Azacitidine and Venetoclax in High-Risk Myelodysplastic Syndrome: A Real-World Perspective from the Glam Registry with Long-Term Follow-up

• Published in: Blood Vol. 144; no. Supplement 1; p. 6718
• Main 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
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 05.11.2024
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-209513

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 (>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 >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<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. Apodaca Chavez:AbbVie: Speakers Bureau; Bristol: Speakers Bureau; Astrazeneca: Speakers Bureau; Novartis: Speakers Bureau. Gomez-De Leon:Abbvie: Honoraria; Amgen: Honoraria; bms: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Sanofi: Honoraria, Other: Advisory board; Janssen: Other: Advisory board.