DISCUSSION
toxicities, MDS, neutropenia
THROMBOCYTOPENIA, DISEASE, NEUTROPENIA
Treatment of patients with MDS with a prior HMA failure remains a significant area of unmet clinical need. Patients have an adverse prognosis and limited treatment options. In this phase 1b study, venetoclax was administered both as monotherapy and in combination with azacitidine in patients with R/R MDS after HMA therapy, with several patients achieving meaningful clinical benefits with the combination. Alternately, the efficacy of venetoclax monotherapy was limited.The patients treated in our study reflect the older patient population with R/R MDS with a median age of 74 years. The majority had very high or high‐risk IPSS‐R disease (73%). They were also heavily pretreated with HMAs, with a median of nine cycles of prior HMA therapy, and 65% received at least six cycles of prior HMA therapy.The severity, incidence, and types of AEs observed with the combination of venetoclax and azacitidine were consistent with the known safety profile of both agents, and no new toxicities for venetoclax were identified. There was no occurrence of TLS, patients were treated in an outpatient setting, and there was no dose ramp‐up for venetoclax. The hematologic toxicities reported were predominantly neutropenia and thrombocytopenia. These known side effects of venetoclax treatment were noted in prior studies of venetoclax in AML.The study demonstrated marrow responses including 7% CR (3/44) and 32% mCR (14/44). While the value of mCR as a response in MDS patients is debated, 6 of the 14 patients who achieved mCR also achieved HI, which is clinically meaningful and has been consistently associated with OS benefits in prior analyses.Notably, the responses were attained early within a median of 1.2 months of treatment and sustained for a median of 8·6 months; with a median OS of 12·6 months. The historic median OS for R/R MDS observed in prior studies is between 4·3 and 5·6 months.Further, the results of our study have been similarly replicated in other studies. A recent retrospective analysis of patients with R/R MDS treated with the combination reported an overall response rate of 44% and median OS of 11·4 months (95% CI, 5·7–not estimable).We observed responses in several genetically mutated subgroups. Our study should be interpreted with caution as it lacks a comparator arm. The small sample size of the dose‐escalation and safety‐expansion cohorts precluded a dose–response analysis of this combination in this R/R MDS population. Similarly, the small number of overall assessed cycles limited the interpretability of PROs.The study demonstrated a manageable safety profile with meaningful clinical benefits with the combination of venetoclax and azacitidine in adult patients with R/R MDS. Additional data, potentially including other combinations with venetoclax should be explored in future studies to enhance clinical responses in this hard‐to‐treat patient population.