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Andrew Wei, MBBS, PhD

MADRID—The combination of venetoclax and low-dose cytarabine (VEN+LDAC) appears to be a feasible treatment option for elderly patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.

In a phase 1/2 study of such patients, VEN+LDAC was considered well-tolerated, conferring moderate myelosuppression and largely low-grade non-hematologic toxicities.

In addition, the combination produced “rapid and durable” responses, and early death rates were low, according to Andrew H. Wei, MBBS, PhD, of Monash University in Melbourne, Victoria, Australia.

However, nearly three-quarters of patients ultimately discontinued the treatment, many due to disease progression.

Dr Wei presented these results at the 22nd Congress of the European Hematology Association (EHA) as abstract S473. AbbVie and Genentech, the companies developing and marketing venetoclax, provided financial support for this study.

“Expression of pro-survival proteins is an established mechanism of chemoresistance in diverse cancers,” Dr Wei noted. “BCL-2 is 1 of 5 pro-survival molecules which functions to sequester pro-apoptotic molecules and tip the balance in favor of cell survival.”

“Venetoclax is a potent and specific inhibitor of BCL-2 which releases these pro-apoptotic molecules, tipping the balance in favor of cell death. Cytotoxic drugs are well-known to increase the burden of BH3-only proteins, and so it was surmised that the combination of chemotherapy, such as cytarabine, with venetoclax could augment the clinical response.”


Dr Wei presented data on 61 AML patients treated with VEN+LDAC. He noted that this was a poor-risk population, with nearly half of patients over the age of 75 at baseline.

The patients’ median age was 74 (range, 66-87), and 64% were male. Nearly half of patients had an ECOG performance status of 1 (49%), 30% had a status of 0, and 21% had a status of 2.

Forty-four percent of patients had secondary AML, and 28% had prior treatment with a hypomethylating agent (HMA). Sixty-one percent of patients had intermediate-risk cytogenetics, and 31% had poor-risk cytogenetics.


The patients received oral venetoclax at 600 mg daily on days 1 to 28 and subcutaneous cytarabine at 20 mg/m2 daily on days 1 to 10 of each 28-day cycle.

In the first cycle, the dose of venetoclax was ramped up gradually—no dose on day 1, 50 mg on day 2, 100 mg on day 3, 200 mg on day 4, 400 mg on day 5, and 600 mg thereafter.

Patients received prophylaxis for tumor lysis syndrome prior to starting cycle 1, and they were hospitalized to enable observation.

The median time on study treatment was 6 months (range, <1 to 19 months). Seventy-two percent of patients discontinued treatment.

Reasons for discontinuation included:

  • Progressive disease without death—26%
  • Progressive disease with death—10%
  • Adverse event (AE) related to progression—10%
  • AE not related to progression—8%
  • Withdrawn consent—8%
  • Other reasons—18%.


The most common AEs of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).

Grade 3/4 hematologic AEs (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), and anemia (28%).

Grade 3/4 non-hematologic AEs (occurring in at least 10% of patients) included hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).

Response and survival

The overall response rate was 65%, with 25% of patients achieving a complete response (CR), 38% having a CR with incomplete blood count recovery (CRi), and 2% experiencing a partial response.

Dr Wei noted that VEN+LDAC was active across subgroups.

The CR/CRi rate was 76% among patients with intermediate-risk cytogenetics and 47% among patients with poor-risk cytogenetics.

The CR/CRi rate was 70% among patients older than 75, 52% among patients with secondary AML, 66% among patients with no prior HMA exposure, and 53% in patients with prior HMA exposure.

“Although responses were slightly lower in patients with poor cytogenetic risk, prior HMA exposure, and secondary AML . . ., these responses are far in excess of what we would expect with [LDAC] alone,” Dr Wei said.

“Furthermore, the median time to response was very rapid, and this is extremely important to get patients into remission and avoid the medium-term consequences of active AML.”

The median time to response was 1 month (range, <1 to 9 months).

The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.

Based on these results, AbbVie has initiated a phase 3 trial comparing VEN+LDAC to LDAC alone in elderly patients with untreated AML who are ineligible for intensive chemotherapy.

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