Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia

Abstract

Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (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, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 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 nausea, 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 cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration 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 (This trial was registered at www.clinicaltrials.gov as #NCT02203773).

HOXA10 induces BCL2 expression, inhibits apoptosis, and promotes cell proliferation in gastric cancer

“…It is noteworthy that BCL2 inhibitors, such as venetoclax (ABT‐199), are clinically explored in several cancer types . However, studies have indicated that the expression levels of anti‐apoptotic proteins, BCL2, Bcl‐xL, and Mcl‐1, are highly variable, manifesting various disease prognosis and venetoclax sensitivity . Thus, further studies are needed to explore whether BCL2 upstream genes, such as HOXA10, could help develop new therapy strategies for GC.…”

Durable remissions with venetoclax monotherapy in secondary AML refractory to hypomethylating agents and high expression of BCL‐2 and/or BIM

“…Interestingly, median OS from venetoclax initiation was significantly longer in patients with primary HMA refractory disease compared to HMA‐responders (126 days vs 15 days; P = 0.018). In previous AML studies, patients with a WBC exceeding 25 G/L were excluded from venetoclax treatment . Despite a baseline WBC of up to 269 G/L (range 0.7‐269 G/L) at venetoclax initiation, we did not observe tumor lysis syndrome.…”

New drugs creating new challenges in acute myeloid leukemia

“…In clinical studies, although the selective BCL‐2 inhibitor venetoclax has modest activity as monotherapy in R/R AML, more impressive results have been observed in two phase 1b/2 studies using venetoclax in combination with either HMA or LDAC in older (≥65 years) patients with newly diagnosed AML unfit for intensive chemotherapy. In a study of 145 patients, venetoclax plus azacitidine or decitabine produced a CR/CRi in 67%, median OS lasting 17.5 months and 46% were alive at 2 years . Similarly, in study of 82 patients (prior HMA exposure allowed), venetoclax plus LDAC (20 mg/m 2 subcutaneous daily d1‐10) produced a CR/CRi in 54%, median OS lasting 10.1 months and 44% were alive at 1 year .…”