A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes

Abstract

Patients with relapsed/refractory (R/R) higher‐risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open‐label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28‐day cycle. Azacitidine was administered on Days 1–7 every cycle at 75 mg/m2/day intravenously/subcutaneously. Responses were assessed per modified 2006 International Working Group (IWG) criteria. Forty‐four patients (male 86%, median age 74 years) received venetoclax + azacitidine treatment. Median follow‐up was 21.2 months. Hematological adverse events of Grade ≥ 3 included febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common Grade ≥ 3 infection. Marrow responses were seen including complete remission (CR, n = 3, 7%) and marrow CR (mCR, n = 14, 32%); 36% (16/44) achieved transfusion independence (TI) for RBCs and/or platelets, and 43% (6/14) with mCR achieved hematological improvement (HI). The median time to CR/mCR was 1.2 months, and the median duration of response for CR + mCR was 8.6 months. Median OS was 12.6 months. Venetoclax + azacitidine shows activity in patients with R/R MDS following prior HMA therapy failure and provides clinically meaningful benefits, including HI and TI, and encouraging OS.

Venetoclax and hypomethylating agent therapy in myelodysplastic syndromes: Big picture perspective

“…Taken together, currently available literature, including the current report by Zeidan et al, 18 suggests a higher response rate from the addition of Ven to HMA in both MDS and AML, in the setting of both newly diagnosed and relapsed/refractory disease. In AML, the combination has been shown to result in longer median survival in newly diagnosed elderly/unfit patients, in a controlled setting, compared to HMA alone 7 .…”

“…18 The particular study is reported in the current issue of the journal with an overall response seen in 39% of patients (CR7%). 18 Not surprisingly, adverse events occurred in all patients, with over a third of patients experiencing grade 3 febrile neutropenia, thrombocytopenia, diarrhea, and nausea, which resulted in treatment interruption and discontinuation in 48% and 21% of patients, respectively. 18 Overall, 33 (75%) of patients discontinued therapy, primarily due to death in 29 (66%) of the patients, four of which were possibly treatment-related.…”

“…Not surprisingly, adverse events occurred in all patients, with over a third of patients experiencing grade 3 febrile neutropenia, thrombocytopenia, diarrhea, and nausea, which resulted in treatment interruption and discontinuation in 48% and 21% of patients, respectively 18 . Overall, 33 (75%) of patients discontinued therapy, primarily due to death in 29 (66%) of the patients, four of which were possibly treatment‐related 18 . It is to be brought to attention that patients with therapy related MDS were excluded from clinical trials.…”

“…However, toxicity was not trivial, with grade 3 or higher adverse events reported in 97% of patients, predominantly neutropenia (51%), febrile neutropenia (46%), and thrombocytopenia (30%) 16,17 . The safety and efficacy of Ven + azacitidine in relapsed/refractory MDS was assessed in a separate phase 1b study (NCT02966782) ( n = 44) in which patients received Ven 100–400 mg for 14 days in combination with azacitidine 75 mg/m 2 for 7 days 18 . The particular study is reported in the current issue of the journal with an overall response seen in 39% of patients (CR7%) 18 .…”

“…The safety and efficacy of Ven + azacitidine in relapsed/refractory MDS was assessed in a separate phase 1b study (NCT02966782) ( n = 44) in which patients received Ven 100–400 mg for 14 days in combination with azacitidine 75 mg/m 2 for 7 days 18 . The particular study is reported in the current issue of the journal with an overall response seen in 39% of patients (CR7%) 18 . Not surprisingly, adverse events occurred in all patients, with over a third of patients experiencing grade 3 febrile neutropenia, thrombocytopenia, diarrhea, and nausea, which resulted in treatment interruption and discontinuation in 48% and 21% of patients, respectively 18 .…”