Azacitidine and Venetoclax in High-Risk Myelodysplastic Syndrome: A Real-World Perspective from the Glam Registry with Long-Term Follow-up
Authors: Apodaca Chavez Elia Ixel , Crisp Renee , Varela Constantino Ana Laura , Enrico Alicia I , Gomez-De Leon Andres , Ovilla-Martínez Roberto , Wernicke Priscilla , Camargo Molano Carlos , Boada Matilde , Velloso Elvira D. R. P. , Schusterschitz Sergio , Kornblihtt Laura , Puente Adriana Karola , Gusmao Breno , Grille Sofia , Barroso Fernando , Gomez Carlos , Alvarado Ibarra Martha , Rangel Gabriela , Iastrebner Marcelo 
Published: December 2024

Introduction
Myelodysplastic syndromes (MDS) are a heterogeneous group of neoplasms characterized by ineffective hematopoiesis, bone marrow failure, and progression to acute myeloid leukemia. According to the IPSS-R scoring system, they are divided into two major groups for treatment purposes: low-risk (≤3.5 points, LR-MDS) and high-risk (&gt;3.5 points, HR-MDS). Currently, the only approved therapy for high-risk cases is hypomethylating agents, with a median overall survival of 16 months. Given the observed synergy and results with azacitidine and venetoclax (AZA + VEN) in acute myeloid leukemia and the unresolved need in this orphan disease, our objective was to describe the real-world experience in a Latin American cohort using AZA + VEN in HR-MDS patients, who currently have no effective treatment options.
Methods
Patients with HR-MDS from Argentina, Brazil, Colombia, Ecuador, Mexico, and Uruguay were retrospectively recruited from 2019 to 2023 and included in the Re-GLAM (Latin American MDS Registry). Inclusion criteria were: having HR-MDS with less than 20% blasts and having received at least one cycle of azacitidine with venetoclax. The treatment groups were: 1) HMA + VEN as first-line treatment with the goal of leading to a hematopoietic stem cell transplant (HSCT), and 2) HMA + VEN as second-line treatment. Response was defined using the 2006 IWG criteria, with response (R) being the sum of complete response(CR), partial response(PR), and stable disease(SD), and the rest being considered non-response (NR). Overall survival (OS) was defined from diagnosis to death or last follow-up, and leukemia-free survival (LFS) from the start of treatment to progression to leukemia.
Results
We recruited 49 MDS patients, 45 (91,8%) with primary MDS, and 34 (69.4%) were men. 98,0% (n=48) had an ECOG ≤2. According to the 2022 WHO classification, the majority had excess blasts type 1 (n=29, 59.2%), with all patients having an IPSS-R score &gt;3.5. The median blasts in bone marrow aspirate was 11% (range;0-19). All received treatment with a hypomethylating agent (48 with azacitidine and 1 with decitabine) plus venetoclax. As first-line treatment in 34 patients (69.4%) and as second-line treatment in the remaining patients. Venetoclax ramp-up dosing was not used, and there were no episodes of tumor lysis syndrome. 95.7% (n=44) received a dose of 400mg, of which 20 adjusted the dose due to antifungal use. 65.3% (n=32) used venetoclax for 14 days. Sixteen patients (32.7%) reached HSCT with a median number of treatment cycles before HSCT of [median 2 (1-12)].
The median follow-up was 41 months (rango; 3-124months). At the last follow-up, 26patients (53,1%) had died. The median OS was 21,9 months (95% CI; 11,6-32,2). When OS was separated by treatment line, no significant difference was found (OS for first-line: 26.96 months (95% CI; 5,4-28,0) vs OS for second-line: 23.8 months (95% CI; 10,7-33,2), p=0.932. The overall response rate (ORR) in the first-line treatment was 67,6% [23/34] (CR 65,2% (15/23), PR 21,7% (5/23), and SD 13,0% (3/23). The median OS for those achieving CR was not achieved (NA) months (95% CI; NA-NA) vs NR:10.71months (95% CI;9.75-11.67), p&lt;0.001. Patients who reached HSCT showed improved OS compared to those who did not (OS: NA months (95% CI; NA-NA) vs 13.11months (95% CI;13.04-30.4), p=0.040. The median LFS was NA months (95% CI NA-NA).
The ORR in the second-line treatment was 60,0% [9/15] (CR 55,6% (5/9), PR 33,3% (3/9), and SD 11,1% (1/9)). The median OS for those achieving CR was NA months (95% CI; NA-NA) vs NR: 14.26 months (95% CI 7.84-20.68), p=0.115. The median LFS was 11.76 months (95% CI;7.97-15.56).
Conclusion
Our real-world evidence (RWE) study includes one of the longest follow-ups of AZA + VEN use in HR-MDS patients. These results suggest that the group that benefits most from the AZA + VEN combination is those who reach HSCT, as it improves OS. The group that does not reach HSCT has a better OS to that observed with azacitidine alone, but onlu in those patients who achieve a CR. No predictive factors of response to AZA + VEN were found, although myeloid mutations were not evaluated, which could potentially explain response probability as seen in other studies.