Venetoclax Plus Low-Dose Cytarabine Improves Survival and Remission in Patients With Chemotherapy-Ineligible AML

Treatment with venetoclax plus low-dose cytarabine (LDAC) led to greater improvements in remission and overall survival (OS), compared with LDAC alone, in patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy because of advanced age or comorbidities, according to a study published in Blood.

In this phase III study, led by Andrew Wei, MD, of Monash University in Melbourne, Australia, researchers also found that this therapy combination was associated with a favorable safety profile, which clinicians may find reassuring, given that the increased risk of treatment-related toxicity associated with intensive chemotherapy often precludes its use in older patients.

The study included 211 adults with newly diagnosed AML who were enrolled at 76 sites across the globe. Participants were older than 75 or were aged ≥18 to 74 with any comorbidity that a physician considered incompatible with conventional intensive chemotherapy.

Specifically, comorbidities that defined eligibility for this study included:

  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 2-3
    cardiac history of congestive heart failure that required treatment or ejection fraction ≤50%
  • chronic stable angina
  • creatinine clearance ≥30 mL/min to <45 ml/min
  • moderate hepatic impairment with total bilirubin >1.5 to ≤3.0 times the upper limit of normal

Patients were randomly assigned to receive either venetoclax plus LDAC (n=143) or placebo plus LDAC (n=68). Venetoclax was administered orally over a 4-day ramp-up period, starting at 100 mg and increasing stepwise to reach a target dose of 600 mg. During this period, patients were hospitalized to evaluate for tumor lysis syndrome and prophylaxis. Hospitalization continued until 24 hours after the target venetoclax dose was achieved.

Venetoclax was then administered at 600 mg on days 4 through 28 of cycle 1 and in subsequent 28-day treatment cycles. Patients in both arms received LDAC 20 mg/m2 as a once-daily injection on days 1 through 10 across all cycles.

The study’s primary endpoint was OS, and secondary efficacy endpoints included stable achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). The investigators also evaluated rates of transfusion independence, event-free survival (EFS), and measurable residual disease.

“There is a long way to go and there is much to learn, but at least the future is brighter than it has ever been for this historically forlorn AML population.”

—Andrew Wei, MD

This was “a challenging patient population,” the authors wrote. At baseline, the median age was 76 years (range = 36-93) and approximately 38% of patients presented with secondary AML. In addition, 32% of patients had disease with poor cytogenetic risk, including 15% who had a TP53 mutation.

In the study, patients randomized to venetoclax plus LDAC had a median treatment duration of 3.9 months (range = 0-17) and received a median of 4 treatment cycles. Patients in the placebo group had shorter median treatment duration (1.7 months; range = 0.1-14) and received fewer treatment cycles (median = 2). However, in both arms, the median time on study for event-free patients was 12 months.

The addition of venetoclax to LDAC appeared to lead to more rapid responses, compared with LDAC alone: In the venetoclax group, 34% of patients achieved a CR/CRi prior to cycle 2 versus 3% in the placebo arm. Venetoclax plus LDAC also resulted in a CR/CRi rate of 48%, compared with 13% in the LDAC-alone arm.

The higher remission rates observed with venetoclax treatment correlated with longer median EFS (4.7 vs. 2 months; hazard ratio [HR] = 0.58; 95% CI 0.42-0.82; p=0.002).

The median OS was numerically longer for patients assigned to the venetoclax plus LDAC group than the placebo group; the comparison did not reach statistical significance and the primary endpoint was not met at the time of the planned analysis (7.2 vs. 4.1 months, respectively; HR=0.75; 95% CI 0.52-1.07; p=0.11).

While there was no significant difference between the two groups in terms of OS, Dr. Wei told ASH Clinical News that an interim analysis performed on March 23, 2020, reported a positive survival outcome with the addition of venetoclax. Detailed study results from this analysis have yet to be released, he added, but with 6 months of additional follow-up, a significantly higher median OS was observed for the venetoclax plus LDAC arm (8.4 vs. 4.1 months; HR=0.70; 95% CI 0.50-0.99; p=0.04).

Regarding secondary efficacy outcomes, the investigators also reported that patients treated with venetoclax plus LDAC had significantly higher rates of transfusion independence compared with those who received LDAC alone (37% vs. 16%; p=0.002).

Dr. Wei and colleagues noted that venetoclax plus LDAC “was well tolerated and manageable,” although patients in the venetoclax arm had higher rates of grade ≥3 adverse events, including febrile neutropenia (32% vs. 29%), neutropenia (47% vs. 16%), and thrombocytopenia (45% vs. 38%).

When asked about the clinical implications of these findings, Dr. Wei said, “With a dearth of alternative treatment options [for older patients with AML], it is likely that physicians will remain attracted to the benefits of higher response rates associated with higher transfusion independence and improved patient-reported outcomes with venetoclax.”

Because glasdegib is the only other FDA-approved drug with randomized data that show improved OS in older patients with AML and comorbidities, Dr. Wei suggested that results from the present study may expand available options for this patient population. “There is a long way to go and there is much to learn,” he said, “but at least the future is brighter than it has ever been for this historically forlorn AML population.”

However, Dr. Wei noted that the 2:1 randomization protocol led to a relatively small number of patients enrolled in the placebo arm, which he suggests likely limited the survival comparison.


Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for patients with untreated AML ineligible for intensive chemotherapy: phase 3 randomized placebo-controlled trial. Blood. 2020 March 27. [Epub ahead of print]