Venetoclax Plus LDAC Tops LDAC Alone in AML

Medscape
01 Jul, 2020 ,

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.

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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 Andrew Wei, MD, Ph.D., 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 makes 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 (Blood. 2020 Jun 11;135(24):2137-45).

In a commentary, Bob Lowenberg, Ph, a hematologist with the Erasmus University Medical Center in Rotterdam, and Gerwin Huls, MD, Ph.D., of the University Medical Center Groningen, both in the Netherlands, said the study "represents a valuable although a moderate step forward on the way to a better therapeutic future for the 'unfit' patient with AML" (Blood. 2020. Jun 11;135(24): 2114-5).

"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 the 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)