At about 18 months’ follow-up in treatment naive acute myelogenous leukemia (AML) patients who were 75 years or older or otherwise unfit for intensive chemotherapy, median overall survival (OS) was 8.4 months when they were randomized to low-dose cytarabine (LDAC) plus the BCL-2 inhibitor venetoclax versus 4.1 months with LDAC plus placebo. The results from the phase 3 trial were reported at the virtual annual congress of the European Hematology Association.
The combination also improved rates of remission, event-free survival, and patient reported outcomes and lessened transfusion requirements. Adverse events were manageable.
The findings position venetoclax add-on with LDAC “as a potential new standard of care” for untreated patients ineligible for intensive chemotherapy, lead investigator, an AML researcher at Monash University, Melbourne, said at the meeting.
The study addresses a substantial unmet need. The median age at AML diagnosis is over 68 years old and comorbidities such as heart failure and reduced creatinine clearance are common, which make the risk of toxicity with standard chemotherapy too high. Single-agent alternatives are of limited benefit, so Dr. Wei’s group and others are looking for better options to plug the treatment gap when standard chemotherapy is contraindicated.
Several combinations are under investigation, including LDAC plus venetoclax, which appears to have a synergistic effect greater than either agent on its own, Dr. Wei and colleagues explained in their journal report, which was published online to coincide with his presentation ().
In a commentary,, a hematologist with the Erasmus University Medical Center in Rotterdam, and , of the University Medical Center Groningen, both in the Netherlands, said the study “represents a valuable although moderate step forward on the way to a better therapeutic future for the ‘unfit’ patient with AML” ( ).
“A challenging AML population”
In the study, 143 patients were randomized to oral venetoclax 600 mg daily and 68 to placebo in 28-day cycles, on a background of LDAC 20 mg/m2 administered subcutaneously on days 1-10 of each cycle.
“This study enrolled a challenging AML population, with nearly 60% age ≥75 years and a high proportion of patients with secondary disease (38%), prior hypomethylating agent (HMA) treatment (20%), poor cytogenetic risk (32%), and TP53 mutations (15%), which are known factors associated with dismal prognosis in AML,” the investigators noted in their report.
There was a numerical benefit in OS at 12 months – the preplanned primary outcome – but it was not statistically significant. At 18 months, however, and after adjustment for a higher rate of secondary AML in the venetoclax arm and other confounders in a post hoc analysis, survival differences reached significance. The 4.3-month OS benefit with the combination translated into a 30% reduction in the risk of death (hazard ratio, 0.70; 95% confidence interval, 0.50-0.99; P = .04)
Survival outcomes “were particularly promising for patient subgroups with NPM1- (median OS, not reached) and IDH1/2-mutant AML (median OS, 19.4 months),” the team noted.
Complete remission (CR) were 48% in the venetoclax arm, compared with 13% in the placebo group, and 34% of venetoclax patients versus 3% of placebo patients went into remission after their first cycle. Venetoclax subjects also had longer median event free survival (4.7 months vs. 2 months); higher rates of red blood cell and platelet transfusion independence (37% vs. 16%); and higher rates of cytometric minimal residual disease levels below 0.1% (6% vs. 1%).
The findings correlated with “strong improvements” in patient-reported outcomes, including fatigue and quality of life, the investigators reported.
Grade 3 or higher adverse events (AEs) included febrile neutropenia (32% in the venetoclax arm versus 29% in the placebo group), neutropenia (47% venetoclax vs. 16% placebo), thrombocytopenia (45% vs. 37%), and anemia (25% vs. 22%). The eight cases of tumor lysis syndrome (TLS) were all in the venetoclax arm. Grade 3 or higher bleeding was higher in the venetoclax arm (11% versus 7%), but the incidence of fatal bleeding was similar between the groups (1.4% venetoclax versus 1.5%).
“Although the venetoclax arm showed modest increases in hematologic AEs, the rate of AEs leading to treatment discontinuation (24% vs. 25%) and the rate of serious AEs such as pneumonia” and sepsis “were nearly identical between” the arms, the team said.
The combination “is more myelosuppressive,” but the effects “were mostly mitigated by venetoclax dose interruptions and reductions.” To mitigate the TLS risk, patients were hospitalized for TLS evaluation and prophylaxis during the 4-day venetoclax ramp-up in the first treatment cycle and for 24 hours after the 600-mg target was reached. “I think this is an extremely important measure to avoid this small but important complication,” Dr. Wei said at the meeting.
A moderate step forward
Dr. Lowenberg and Dr. Huls noted in their commentary that, despite the favorable outcomes, “the results are still sobering with a rapid drop of the survival curves to values of [around] 25% or less within 18 months, and event-free survival rates even falling to considerably lower levels.”
Also, there was a “weak correlation between the relatively wide differences in comparative CR/CRi rates and the much smaller differences in survival,” perhaps “due to a limited depth of the complete responses following venetoclax-LDAC therapy or the early development of therapeutic resistance,” they said.
The commentary also noted another option, adding the hedgehog pathway inhibitor glasdegib, instead of venetoclax, to LDAC. It also improved survival in a similar randomized study in unfit AML and high-risk myelodysplastic syndrome patients, from a median survival of 4.9 months with LDAC alone to 8.8 months with the combination (Leukemia. 2019 Feb;33(2):379-389. doi:
Another alternative approach – venetoclax plus the HMA agent azacitidine – garnered a lot of attention at the meeting when it wasthat the combination had a median overall survival of 14.7 months, versus 9.6 months with azacitidine alone, in patients ineligible for intensive chemotherapy. CR/CRi rates were 66% with the combination, versus 28%.
“It seems like the results were better with the combination of venetoclax and azacitidine” than venetoclax plus LDAC, said, of Lund (Sweden) University, who moderated Dr. Wei’s presentation.
He wanted to know if there was a way to identify patients who would do better on one regimen versus the other and was curious about the fact that the azacitidine study used a dose of 400 mg venetoclax, instead of 600 mg.
Dr. Wei noted the high incidence of poor prognostic factors in his study, including prior HMA treatment in 20%, but also that “we don’t know for sure” if there’s a clinically meaningful benefit with the higher dose.
He also said the optimal number of venetoclax cycles for best response is unknown. For now, treatment is “recommend until either [disease] progression, dose intolerance, or patient or physician preference,” he noted. Venetoclax subjects in his study had a median of four treatment cycles versus two in the placebo group. Combination patients in the azacitidine study had a median of seven cycles versus 4.5 with placebo.
Venetoclax already carries anin the United States in combination with azacitidine, decitabine, or LDAC for newly-diagnosed AML in adults 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy, at a daily dosage of 400 mg with HMAs and 600 mg with LDAC.
Labeling notes that “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”
Both venetoclax trials were sponsored by the drug’s maker, AbbVie, which was involved with data interpretation and other matters. Dr. Wei is a consultant for and receives research funding from the company and also receives royalty payments in relation to venetoclax. The commentators did not have any competing financial interests. Disclosures, if any, were not reported for Dr. Juliusson.
SOURCE: Wei AH et al. EHA Congress, Abstract .