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1823 Venetoclax in Combination with Hypomethylating Agent (HMA) Compared to HMA Alone Improves Response but Not Survival in TP53-mutated High-Risk Myelodysplastic Syndrome: Real-World Mayo Clinic Series

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
MDS, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Saturday, December 7, 2024, 5:30 PM-7:30 PM

Talha Badar, MD1, Kashish J. Shah, MBBS2*, Mobachir El Kettani, MD2*, James M. Foran, MD3, Mohamed A. Kharfan-Dabaja, MD, MBA4, Hemant S. Murthy, MD2, Naseema Gangat, MBBS5, Aref Al-Kali, MD6, Mithun V Shah, M.D., Ph.D.5, Hassan B Alkhateeb, MD5*, Antoine N. Saliba, MD5, William J. Hogan, MD5, Cecilia Y. Arana Yi, MD7, Lisa Sproat, MD8, Jeanne Palmer, MD9, Mark R. Litzow, MD5 and Mrinal M. Patnaik, MD, MBBS10

1Division of Hematology-Oncology, Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL
2Mayo Clinic, Jacksonville, FL
3Division of Hematology & Medical Oncology, Mayo Clinic, Jacksonville, FL
4Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
5Division of Hematology, Mayo Clinic, Rochester, MN
6Mayo Clinic, Rochester
7Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ
8Mayo Clinic, Phoenix, AZ
9Mayo Clinic - Arizona, Scottsdale, AZ
10Mayo Clinic, Rochester, MN

Background

TP53-mutant (mt) myelodysplastic syndromes (MDS) are high-risk (HR) neoplasms, with high rates of AML progression and suboptimal response to hypomethylating agents (HMA). Given the lack of effective therapies for HR-MDS, azacitidine (AZA) was combined with venetoclax (VEN) in a phase Ib MDS study demonstrating safety and early efficacy (Garcia et al. ASH abstract 2023). We retrospectively sought to explore clinical outcomes comparing VEN + HMA, to HMA alone in TP53mt HR-MDS.

Methods

Among 221 TP53mt MDS pts treated at the Mayo Clinic between January 2007 and April 2024, we reviewed outcomes of pts who received HMA alone (n=98) or HMA+VEN combination (n=34) as their first-line chemotherapy regimen. MDS diagnosis was based on the 5th edition of WHO classification of hematolymphoid tumors (Khoury et al. Leukemia 2022). Responses were assessed according to the International Working Group 2006, MDS response criteria (Cheson et al Blood 2006).

Results

Baseline characteristics and response

The median age (years [yrs]) was 65 (R,37-80) and 70 (range [R], 19-87) yrs in the HMA + VEN and HMA alone groups (gps) (p= 0.42), respectively. The median bone marrow (BM) blast % (9.5 [R, 0-18] vs 5 [R, 0-16], p= 0.01) and TP53 variant allele frequency (VAF) (42 [R, 6-96] vs 37 [R, 2-94], p= 0.03) were significantly higher in HMA + VEN compared to HMA gps, respectively. However, proportion of pts with biallelic (BA)/multihitTP53mt (85% vs 79%, p= 0.61) and complex cytogenetics (CG) (85% vs 81%, p= 0.85) were not different between HMA + VEN and HMA alone gps. The distribution of pts with frequently occurring myeloid co-mutations (ASXL1, TET2, DNMT3A, RAS, BCOR and splicing factor) were not significantly (NS) different between the two gps. IPSS-M scores were assessed in 108 (83%) pts; HR/very HR-MDS as per IPSS-M were NS different between HMA + VEN and HMA gps (100% vs 91%, p= 0.12). While the overall response rate (ORR) (76% vs 49%, p= 0.01) and marrow complete remission (mCR) rates (21% vs 7%, p= 0.05) were higher with HMA+VEN compared to HMA, CR rates were similar (17% vs 12%, p= 0.47). Higher proportion of pts were bridged to allogeneic stem cell transplantation (allo-HCT) (41% vs 20%, p= 0.02), while AML progression rates (29% vs 31%, p= >0.99) were comparable between HMA + VEN and HMA gps, respectively. The non-relapse mortality (NRM) at day 60 (3% vs 3%, p=0.96) and day 90 (3% vs 4%, p=0.75) were comparable between HMA + VEN and HMA gps, respectively.

RFS and OS

The median follow-up from the time of initiation of HMA or HMA + VEN was 9.7 months (mo) (R, 0.3-90.6). The median RFS (8.47 vs 9.90 mo, p= 0.83) and OS (16.33 vs 14.20 mo, p= 0.66) from the time of initiation of therapy were comparable between the two gps. Similarly, among transplanted pts, there was no OS difference between HMA (21.7 mo) and HMA + VEN (18.43 mo) gps, respectively (p= 0.72). Comparable results for OS and RFS were obtained in both gps after censoring pts at the time of allo-HCT.

Multivariable analysis for RFS and OS

We conducted multivariable analysis (MVA) for RFS and OS using baseline variables that were significant/ trended towards significance (p<0.1), on univariate analysis (UVA) censored at the time of allo-HCT.

Achieving ORR (HR; 0.30, 95% CI: 0.14-0.62, p= 0.001) retained significance for better RFS in MVA. Interestingly CR (HR; 1.74, 95% CI; 0.63-4.77, p= 0.28), BA TP53mt (HR; 1.27, 95% CI; 0.13-11.72, p= 0.83) and complex CG (HR; 1.52, 95% CI 0.16-14.03, p= 0.70) did not retain significance for RFS in MVA.

In MVA for OS, achievement of ORR (HR; 0.56, 95% CI; 0.30-1.05, p=0.07) and CR (HR; 0.32, 95% CI; 0.09-1.11, p=0.071) trended towards favorable OS. BA TP53mt status (p= 0.42) and complex CG (p= 0.19) did not significantly impact OS in UVA.

Conclusion

We conclude that while HMA+VEN combination therapy in comparison to HMA monotherapy led to improved response rates, with higher percentage of pts being bridged to allo-HCT, this was not associated with reduced risk of AML transformation, or improved RFS/OS. We eagerly await results from the prospective randomized trial of VEN + AZA in treatment-naïve HR-MDS (VERONA).

Disclosures: Badar: Morphosys: Other: Advisory Board; pfizer: Other: Advisory board; Takeda: Other: advisory board . Kharfan-Dabaja: Novartis: Research Funding; Kite Pharma: Honoraria; Bristol Myers Squibb: Research Funding; Pharmacyclics: Research Funding. Murthy: CRISPR therapeutics,: Consultancy, Membership on an entity's Board of Directors or advisory committees; Senti Bioscience: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gangat: DISC Medicine: Consultancy, Other: Advisory Board ; Agios: Other: Advisory Board. Litzow: Abbvie: Research Funding; Amgen: Research Funding, Speakers Bureau; Actinium: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Sanofi: Research Funding; Beigene: Speakers Bureau; Biosight: Other: Data Safety Monitoring Committee. Patnaik: Epigenetix: Research Funding; Polaris: Research Funding; Kura Oncology: Research Funding; StemLine: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Solu therapeutics: Research Funding.

*signifies non-member of ASH