Phase I study of lower dose CPX-351 combined with venetoclax for patients with higher-risk myelodysplastic syndrome or chronic myelomonocytic leukemia after hypomethylating agents failure

Abstract

Abstract Background: Patients (pts) with relapsed/refractory (R/R) higher-risk (HR) myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MDS/MPN) who have failed hypomethylating agent (HMA) have limited treatment options and poor outcomes. We previously demonstrated that the use of lower doses of CPX-351 (50 units/m2) are safe and effective in these pts (Montalban-Bravo, BJHaem 2023). Venetoclax (VEN) therapy enhances antileukemic efficacy of cytotoxic agents. Prior data suggest BCL2 upregulation in hematopoietic stem-progenitor populations is a mechanism of MDS progression. Therefore, this study aims to evaluate the safety and efficacy of the CPX-351 and VEN combination in pts with HMA-failure HR MDS or MDS/MPN. Methods: We conducted a phase I/II clinical trial for adult pts with R/R MDS or MDS/MPN after HMA failure (NCT03896269). Eligible pts had higher-risk (HR) disease by IPSS and ≥5% bone marrow (BM) blasts or 10-19% BM blasts and must be considered candidates for intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT). Pts with complex and/or monosomal karyotypes in the presence of TP53 mutations were excluded. The phase I (dose-escalation) used a Bayesian optimal interval (BOIN) design to identify the maximum tolerated dose (MTD). During induction, pts received CPX-351 at 50 units/m² (dauno 22mg/m² and araC 50mg/m²) intravenously on days 1, 3, and 5, in combination with VEN on days 1-7 of a 28-day cycle. For re-induction and consolidation, CPX-351 at 50 units/m² was given on days 1 and 3, with VEN on days 1-7, for up to two cycles. Maintenance therapy consisted of azacitidine 75 mg/m² on days 1-5 and VEN on days 1-7. VEN dose level 1 was 400 mg daily, and dose level -1 was 200 mg. The primary objective was to assess the safety, tolerability, and MTD of the CPX-351 and VEN combination. The secondary objective was to evaluate clinical efficacy. Here, we report results from the phase I portion. Results: As of 28 July 2025, 6 pts were enrolled. Pts had a median age of 68 years (range, 52-72). 4 pts (67%) had MDS and 2 (33%) had CMML. One pt (17%) had intermediate-1 risk by IPSS and 10% blasts, 4 (66%) had intermediate-2 and 1 (17%) had high-risk disease. By IPSS-M, 3 pts were high-risk and one was very-high risk; pts with CMML were intermediate-2 and high-risk by CPSS-Mol. The median number of prior lines of therapy was 1 (range, 1-3); one pt (17%) had prior VEN and allo-SCT. 3 pts (50%) received VEN 400mg daily (DL1), and 3 (50%) received 200mg daily (DL-1). Pts received a median of one cycle of therapy (range, 1-3). The most common treatment-emergent adverse event (TEAEs) were mucositis (4pts, 67%), fever (4 pts, 67%), bleeding (3 pts, 50%), hypercalemia (3 pts, 50%), and hyperphosphatemia (3 pts, 50%). The most common grade ≥3 TEAEs were thrombocytopenia (3 pts, 50%), febrile neutropenia (2 pts, 33%), pneumonia (2 pts, 33%), and infection (2 pts, 33%). No 4-week and 8-week mortality were observed. One pt treated in DL1 experienced DLT in the form of prolonged myelosuppression. According to 2006 IWG response criteria, 3 pts (50%) achieved complete remission (CR), one pt (17%) achieved mCR, and one additional pt (17%) achieved mCR + HI, for an ORR of 84%, after a median of one cycle of therapy. Based on 2023 IWG response criteria, ORR was 84% (5 pts) including CR in 3 pts (50%), CR bilineage in 1 pt (17%), and CR unilineage in 1 pt (17%). The one pt (17%) with no response had previously received VEN and allo-SCT and is currently undergoing a re-induction cycle. Among responder pts with count recovery, the median time to neutrophil (≥1x109/L) and platelet (≥100x109/L) recovery were 33 and 26 days, respectively. At the cutoff date, 4 pts discontinued the trial to proceed to allo-SCT and 2 pts are currently receiving therapy. No pts had progressed to AML or died at a median follow-up of 7.6 months. Among responders, 1 of 2 pts with cytogenetic abnormalities at study enrollment achieved a complete cytogenetic response. All 4 pts with sequential next-generation sequencing (NGS) data at the time of response showed a reduction in variant allele frequencies (VAFs) of baseline somatic mutations or complete clearance of mutations. Conclusion: Lower-dose CPX-351 combined with VEN was well tolerated and demonstrated a high early response rate in this high-risk population, with a substantial number of pts undergoing allo-SCT. Enrollment is ongoing to further evaluate efficacy in a larger cohort.