolyte imbalances and metabolic issues, which can ultimately be fatal. TLS was reported in 5.6% of patients in the VEN-LDAC group and in none in the PLA-LDAC group; SAEs were reported in 1.4% of patients treated with VEN-LDAC and in none with PLA-LDAC. The product monograph recommends a 3-day dose ramp-up for VEN when combined with LDAC and regular blood chemistry monitoring on each ramp-up, as well as prophylactic hydration and anti-hyperuricemics as a means of preventing and reducing harm from TLS when it does occur. The product monograph also recommends avoiding concomitant use of strong cytochrome P450 (family 3, subfamily A) inhibitors, as VEN is a substrate for this isozyme.

There was no clear numerical difference between VEN-LDAC and PLA-LDAC when it came to overall infections and infestations, which occurred in 64.8% versus 60.3% of patients, respectively. The only serious infection that occurred numerically more frequently in the VEN-LDAC group was pneumonia, which was reported in 4.9% of patients treated with VEN-LDAC and in none with placebo. The product monograph recommends that patients treated with VEN be monitored for the development of fever and other signs of infection, and have CBCs taken on a regular basis.

Other notable harms included the development of a second primary malignancy and hemorrhage. Hemorrhage is noted as a cause of some fatal AEs in the product monograph, which cites data from both the trial that combined VEN-LDAC and the trial that combined VEN-AZA.

Conclusions

One multinational, sponsor-funded, double-blind, placebo-controlled RCT was included in this review. The VIALE-C trial evaluated the treatment effect of combination therapy VEN-LDAC compared to LDAC alone in patients with AML who were ineligible to receive intensive induction chemotherapy. Although results for the primary outcome, OS, were not statistically significant, there were consistent improvements in secondary outcomes (e.g., EFS, CR + CRi rate, CR + CRh rate, and transfusion independence) in favour of VEN-LDAC versus LDAC alone. HRQoL and symptoms (fatigue) are deemed important outcomes by patients; however, analyses of these factors were confounded by the large amount of attrition that occurred in both treatment groups and the early failure of the statistical testing hierarchy of outcomes. The treatment effects of VEN-LDAC and VEN-AZA may be comparable; however, comparative efficacy was based on a small ITC with limitations, and only OS and CR + CRi were assessed. It remains uncertain whether VEN-LDAC is better than AZA alone because the ITC failed to show consistent results based on OS and CR + CRi. Neutropenia was the most common AE associated with the use of VEN-LDAC. Although there was no clear indication of more infections, there were numerically more cases of pneumonia among patients in the VEN-LDAC group compared with those in the LDAC alone group.

References

1.Canadian Cancer Society. Acute myelogenous leukemia (AML). 2021; www.cancer.ca, 2021.

2.Center for Drug Evaluation R. Medical review(s). Brand Name (Generic) administration. Company: Manufacturer. Application No.:XXXXX. Approval date: MM/DD/YYYY (FDA approval package). Silver Spring (MD): U.S. Food and Drug Administration (FDA); 1800: URL. Accessed 1800 Jan 01.

3.Clinical Study Report: M16-043. A randomized, double-blind, placebo controlled phase 3 study of venetoclax co-administered with low dose cytarabine versus low dose cytarabine in treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy [internal sponsor's report]. North Chicago (IL): AbbVie; 2020 Mar 20.

4.Abdallah M, Xie Z, Ready A, Manogna D, Mendler JH, Loh KP. Management of Acute Myeloid Leukemia (AML) in Older Patients. Curr Oncol Rep. 2020;22(10):103. PubMed

5.Venclexta (venetoclax): 10 mg, 50 mg, and 100 mg tablets [product monograph]. St-Laurent (QC): AbbVie Corporation; 2020 Dec 3.

6.Canadian Pharmacists Association. electronic Compendium of Pharmaceuticals and Specialties (eCPS). 2021.

7.Stahl M, Menghrajani K, Derkach A, et al. Clinical Outcomes of Acute Myeloid Leukemia Patients Bridged to Allogeneic Stem Cell Transplant By Venetoclax Combination Therapy. Blood. 2020;136(Supplement 1):16-17.

8.McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS Peer Review of Electronic Search Strategies: 2015 guideline statement. J Clin Epidemiol. 2016;75:40-46. PubMed

9.Grey matters: a practical tool for searching health-related grey literature. Ottawa (ON): CADTH; 2019: https://www.cadth.ca/grey-matters. Accessed 2021 Feb 11.

10.Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137-2145. PubMed

11.Clinical Study Report [interim]: study M15-656. A randomized, double-blind, placebo controlled phase 3 study of venetoclax in combination with azacitidine versus azacitidine in treatment naive subjects with acute myeloid leukemia who are ineligible for standard induction therapy [internal sponsor's report]. North Chicago (IL): AbbVie; 2020 May 8.

12.Health Canada reviewer's report: Venetoclax (Venclexta) [internal sponsor's report]. Ottawa (ON): AbbVie; 2020.

13.Center for Drug Evaluation Research. Medical review(s). Venclexta (venetoclax) administration. Company: AbbVie Inc. Application No.: 208573. Approval date: 10/16/2020 (FDA approval package). Silver Spring (MD): U.S. Food and Drug Administration (FDA); 2020: URL. Accessed 2021 May 14.

14.Center for Drug Evaluation R. Statistical review(s). Venclexta (Venetoclax) administration. Company: AbbVie Inc. Application No.:208573Orig1s020, s021. Approval date: 10/16/2020 (FDA approval package). Silver Spring (MD): U.S. Food and Drug Administration (FDA); 2020: URL. Accessed 1800 Jan 01.

15.Drug Reimbursement Review sponsor submission: Venclexta (venetoclax) in combination with low-dose cytarabine for the treatment of acute myeloid leukemia (AML), 10 mg, 50 mg, and 100 mg tablets [internal sponsor's package]. Pointe-Claire (QC): AbbVie Corporation; 2021 Jan 22.

16.AbbVie Corporation response to April 6, 2021 DRR request for additional information regarding Venclexta (venetoclax) DRR review: compliance for PRO instruments [internal additional sponsor's information]. Pointe-Claire (QC): AbbVie Corporation; 2021 Apr 20.

17.Center for Drug Evaluation and Research FaDA. Acute Myeloid Leukemia: Developing Drugs and Biological Products for Treatment Guidance for Industry. 2020.

18.Estey E, Othus M, Lee SJ, Appelbaum FR, Gale RP. New drug approvals in acute myeloid leukemia: what's the best end point? Leukemia. 2016;30(3):521-525. PubMed

19.Clinical Group. Clinical Efficacy and Safety of Treatments in Naive Acute Myeloid Leukemia Patients who are Ineligible for Intensive Chemotherapy: A Systematic Literature Review. 2021.

20.Analysis Group. Study Report: Indirect Comparisons of Venetoclax Combinations and Other Treatments in Treatment Naive Patients with Acute Myeloid Leukemia (AML) who are Ineligible for Induction Chemotherapy. 2021.

21.Braun DP, Gupta D, Grutsch JF, Staren ED. Can changes in health related quality of life scores predict survival in stages III and IV colorectal cancer? Health Qual Life Outcomes. 2011;9:62. PubMed

22.Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139-144. PubMed

23.Snyder CF, Blackford AL, Sussman J, et al. Identifying changes in scores on the EORTC-QLQ-C30 representing a change in patients' supportive care needs. Qual Life Res. 2015;24(5):1207-1216. PubMed

24.DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. PubMed

25.Ameringer S, Elswick Jr RK, Menzies V, et al. Psychometric evaluation of the PROMIS Fatigue-short form across diverse populations. Nurs Res. 2016;65(4):279. PubMed

26.Giesinger JM, Kieffer JM, Fayers PM, et al. Replication and validation of higher order models demonstrated that a summary score for the EORTC QLQ-C30 is robust. J Clin Epidemiol. 2016;69:79-88. PubMed

27.EQRTC. EORTC Quality of life: FAQs. 2021; https://qol.eortc.org/faq/. Accessed 2021 Mar 19.

28.EORTC QLC-C30 scoring manual. Brussels (BE): EORTC; 2001: https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf. Accessed 2021 Mar 19.

29.Davda J, Kibet H, Achieng E, Atundo L, Komen T. Assessing the acceptability, reliability, and validity of the EORTC Quality of Life Questionnaire (QLQ-C30) in Kenyan cancer patients: a cross-sectional study. Journal of Patientreported Outcomes. 2021;5(1):4. PubMed

30.Luo N, Fones CS, Lim SE, Xie F, Thumboo J, Li SC. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-c30): validation of English version in Singapore. Qual Life Res. 2005;14(4):1181-1186. PubMed

31.Bedard G, Zeng L, Zhang L, et al. Minimal important differences in the EORTC QLQ-C30 in patients with advanced cancer. Asia Pac J Clin Oncol. 2014;10(2):109-117. PubMed

Appendix 1: Literature Search Strategy

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946–present)

• Embase (1974–present)

• Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: February 11, 2021

Alerts: Weekly search updates until project completion

Study types: No filters were applied to limit the retrieval by study type

Limits:

• Publication date limit: none

• Language limit: none

• Conference abstracts: excluded

Table 24: Syntax Guide

Multi-Database Strategy

1. (venetoclax* or Venclexta* or Venclyxto* or ABT199 or ABT-199 or GDC0199 or GDC-0199 or RG7601 or RG-7601 or N54AIC43PW).ti,ab,kf,ot,hw,nm,rn.

2. exp Leukemia, Myeloid, Acute/

3. (AML or ANLL).ti,ab,kf.

4. (Acute adj5 (granulocytic* or myeloblastic* or myelocytic* or myelogenous* or myeloid* or nonlymphoblastic* or non-lymphoblastic* or nonlymphocytic* or non-lymphocytic* or basophilic* or eosinophilic* or erythroblastic* or megakaryoblastic* or monocytic* or megakaryocytic* or myelomonocytic*) adj5 (leukemia* or leukemia*)).ti,ab,kf.

5. (erythroleukemia* or erythroleukemia*).ti,ab,kf.

6. ((mast-cell or promyelocytic*) adj3 (leukemia* or leukemia*)).ti,ab,kf.

7. or/2 to 6

8. 1 and 7

9. 8 use medall

10. *venetoclax/ or (venetoclax* or Venclexta* or Venclyxto* or ABT199 or ABT-199 or GDC0199 or GDC-0199 or RG7601 or RG-7601).ti,ab,kw,dq.

11. exp Acute myeloid leukemia/

12. (AML or ANLL).ti,ab,kw,dq.

13. (Acute adj5 (granulocytic* or myeloblastic* or myelocytic* or myelogenous* or myeloid* or nonlymphoblastic* or non-lymphoblastic* or nonlymphocytic* or non-lymphocytic* or basophilic* or eosinophilic* or erythroblastic* or megakaryoblastic* or monocytic* or megakaryocytic* or myelomonocytic*) adj5 (leukemia* or leukemia*)).ti,ab,kw,dq.

14. (erythroleukemia* or erythroleukemia*).ti,ab,kw,dq.

15. ((mast-cell or promyelocytic*) adj3 (leukemia* or leukemia*)).ti,ab,kw,dq.

16. or/11 to 15

17. 10 and 16

18. 17 use oemezd

19. 18 not (conference review or conference abstract).pt.

20. 9 or 19

21. remove duplicates from 20

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

[Search terms: Venclexta (venetoclax), acute myeloid leukemia]

WHO ICTRP

International Clinical Trials Registry Platform, produced by the WHO. Targeted search used to capture registered clinical trials.

[Search terms: Venclexta (venetoclax), acute myeloid leukemia]

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

[Search terms: Venclexta (venetoclax), acute myeloid leukemia]

EU Clinical Trials Register

European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

[Search terms: Venclexta (venetoclax), acute myeloid leukemia]

Grey Literature

Search dates: February 8 to 22, 2021

Keywords: Venclexta (venetoclax), acute myeloid leukemia

Limits: Publication years: none

Updated: Search updated before the completion of stakeholder feedback period

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool For Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Internet Search

• Open Access Journals

Appendix 2: Excluded Studies

Note that this appendix has not been copy-edited.

Table 25: Excluded Studies

Appendix 3: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Table 26: Subgroup Analyses (Final Analysis)

AML = acute myeloid leukemia; CI = confidence interval; CMML = chronic myelomonocytic leukemia; CTC = common terminology criteria; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EDC = electronic data capture; FEV₁ = forced expiratory volume in 1 second; FLT-3 = FMS-like tyrosine kinase-3; HR = hazard ratio; IDH = isocitrate dehydrogenase; MDS = myelodysplastic syndrome; SD = standard deviation; NPM-1 = nucleophosmin-1

Source: Clinical Study Report for VIALE-C.³

Table 27: Health-Related Quality of Life and Fatigue Symptom Scales