Venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with therapy-related myeloid neoplasms, antecedent myelodysplastic syndromes, or myelodysplastic/myeloproliferative neoplasms.
Authors: Pullarkat Vinod , Pratz Keith , Dohner Hartmut , Recher Christian , Thirman Michael J. , Dinardo Courtney Denton , Fenaux Pierre , Schuh Andre C. , Wei Andrew H. , Pigneux Arnaud , Jang Jun Ho , Juliusson Gunnar , Miyazaki Kazuhito , Selleslag Dominik , Arellano Martha Lucia , Naqvi Kiran , Yu Jun , Ridgeway Jean , Potluri Jalaja , Konopleva Marina 
Published: June 2021

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Background: Patients (pts) with therapy-related myeloid neoplasms (tMN), antecedent myelodysplastic syndrome, or antecedent myelodysplastic/myeloproliferative neoplasms (A-MDS/MPN) may have poor outcomes due to age and adverse genetic/karyotypic features. In the VIALE-A study, pts with tMN and A-MDS/MPN unfit for intensive chemotherapy treated with venetoclax (Ven) and azacitidine (Aza) demonstrated superior response rates and overall survival (OS) than Aza alone. Herein, the efficacy and safety of Ven+Aza among pts with tMN and A-MDS/MPN are described. Methods: Data were pooled from pts enrolled in VIALE-A (NCT02993523) comparing pts who received Ven+Aza or placebo (Pbo)+Aza and a prior phase 1b study (NCT02203773) where pts received Ven+Aza. Enrolled pts were ≥18 years, treatment-naïve with no prior exposure to hypomethylating agents, and ineligible for intensive chemotherapy. Pts on Ven+Aza received Ven 400 mg orally (days 1–28) and Aza (75 mg/m2; days 1-7/28-day cycle). Composite complete remission rate (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]), duration of response (DoR), and OS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: In this pooled analysis, tMN was observed in (Ven+Aza/Pbo+Aza) 31/9 and A-MDS/MPN in 59/26 pts. Poor-risk cytogenetics were observed in 18 (58%)/6 (67%) with tMN (5 or 5q deletion [del]: 4/1 ; 7 or 7q del: 6/1 ; complex [≥ 3 clonal abnormalities]: 10/4), and 19 (32%)/13 (50%) with A-MDS/MPN (5 or 5q del: 10/5; 7 or 7q del: 6/1; complex: 14/9). TP53 mutation was observed in 5/3 pts with tMN and 8/0 pts with A-MDS/MPN. Pts with tMN received a median (Ven+Aza/Pbo+Aza) of 5/4 cycles of treatment. CRc was achieved by 19 (61%)/1 (11%). The mDoR was not reached (NR) (95% CI: 17.8, NR)/8.5 (NR, NR) months. The mOS was 16.4 (95% CI: 4.1, NR)/11.3 (0.6, 17.5) months. Pts with A-MDS/MPN received a median (Ven+Aza/Pbo+Aza) of 9/5 cycles of treatment. CRc was achieved by 39 (66%)/7 (27%) pts with mDoR of 17.3 (95% CI: 9.6, NR)/5.8 (1.1, NR) mos. The mOS was 15.9 (95% CI: 11.5, NR)/10.1 (4.7, 14.5) mos. Common grade≥3 adverse events (Ven+Aza/Pbo+Aza) were febrile neutropenia (tMN: 39%/11% and A-MDS/MPN: 36%/12%) neutropenia (tMN: 29%/33%; A-MDS/MPN: 39%31%), and thrombocytopenia (tMN: 32%/33%; A-MDS/MPN: 39%/62%). Conclusions: Ven+Aza compared to Aza monotherapy resulted in higher CRc rates with longer DoR and median OS among treatment-naïve pts with tMN and A-MDS/MPN ineligible for intensive chemotherapy. The safety profile was similar to overall pts with the Ven+Aza combination. Outcomes by cytogenetic and molecular risk-groups will be presented. Clinical trial information: NCT02993523, NCT02203773.