Real‐world experience with venetoclax and hypomethylating agents in myelodysplastic syndromes with excess blasts

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

“…Nonetheless, response rates observed in retrospective real‐world series corroborate clinical trial results with overall response rates of 75% and 44% in treatment‐naïve and relapsed/refractory MDS patients, respectively 19 . Likewise, among 40 patients with MDS with excess blasts (MDS‐EB) treated with Ven + HMA therapy at the Mayo Clinic, overall response rate was 69% with upfront therapy and 75% in the relapsed/refractory setting 11 . Notably, in this particular study, superior responses (CR/mCR rate; 92%) were observed in patients harboring ASXL1 mutations 11 .…”

“…Subsequently, in 2020, Ven + HMA received FDA approval for treatment‐naïve elderly and/or unfit patients with AML based on results from the phase III VIALE‐A study 7 . Furthermore, the regimen is increasingly used on an off‐label basis for relapsed/refractory AML, 8–10 and related myeloid malignancies, inclusive of MDS, 11 chronic myelomonocytic leukemia (CMML), 12 myeloproliferative neoplasms (MPN) with blast phase (BP) transformation (MPN‐BP) 13 and blastic plasmacytoid dendritic cell neoplasm (BPDCN) 14 . Exacerbation of pre‐existing cytopenias with Ven + HMA therapy in patients with MDS remains a valid concern since treatment‐emergent myelosuppression was common in patients with AML with grade 3 or higher thrombocytopenia documented in 45%, and febrile neutropenia in 42% of patients treated on the VIALE‐A clinical trial 7 .…”

Predictors of response to venetoclax plus hypomethylating agent therapy and survival in blastphase myeloproliferative neoplasm

“…13 In addition, ASXL1 mutations have been shown to confer sensitivity to Ven+HMA in both AML and MDS with excess blasts, unlike the case in MPN-BP. 14,15 The prognostic impact of ASXL1 mutations in blast phase MPN differs from that in MDS and de novo AML as shown in our prior work in which the presence of RUNX1 mutations but not ASXL1 predicted inferior survival in MPN-BP. 16 In an analysis of paired chronic and blast phase samples, ASXL1 mutations were detected only during blast phase disease in 33%, 16 which might explain the discrepancy in response rates to Ven+HMA.…”

Assessing the role of venetoclax in combination with hypomethylating agents in higher risk myelodysplastic syndrome

“…No difference in CR/mCR rates were found between those who were HMA-exposed, HMA-failure, or HMA naïve. HMA/Venetoclax CR/mCR was more likely in patients with ASXL1, SRSF2, or IDH2 [11].…”

“…All IPSS-R risk categories were included, and 23 patients received decitabine and 17 patients received azacitadine. Thirty-eight patients were included in final analyses, and results demonstrated 30% with CR, 37.5% with mCR, and of those with mCR, 27% had HI [11]. Of the 27 patients with CR or mCR, 11 patients proceeded to AHSCT.…”