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3206 Clinical Utilization and Outcomes of Hypomethylating Agents and Venetoclax in Patients with Myelodysplastic Syndrome – a Multicenter Retrospective Analysis

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, MDS, Combination therapy, Adult, Epidemiology, Elderly, Clinical Research, Chronic Myeloid Malignancies, Diseases, Real-world evidence, Treatment Considerations, Young adult , Myeloid Malignancies, Study Population, Human
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Guru Subramanian Guru Murthy, MBBS1, Somedeb Ball, MD2, Jonathan Feld, MD3, Ramzi Abboud4, Michael Haddadin, MBBS5, Shyam Ajay Patel, MD, PhD6, Ashwin Kishtagari, MBBS7, Hayley Hawkins8*, Veronica Guerra, MD9*, Emily Dworkin, PharmD10*, Reema K. Tawfiq, MD11, Dominika Dulak, MD12, Amber Feng, MD13*, Christina Cotte14*, Adam Cohen-Nowak15*, Asmita Shukla, MD16, Suresh Kumar Balasubramanian, MD17, Eric S. Winer, MD18, Charles Foucar, MD19, Yasmin Abaza, MD15, Rory M. Shallis, MD20, Chenyu Lin, MD21, Talha Badar, MD22, Anand Ashwin Patel, MD23, Annie Im, MD24, Aniko Szabo, PhD1* and Ehab L. Atallah, MD25

1Medical College of Wisconsin, Milwaukee, WI
2Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN
3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
4Washington University School of Medicine, Clayton, MO
5Fred & Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE
6UMass Chan Medical School, Worcester, MA
7Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Franklin, TN
8Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
9Washington University St Louis, St Louis
10Department of Pharmacy, University of Chicago, Chicago, IL
11Division of Hematology and Medical Oncology, Mayo Clinic, Jacksonville, FL
12Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA
13Duke University Hospital, Durham, NC
14Yale University, New Haven, CT
15Northwestern University, Chicago, IL
16Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, MI
17Department of Oncology, Karmanos Cancer Institute/Wayne State University, Troy, MI
18Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
19University of New Mexico, Ann Arbor, MI
20Department of Internal Medicine, Section of Hematology, Yale School of Medicine - Yale Cancer Center, Killingworth, CT
21Duke University Cancer Institute, Durham, NC
22Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
23Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
24UPMC Hillman Cancer Center, Univ. of Pittsburgh Cancer Institute, Pittsburgh, PA
25Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI

Background: Hypomethylating agents (HMA) with venetoclax (VEN) have shown encouraging clinical efficacy in single arm clinical trials for patients with myelodysplastic syndrome (MDS) (Garcia JS et al. ASH 2023, Zeidan AM et al. Am J Hematol. 2023). Many centers have started utilizing HMA-VEN in the clinical management of MDS due to unmet need, pending results of the ongoing phase 3 randomized clinical trial (VERONA) using this combination. However, real world studies with large sample size investigating the use of these agents in MDS, practice patterns and clinical outcomes are lacking.

Methods: This is a multicenter retrospective study of 13 US academic medical centers. We included contemporary cohorts of adults (age≥18 years) with MDS who were treated with upfront combination of HMA-VEN, upfront HMA monotherapy, or VEN added after inadequate response or progression on HMA (post-HMA failure VEN). Outcomes analyzed includes clinical response, adverse events (AE) of interest, dose administration and survival. Descriptive statistics were used for baseline characteristics. Overall survival and event free survival (EFS: progression, leukemic transformation, death as events) analysis was conducted using Kaplan-Meier method. Determinants of outcomes were analyzed using multivariable regression models. All analyses were conducted at a significance level of p<0.05.

Results: Among 454 patients included, 258 patients received VEN in combination with HMA [upfront HMA-VEN (n=175), post-HMA failure VEN (n=83)] and 196 patients received HMA monotherapy. Median age was 69 (59-77) years and majority of patients had MDS with excess blasts (75%), high risk (31.9%) or very-high (41.8%) risk disease by IPSS-R, 23.7% had therapy related disease, 33% had deletion17p or TP53 mutation and 40.9% underwent allogeneic stem cell transplantation. VEN was predominantly started in outpatient setting (78.6%) with tumor lysis syndrome (TLS) prophylaxis and VEN doses ranged from 70-400mg, adjusted for concomitant antifungal drugs. Incidence of TLS was minimal (No TLS- 92.9%, lab-only TLS 6.2%, 1 pt with clinical TLS). Neutropenic fever was the main AE noted [upfront VEN-HMA (34.2%), HMA monotherapy (22.5%), post-HMA VEN (44.5%)].

In the upfront setting, response rate was significantly higher with HMA-VEN than HMA monotherapy (CR: 33% vs 12%; marrow CR: 40% vs 27%, p<.001). VEN given in the post HMA failure setting also resulted in encouraging response rates (CR 10%, marrow CR 32%). After adjusting for covariates in multivariable analysis, patients treated with HMA-VEN in the upfront setting had significantly improved event free survival as compared to HMA monotherapy (HR 0.59, HR 0.44-0.78, p<0.01), but overall survival did not reach statistical significance (overall survival HR 0.77, 95%CI 0.57-1.04, p=0.08).

Conclusions: In this large multicenter retrospective analysis from US academic medical centers, we found that VEN in combination with HMA resulted in encouraging clinical outcomes and was effectively administered in the outpatient setting with minimal TLS. Infection risk management and supportive measures would be important to improve the ability to use this treatment widely, pending results of the ongoing phase 3 randomized clinical trial. Updated results with additional variables will be available at the main meeting.

Disclosures: Guru Murthy: BeiGene: Other: Advisory board, Research Funding; Pfizer: Other: Advisory board; Gilead Sciences/Kite: Other: Advisory board, Research Funding; Stemline: Speakers Bureau; Syndax: Other: Advisory Board; Autolus: Other: Advisory board; Rigel: Speakers Bureau; BMS: Other: Advisory Board; Amgen: Consultancy, Speakers Bureau; LOXO/Lilly: Research Funding; Zentalis: Research Funding; Schrodinger: Research Funding; Merck: Research Funding. Feld: Syros Pharmaceuticals: Research Funding; Oryzon Genomics: Research Funding; Taiho Pharmaceutical: Research Funding. Patel: Syndax: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Kishtagari: Geron Coporation: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Sevier Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Syndex: Current equity holder in publicly-traded company. Dworkin: AbbVie: Honoraria. Balasubramanian: Kura Oncology: Research Funding; Alexion AstraZeneca: Speakers Bureau. Foucar: Novartis: Research Funding. Shallis: Gilead Sciences, Inc: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: Steering Commitee; Rigel: Consultancy, Honoraria; Kura Oncology: Consultancy, Honoraria. Lin: Autolus: Consultancy; Rigel: Consultancy; ADC Therapeutics: Consultancy. Badar: Morphosys: Other: Advisory Board; Takeda: Other: advisory board ; pfizer: Other: Advisory board. Patel: Sumitomo: Research Funding; Bristol Myers Squibb: Honoraria; Sobi: Honoraria; AbbVie: Honoraria; Pfizer: Research Funding; Kronos Bio: Research Funding. Atallah: Novartis Pharmaceuticals Corporation: Honoraria.

OffLabel Disclosure: Venetoclax in MDS

*signifies non-member of ASH