Imagine a treatment that could offer a glimmer of hope to patients battling high-risk blood cancers, achieving a staggering 91% response rate. That’s exactly what a groundbreaking study has revealed for individuals with high-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML). But here's where it gets even more compelling: the combination of oral decitabine/cedazuridine (Inqovi) and venetoclax (Venclexta) not only demonstrated remarkable response rates but also delivered a median overall survival (OS) of 30 months in these challenging conditions. This is the part most people miss—how a carefully designed treatment regimen can transform outcomes for patients who previously had limited options.
In a single-center phase 1/2 trial (NCT04655755), researchers evaluated this innovative therapy in 69 treatment-naive patients. The results, presented at the 2025 ASH Annual Meeting, were nothing short of remarkable. Patients achieved a 91% overall response rate (ORR) according to the International Working Group (IWG) 2006 criteria, with 45% reaching complete remission (CR) and 46% achieving marrow CR (mCR). What’s truly striking is the speed of these responses—the median time to first response was just 1 cycle, and the best response was typically seen within 1 to 5 cycles. Even when applying the more stringent IWG 2023 and ELN 2022 criteria, CR rates remained impressive at 54% and 64%, respectively.
Survival outcomes were equally encouraging. The median OS for the entire cohort was 30 months, with 1- and 3-year OS rates of 68.8% and 40.7%, respectively. Event-free survival (EFS) mirrored this success, with a median of 21.2 months and 1- and 3-year rates of 60.7% and 32.6%. At a median follow-up of 25 months, the duration of response had not yet been reached, suggesting sustained benefits.
But here’s the controversial part: While the combination therapy showed immense promise, it also came with significant side effects. Grade 3 adverse effects (AEs) were observed in 78% of patients, and a staggering 91% experienced grade 4 AEs. Cytopenias, particularly anemia, thrombocytopenia, and neutropenia, were the most common high-grade toxicities. Febrile neutropenia and serious infections, including sepsis and pneumonia, further complicated treatment for some patients. Lead author Alex Bataller, MD, PhD, emphasized the critical need for infection prophylaxis and dose adjustments to manage these risks. Notably, 75% of patients required dose reductions during treatment.
Another intriguing aspect is the role of hematopoietic stem cell transplantation (HSCT) in this regimen. Of the 38 patients who proceeded to HSCT, 37 achieved CR or mCR before transplantation. The median OS in this subgroup was not reached, with 1- and 3-year OS rates of 70.4% and 50.7%, respectively. However, six patients experienced disease progression or transformation to acute myeloid leukemia post-HSCT, and eight died in CR following transplantation. This raises the question: Is the risk of HSCT justified by the potential for long-term survival?
The trial’s design was meticulous, enrolling patients with previously untreated HR-MDS or CMML with excess blasts. Phase 1 focused on dose escalation, determining that decitabine/cedazuridine 35 mg/100 mg for 5 days plus venetoclax 400 mg for 14 days was the recommended phase 2 dose (RP2D). Phase 2 confirmed the efficacy of this regimen in 60 additional patients. The study population was diverse, with a median age of 71 years and a majority of male participants. Cytogenetic risk profiles underscored the high-risk nature of the cohort, with 25% classified as very poor risk.
Here’s a thought-provoking question for you: Given the high response rates and survival benefits, should this combination become the new standard of care for HR-MDS and CMML, despite the significant toxicity profile? Or is further research needed to refine the treatment and minimize risks? Share your thoughts in the comments below—this is a conversation that could shape the future of blood cancer treatment.
