Venetoclax Plus 10-Day Decitabine Produces Responses in High-Risk MDS, AML

Venetoclax (Venclexta) in combination with 10-day 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 syndrome (MDS), according to data from a phase 2 study (NCT03404193) shared at the 2024 ASCO Annual Meeting.

Findings showed that the overall response rates (ORRs) were 88% in patients with newly diagnosed AML (n = 88), 77% in patients with previously untreated secondary AML (n = 17), 67% in patients with previously treated secondary AML (n = 30), 58% in patients with relapsed/refractory AML (n = 72), and 52% in patients with high-risk MDS (n = 21). In the newly diagnosed AML group, 66% achieved a complete response (CR) and 15% achieved a CR with incomplete hematologic recovery (CRi), resulting in a combined CR and CRi rate of 81%. In untreated secondary AML, 47% of patients achieved a CR and 18% achieved a CRi, resulting in a CR/CRi rate of 65%. In the treated secondary AML group, 27% had a CR and 20% experienced a CRi, resulting in a CR/CRi rate of 57%. In the relapsed/refractory AML group, 21% experienced a CR and 19% achieved a CRi, resulting in a CR/CRi rate of 40%. In high-risk MDS, 24% of patients achieved a CR and 10% had a CRi, leading to a CR/CRi rate of 33%.

“Ten-day decitabine plus venetoclax [was] highly effective in newly diagnosed and relapsed/refractory AML,” lead study author Mahesh Swaminathan, MB, BS, of The University of Texas MD Anderson Cancer Center in Houston, and colleagues wrote in a poster presentation of the data. “Survival benefit [was] more pronounced in patients who underwent stem cell transplant.”

The Methodology of the Investigation

The single-institution phase 2 study conducted at MD Anderson Cancer Center evaluated patients with newly diagnosed AML, including secondary AML with no prior therapy and prior treatment for MDS or Chronic myelomonocytic leukemia who were unsuitable for intensive chemotherapy; relapsed/refractory AML; high-risk MDS; or blastic plasmacytoid dendritic cell neoplasm.

For patients with white blood cell counts greater than 10,000 U/dL, cytoreduction was administered with hydroxyurea and/or cytarabine up to 2 g/m². Induction treatment consisted of decitabine at 10 mg/m² for 10 days plus venetoclax on days 1 through 28; venetoclax was given on a daily ramp-up schedule. Consolidation therapy was given in cycles 2 through 24 consisting of decitabine for 5 days plus venetoclax on days 1 through 21. Targeted therapies such as FLT3, IDH1/IDH2, and BCR-ABL1 inhibitors were allowed for corresponding molecular aberrations. Central nervous system (CNS) prophylaxis was allowed in patients at high-risk for CNS disease. Each cycle lasted every 4 to 8 weeks, and participants could receive up to 24 cycles.

The primary end point of the trial was ORR as defined by revised International Working Group (IWG) criteria in AML and modified IWG criteria for MDS. Duration of response (DOR), relapse-free survival (RFS), and overall survival (OS) served as the trial’s secondary end points.

Patient Characteristics and Composition

In the patient population with newly diagnosed AML, the median age was 73 years (range, 61-89), 74% of patients were 70 years of age or older, and 51% of patients were male. A majority of patients (67%) had an ECOG performance status of 0 or 1. Regarding European LeukemiaNet (ELN) 2022 risk classification, 9% were favorable, 15% were intermediate, and 76% were adverse. Thirty percent of patients had NPM1 mutations, 18% had FLT3 mutations (ITD only, 10%; TKD only, 7%; both, 1%), 31% had TP53 mutations, 17% had RUNX1 alterations, 11% had ASXL1 mutations, 28% had IDH1/2 mutations, and 22% had K/NRAS mutations. In regard to laboratory values, the median bone marrow (BM) blasts rate was 46% (range, 20%-90%), the median peripheral blood (PB) blasts were 10% (range, 0%-91%), the median white blood cell (WBC) count was 2.9 K/uL (range, 0.7-2.25), the median hemoglobin (Hb) was 8.7 g/dL (range, 6.6-11.4), the median platelet count was 40 K/uL (range, 5-368), and the median lactate dehydrogenase (LDH) was 303 U/L (range, 138-1898).

In the secondary AML patient population, the median age was 71 years (range, 64-82) in the previously untreated group and 71 years (range, 49-84) in the previously treated group; 71% and 53% of patients were 70 years of age or older, respectively; a majority of patients were male (71%; 53%) and had an ECOG performance status of 0 or 1 (59%; 80%). Notably, the median prior lines of therapy in the pretreated group was 1 (range, 1-4).

Regarding ELN 2022 risk classification in untreated and pretreated secondary AML, 0% and 10% were favorable, respectively; 18% and 3% were intermediate; and 82% and 87% were adverse. Mutations present included NMP1 (0; 10%), FLT3 (0%; 7% [ITD only, 0%, 0%; TKD only, 0%, 3%; both, 0%, 3%]), TP53 (41%; 27%), RUNX1 (0%; 33%), ASXL1 (29%; 17%), IDH1/2 (6%; 13%), and K/NRAS (18%; 27%). Furthermore, the median BM blasts were 30% (range, 11%-85%) and 31% (range, 20%-86%); the median PB blasts were 4% (range, 0%-80%) and 6% (range, 0%-77%); the median WBC was 4.5 K/uL (range, 1.0-9.2) and 22.4 K/uL (range, 0.3-8.3); the median Hb was 9.0 g/dL (range, 7.5-11.5) and 8.2 g/dL (range, 6.7-13.8); the median platelet count was 56 K/uL (range, 11-310) and 34 K/uL (range, 5-236); and the median LDH was 348 U/L (range, 154-957) and 255 U/L (range 139-1023).

In the patient population with relapsed/refractory AML, the median age was 64 years (range, 18-85), 39% of patients were 70 years of age or older, and 61% of patients were male. A majority of patients (71%) had an ECOG performance status of 0 or 1. The median number of prior therapies was 2 (range, 1-8).

Regarding ELN 2022 risk classification in the relapsed/refractory AML group, 3% were favorable, 18% were intermediate, and 79% were adverse. Nineteen percent had NPM1 mutations, 17% had FLT3 mutations (ITD only, 13%; TKD only, 3%; both, 1%), 19% had TP53 mutations, 17% had RUNX1 mutations, 14% had ASXL1 mutations, 14% had IDH1/2 mutations, and 22% had K/NRAS mutations. The median BM blasts were 31% (range, 1%-96%), the median PB blasts were 24% (range, 0%-94%), the median WBC was 3.3 K/uL (range, 0.1-21.3), the median Hb was 8.7 g/dL (range, 6.6-14.3), the median platelet count was 30 K/uL (range, 8-427), and the median LDH was 252 U/L (range, 103-1760).

In the patient population with high-risk MDS, the median age was 71 years (range, 32-84), 57% of patients were 70 years of age or older, and 43% of patients were male. A majority of patients (81%) had an ECOG performance status of 0 or 1. The median number of prior therapies was 1 (range, 0-2).

Regarding Revised International Prognostic Scoring System classification, 43% of patients were good, 38% were intermediate, and 19% were poor. No patients had NPM1 mutations, 10% had FLT3 mutations (ITD only, 5%; TKD only, 5%; both, 0%), 14% had TP53 mutations, 29% had RUNX1 mutations, 38% had ASXL1 mutations, none had IDH1/2 mutations, and 29% had K/NRAS mutations. The median BM blasts were 10% (range, 1%-18%), the median PB blasts were 2% (range, 0%-16%), the median WBC was 4.2 K/uL (range, 1.4-8.4), the median Hb was 8.5 g/dL (range, 5.4-11.9), the median platelet count was 39 K/uL (range, 8-527), and the median LDH was 219 U/L (range, 126-759).

Uncovering Additional Data

In total, patients with newly diagnosed and relapsed/refractory AML had a respective median OS of 15.7 months (95% CI, 10.5-25.4) and 7.6 months (95% CI, 5.9-15.3); these numbers were 8.5 months (95% CI, 3.9-18.8) and 11.1 months (95% CI, 5.5–not applicable [NA]), respectively, in patients with treated or untreated secondary AML (log-rank P = .034).

The median RFS was 10.0 months (95% CI, 8.3-18.8) in newly diagnosed AML, 7.5 months (95% CI, 5.4-16.1) in relapsed/refractory AML, 7.8 months (95% CI, 3.2-13.3) in treated secondary AML, and 5.1 months (95% CI, 2.5-NA) in untreated secondary AML (log-rank P =.165).

Regarding minimal residual disease (MRD), MRD negativity was achieved in 65%, 42%, 50%, 43%, and 19% of patients with evaluable disease in the 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, respectively.

Across patients with newly diagnosed AML, secondary AML, relapsed/refractory AML, or high-risk MDS, 2%, 0%, 1%, and 5% were still on study treatment at data cutoff, respectively. Reasons for discontinuing the study included relapsed disease (27%; 28%; 17%; 14%), transplant (19%; 15%; 24%; 24%), death (14%; 13%; 6%; 0%), patient withdrawal (15%; 6%; 10%; 5%), treatment completion (9%; 0% 3%; 0%), inadequate response (8%; 25%; 33%; 38%), toxicity (3%; 4%; 7%; 0%), debilitated state (2%; 9%; 0%; 0%), and transformation (high-risk MDS, 14%).

All-grade adverse effects (AEs) for the overall population included infection with an absolute neutrophil count (ANC) of less than 1.0 x 109/L (42%), infection with ANC greater than 1.0 x 109/L (38%), febrile neutropenia with ANC less than 1.0 x 109/L (32%), thrombocytopenia (16%), neutropenia (13%), oral mucositis (13%), nausea (7%), diarrhea (5%), constipation (4%), tumor lysis syndrome (4%), renal failure (3%), colitis (3%), hyperbilirubinemia (2%), and fatigue (2%). Grade 4 AEs included infection with ANC greater than 1.0 x 109/L (1%), thrombocytopenia (15%), neutropenia (13%), tumor lysis syndrome (1%), and renal failure (1%); grade 5 AEs including infection with ANC less than 1.0 x 109/L (3%) and infection with ANC greater than 1.0 x 109/L (2%).

Study authors concluded that more clinical trials are needed to further evaluate the 10-day decitabine plus venetoclax regimen.

Reference

Swaminathan M, Dinardo CD, Maiti A, et al. A phase II study of venetoclax (VEN) in combination with 10-day decitabine (DEC) in older/unfit pts with newly diagnosed (ND) or pts with relapsed/refractory (R/R) acute myeloid leukemia (AML), or high-risk myelodysplastic syndrome (HR-MDS). J Clin Oncol. 2024;42(suppl 16):6549. doi:10.1200/JCO.2024.42.16_suppl.6549