Venetoclax/venetoclax plus 10 days of decitabine responds to high-risk MDS, AML

Based on data from a Phase 2 study (NCT03404193) shared in 2024, venetoclax combined with 10 days of decitabine demonstrated safety and efficacy in older/unfit patients with newly diagnosed acute myeloid leukemia (AML), patients with relapsed/refractory AML, and patients with high-risk myelodysplastic syndromes (MDS).

The results showed that the overall response rate (ORR) was 88% (n=88) in patients with newly diagnosed AML, 77% (n=17) in patients with previously untreated secondary AML, 67% (n=30) in patients with previously treated secondary AML, 58% (n=72) in patients with relapsed/refractory AML, and 52% (n=21) in patients with high-risk MDS. In the newly diagnosed AML group, 66% achieved complete response (CR) and 15% achieved CR with incomplete hematological recovery (CRi), for an overall rate of CR and CRi of 81%. In untreated secondary AML, 47% of patients achieved CR, 18% achieved CRi, and the CR/CRi rate was 65%. In the treated secondary AML group, 27% had CR and 20% had CRi, for a CR/CRi rate of 57%. In the relapsed/refractory AML group, 21% experienced CR, 19% achieved CRi, and the CR/CRi rate was 40%. In high-risk MDS, 24% of patients achieved CR, 10% developed CRi, and the CR/CRi rate was 33%.

10 days of decitabine plus venetoclax was highly effective in newly diagnosed and relapsed/refractory AML, and the survival benefit was even more pronounced in patients who received stem cell transplants. The single-institution phase 2 study conducted at MD Anderson Cancer Center evaluated patients with newly diagnosed AML, including patients with previously untreated secondary AML and previously treated MDS or chronic myelomonocytic leukemia who were not candidates for intensive chemotherapy; relapsed/refractory AML with high-risk MDS; or blastic plasmacytoid dendritic cell neoplasms. The primary endpoint of the trial was ORR as defined by the revised International Working Group (IWG) AML criteria and the revised IWG MDS criteria. Duration of response (DOR), relapse-free survival (RFS) and overall survival (OS) were secondary endpoints of the trial.

Overall, new diagnoses and relapses/The median OS of patients with refractory AML was 15.7 months (95% CI, 10.5-25.4) and 7.6 months (95% CI, 5.9-15.3) respectively; in patients with treated or untreated secondary Among patients with AML, these figures were 8.5 months (95% CI, 3.9-18.8) and 11.1 months (95% CI, 5.5-not applicable [NA]) (log-rank P = 0.034). Median RFS was 10.0 months (95% CI, 8.3-18.8) for newly diagnosed AML and 7.5 months (95% CI, 5.4-16.1) for relapsed/refractory AML and treated It was 7.8 months (95% CI, 3.2-13.3) for secondary AML and 5.1 months (95% CI, 2.5-NA) for untreated secondary AML (log-rank P=0.165).

Regarding minimal residual disease (MRD), in newly diagnosed AML (n=74), untreated secondary AML (n=12), treated secondary AML (n =20), relapsed/refractory AML (n=30), and high-risk MDS (n=21) cohorts, 65%, 42%, 50%, 43%, and 19% of patients with evaluable disease achieved MRD negativity, respectively.

Among patients with newly diagnosedAML, secondary AML, relapsed/refractory AML, or high-risk MDS, 2%, 0%, 1%, and 5%, respectively, were still receiving study treatment at the time of data cutoff. Reasons for study discontinuation included recurrent disease (27%; 28%; 17%; 14%), transplantation (19%; 15%; 24%; 24%), death (14%; 13%; 6%; 0%), patient Discontinuation (15%; 6%; 10%; 5%), treatment completion (9%; 0%; 3%; 0%), inadequate response (8%; 25%; 33%; 38%), toxicity (3%; 4%; 7%; 0%).

All-grade adverse reactions in the overall population(AE) included infections with absolute neutrophil count (ANC) less than 1.0x10^9/L (42%), neutrophils exceeding 1.0x Infection of 10^9/L (38%), febrile neutropenia with neutrophils less than 1.0x10^9/L (32%), thrombocytopenia (16%), neutropenia (13%), oral mucositis (13% ), nausea (7%), diarrhea (5%), constipation (4%), tumor lysis syndrome (4%), renal failure (3%). Grade 4 AEs include infection (1%) with ANC greater than 1.0x10^9/L, thrombocytopenia (15%), moderate Neutropenia (13%), tumor lysis syndrome (1%), and renal failure (1%); Grade 5 AEs included infections with ANC less than 1.0x10^9/L (3%) and infections with ANC greater than 1.0x10^9/L (2%).

The study authors concluded that additional clinical trials are needed to further evaluateThe 10-day decitabine plus venetoclax regimen.

Reference materials:https://www.onclive.com/view/venetoclax-plus-10-day-decitabine-produces-responses-in-high-risk-mds-aml