PracticeUpdate Oncology February 2019

EDITOR’S PICKS 14

Venetoclax Plus Decitabine or Azacitidine in Treatment-Naive, Elderly Patients With AML Blood

Take-home message • This phase Ib study evaluated venetoclax plus decitabine or azac- itidine in treatment-naïve, elderly patients with AML. The objective response rate was 67%, with a median duration of response of 11.3 months. The median overall survival was 17.5 months. • Combining ventoclax with decitabine or azacitidine was found to be both effective and well-tolerated among elderly patients with AML. Abstract Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. BCL-2 overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multi- center, phase 1b dose-escalation and expansion study. Patients (N=145) were ≥65 years with treatment-naive AML ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decit- abine (20 mg/m 2 , days 1-5; intravenously [IV]) or azacitidine (75 mg/m 2 , days 1-7; IV or subcuta- neously). In the expansion, 400 mg or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nau- sea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR+CRi rate of 73% in the venetoclax 400-mg + HMA cohort. Patients with poor-risk cytoge- netics and those ≥75 years had CR+CRi rates of 60% and 65%, respectively. The median dura- tion of CR+CRi (all patients) was 11.3 months and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400 mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML. Venetoclax Combined With Decitabine or Azacitidine in Treatment-Naive, Elderly Patients With Acute Myeloid Leukemia. Blood 2018 Oct 25;[EPub Ahead of Print], CD DiNardo, K Pratz, V Pullarkat, et al. www.practiceupdate.com/c/76020

COMMENT By Isabel Cunningham MD

A T LAST!!!! At last! – there is a new combination therapy for AML based on completely different means of cell kill – here combining an oral inhibitor of BCL2 with either azacytidine or decitabine. At last! – there is a way to optimize hypomethylating drugs that had not found a reliable place in AML treatment in many years. It is known that many genes in AML are silenced by methylation, as they are in solid cancers, so demethylation has long made sense, but none of many trials has produced comparable success to this combination. At last! – a drug found effective in lymphomas, CLL, and myeloma is effective in myeloid leukemia. If mechanisms of drug resistance are shared by different cancers, this should propel development of treatments that will benefit large patient populations. This dose-finding report, from 10 major cancer centers, shows remarkable response in de novo AML patients over 65, even with secondary leukemia. The authors combine CR and CRi rates as 73% in the group dosed with venetoclax 400 mg with a hypometh- ylating agent. For those of us who stand by complete remission (with count recovery) as the gold standard for durable success in AML, it is noteworthy that they document a significant difference in median remission duration between CR (12.5 months) and CRi (6.8 months). This well-tolerated combination, with less required time in the hospital and less treat- ment-related morbidity and mortality, is moving into phase III trials and will surely be practice-changing.

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