Oral decitabine/cedazuridine in combination with venetoclax in treatment-naïve high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia: Updates of a Phase 1/2 clinical trial

Abstract Background: The standard of care treatment for patients with high-risk myelodisplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML) are hypomethylating agents (HMA). Hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for eligible patients with these diseases. Outcomes of HR-MDS and CMML with single-agent HMA are poor, warranting novel combinations to improve survival. We provide the results of a phase 1/2 clinical trial of the combination of oral decitabine/cedazuridine (DEC-C) with the BCL2 inhibitor venetoclax (Ven) in patients with untreated HR-MDS and CMML. Methods: We conducted a phase I/II open-label, single center clinical trial (NCT04655755). Eligibility criteria included patients with untreated HR-MDS (IPSS intermediate-2 or high, IPSS-R ³ 3. 5 or IPSS-M ³ 0) or CMML with excess blasts. The phase I portion (dose escalation) used a standard 3+3 study design to identify the recommended phase II dose (dose expansion). In this last phase efficacy was evaluated. Results: Between January 2021 and August 2024, 69 patients were enrolled. Nine patients were enrolled in the phase I portion: 3 patients received Ven 200mg on days 1-14 and 6 patients received 400mg on days 1-14, all with 5 days DEC-C 100/35mg on days 1-5. No dose-limiting toxicities registered, and the phase II dose was established as Ven 400mg days 1-14. The median age of the entire cohort was 71 years old (21-94), with 49 (70%) male patients. The WHO 2016 diagnosis was MDS with excess-blasts 1 (n=13, 19%), MDS with excess-blasts 2 (n=46, 67%), CMML (n=9, 13%) and atypical chronic myeloid leukemia (n=1, 1%). In patients with MDS, the IPSS-M category was moderate high (n=4, 7%), high (n=19, 32%), and very high (n=36, 61%). The most common mutations were ASXL1 (n=29, 42%), RUNX1 (n=20, 29%), SRSF2 (n=17, 25%) TP53 (n=17, 25%, 15 being multi-hit TP53) and TET2 (n=14, 20%). The median number of cycles received per patient was 3 (1-25). The overall response rate by the IWG 2006 response criteria was 91% (63/69), with 31 (45%) patients achieving complete remission (CR), 20 (29%) patients achieving marrow CR (mCR) with hematological improvement (mCR-HI) and 12 (17%) patients achieving mCR. The median number of cycles to achieve first response and best response was 1 (1-3) and 1 (1-6), respectively. The overall response rate by the IWG 2023 response criteria was 81% (56/69), with 37 patients achieving CR (54%) and 19 patients (27%) achieving CR with limited count or partial hematologic recovery. The 4- and 8-week mortality was 1% and 4%, respectively. At the cutoff time 5 patients were remaining in the trial. The reasons for trial discontinuation were: undergoing HSCT (n=38, 55%), disease progression (n=11, 16%), death (n=8, 12%), patient or physician decision (n=5, 7%) and no response (n=2, 3%). Among patients who died while on study drugs, 4 patients died due to sepsis during cycles 2 and 3, two patients died during cycle 1 of cardiac arrest and pneumonia, and the remaining 2 patients died due to progressive dementia (cycle 5) and due to unknown reasons (cycle 7). Among patients undergoing HSCT (n=38), the median age was 68 (21-78), the median number of cycles before HSCT was 2 (1-11) and their best responses according to the IWG 2006 criteria were CR (47%), mCR (21%), mCR-HI (29%) and stable disease (3%). The median duration of response was not reached. After a median follow-up of 25 months, the median overall survival (OS) and the 2-year OS was 30 months and 55%, respectively. The event-free survival (EFS) and the 2-year EFS was 21 months and 48%, respectively. Patients with ASXL1mut had a median OS not reached (vs 18 months in patients with ASXL1wt, P=0.008). Patients with TP53mut had a median OS of 17 months (vs 31 months in patients with TP53wtP=ns). Myelosuppression was an expected effect of the combination. The median time to neutrophil and platelet recovery after the first cycle was 40 and 26 days, respectively. After first cycle, 82% of patients required Ven dose reduction in the subsequent cycles.Conclusion: The combination of DEC-C with Ven is a feasible combination, well-tolerated and with a high response and HSCT rate in high-risk MDS and CMML.