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4938 Redefining Clinical Response Criteria in Myelodysplastic Syndromes to Better Forecast Post-Transplant Outcomes

Program: Oral and Poster Abstracts
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Poster III
Hematology Disease Topics & Pathways:
Research, MDS, Adult, Clinical Research, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies, Profiling, Study Population, Human
Monday, December 9, 2024, 6:00 PM-8:00 PM

Luis E. Aguirre, MD1, Haesook T. Kim, PhD2, Hany Elmariah, MD, MS3, Stacey M. Frumm, MD4, Amar H. Kelkar, MD, MPH, FACP1, Vincent T. Ho, MD1*, Mahasweta Gooptu, MD5, John Koreth, MD, MBBS, PhD, DPhil1, Roman M. Shapiro, MD1, Rizwan Romee, MD1, Sarah Nikiforow, MD, PhD1, Joseph H. Antin, MD1, Robert J. Soiffer, MD1, Benjamin Rolles, MD1, Shai O. Shimony, MD1, Marlise R. Luskin, MD1, Jacqueline S. Garcia, MD1, Kelly Ling, PA-C1*, Evan C. Chen, MD1, Martha Wadleigh, MD1, Eric S. Winer, MD1, Richard M. Stone, MD1, Daniel J. DeAngelo, MD, PhD1, Najla H. Al Ali, Ms6*, Corey S. Cutler, MD, MPH1, Rami S. Komrokji, MD7 and Maximilian Stahl, MD1

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
3Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
4Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
5Department of Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA
6Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
7Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL

Background: The International Working Group (IWG) 2023 response criteria are the new standard by which treatment responses in myelodysplastic syndromes (MDS) are evaluated. However, these criteria have not yet been validated to predict outcomes in pts undergoing allogeneic hematopoietic stem cell transplantation (HCT). We set out to determine the significance of pre-transplant response to hypomethylating agent (HMA) therapy based on IWG 2023 criteria in predicting transplant outcomes in MDS. In addition, we propose a novel prognostic tool based on redefined pre-transplant-specific response criteria to better predict HCT outcomes.

Methods: We analyzed pts with higher-risk MDS who were treated with HMA followed by HCT at 2 large academic centers: Dana-Farber Cancer Institute and Moffitt Cancer Center. Pre-HCT responses were estimated from marrow specimens sampled closest to HCT and from phlebotomy specimens drawn closest to conditioning therapy. Responses evaluated by IWG 2023 criteria were defined as complete remission (CR), CR with bi-lineage (CRbi), CR with unilineage (CRuni) or CR with partial (CRh) hematological recovery. Composite CR (cCR) was defined as CR+CRbi+CRuni+CRh. The primary outcome was post-HCT progression-free survival (PFS), defined as time from HCT to relapse, progression or death.

Results: A total of 280 pts underwent HCT. 62% were male. At diagnosis, 50.7% presented with MDS IB-2, 34.3% with MDS IB-1 and ~15% with MDS-LB. The median age at HCT was 65 yrs (range 22-79). Pts received a median of 4 cycles of HMA prior to HCT. Based on baseline IPSS-M risk, 251 pts were classified as very low/low/moderate low (16.8%), moderate high/high (42.2%), and very high-risk 30.7 %). Pre-HCT IWG 2023 responses were: CR (24.6%), CRbi (19.6%), CRuni (13.6%), CRh (3.2%), PR (1.4%), HI (7.1%) with 27.1% exhibiting no response (NR) and 2.9% with progressive disease (PD). The mOS for the cohort was 52 mos (95%CI 32-74) with a median f/u time among survivors of 62 mos. 5yr PFS was 43% (95% CI: 37-49%) and 5yr OS was 48% (95% CI: 42-54%). 5yr PFS based on IWG 2023 were: 56% (CR), 35% (CRbi), 35% (CRuni), 56% (CRh), 38% (PR), 60% (HI), 36% (NR) and 38% for PD (p=0.24). IWG 2023 failed to accurately predict post-HCT PFS (c-index 0.525, p=.51). Similarly, when IWG 2023 responses were dichotomized, 5y PFS was 45% with cCR and 41% without cCR (p=0.1, c-index 0.525). 5y PFS was 58%, 45% and 29% for low, high and very high IPSS-M groups, respectively (p=.0012, c-index 0.574).

As there was no prognostic distinction among CR categories, we evaluated the response components and found that only Hb and PLT significantly impacted HCT outcomes, while ANC and marrow blast % did not. 5y PFS was 38% for pre-HCT Hb<10 vs 49% for Hb≥10 (p=.03), and 35% for PLT<100k vs 52% for PLT≥100k (p=.002). 5y PFS for pts with <5%, 5-9% and ≥10% blasts were 42.5%, 53% and 35% respectively (p=.61). 5y PFS was 45% for ANC<1 vs 43% for ANC≥1 (p=.76).

We then used recursive partitioning to identify cutoff values for blasts, PLT, and Hb in the pre-HCT setting. The model produced 3 segregated PLT categories with distinct PFS: <40k, 40k-160k, and ≥160k (5y PFS: 18%, 42%, 63% respectively, p<.0001, c-index: 0.593) and 3 segregated categories for Hb <10, 10-13, ≥13 (5y PFS: 38%, 45%, 68% respectively, p=.01, c-index: 0.5595). Lastly, blast % was dichotomized into <10% and ≥10% categories with 5yr PFS of 44% and 35% respectively. We then assigned a score to each category: 3 for PLT <40k, 2 for blasts ≥10% OR Hb <10, 1 for blasts <10%, PLT 40k-160k OR Hb 10-13, and 0 for PLT ≥ 160k OR Hb ≥13. Based on the summed score from these categories we established 3 discrete pre-HCT response strata: favorable (1-2), intermediate (3-4) and poor (≥5). 5y PFS for these response categories was 70%, 40% and 24% (p<.0001, c-index 0.61), a notable improvement over IWG 2023 (c-index 0.526) and IPSS-M (c-index 0.574).

In multivariable analysis after adjusting for patient, HCT, and disease-related factors, the HRs for PFS were 2.9 (95%CI 1.7-5.1, p=.0001) for the intermediate group and 5.7 (95%CI 3-10.9, p<.0001) for the poor-risk group (c-index: 0.692).

Conclusion: The IWG 2023 response criteria do not adequately predict outcomes for pts treated with HMA followed by HCT. To address this, we developed a risk model based on pre-HCT specific response criteria, which provides a more accurate prediction of HCT outcomes. To ensure applicability, this model will require validation in prospective settings.

Disclosures: Elmariah: BMS: Research Funding; Shoreline Biosciences: Consultancy. Ho: Omeros: Research Funding; CareDx: Research Funding; Jazz: Research Funding; Alexion: Consultancy; Allovir: Consultancy. Gooptu: Syndax: Consultancy, Other: Travel expenses. Koreth: Biopharm Communications LLC: Honoraria; Tr1X Inc: Consultancy; Biolojic Design Inc: Consultancy; Cue Biopharma Inc: Consultancy; Gentibio Inc: Consultancy; Equillium Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Iovance Inc: Research Funding; Clinigen Labs Inc: Research Funding; Miltenyi Biotec GMBH: Research Funding; Regeneron Inc: Research Funding; BMS Inc: Research Funding; Cugene Inc: Membership on an entity's Board of Directors or advisory committees; Mallinckrodt Inc: Membership on an entity's Board of Directors or advisory committees; CSL Behring Inc: Consultancy. Shapiro: Hansa Biopharma: Consultancy; Miltenyi: Other: Paid lecture. Romee: Skyline Therapeutics: Research Funding; CRISPR Therapeutics: Research Funding; Glycostem: Membership on an entity's Board of Directors or advisory committees. Soiffer: Jasper: Consultancy; Vor Biopharma: Consultancy; Smart Immune: Consultancy; Neovii: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Astellas: Consultancy. Luskin: Pfizer: Honoraria; KITE: Honoraria; Jazz: Honoraria; AbbVie: Research Funding; Novartis: Honoraria, Research Funding. Garcia: Newave: Research Funding; Servier: Consultancy; Taiho: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen: AbbVie: Consultancy; Rigel: Consultancy. Stone: Janssen: Other: Research funding to my institution; Glaxosmithkline: Consultancy; Curis Oncology: Consultancy; AbbVie: Consultancy, Other: Research funding to my institution; Daiichi Sankyo: Consultancy; ENSEM: Consultancy; Epizyme: Consultancy, Other: DSMB; BerGenBio: Consultancy; AMGEN: Consultancy; Syntrix: Other: DSMB; Hermavant: Consultancy; Glycomimetrics: Consultancy; CTI Biopharma: Consultancy; Bristol Meyers Squibb: Consultancy; Rigel: Consultancy; Syndax: Other: Research funding to my institution; AvenCell: Consultancy; Takeda: Other: DSMB; Jazz: Consultancy; Kura Oncology: Consultancy; Lava Therapeutics: Consultancy; Cellarity: Consultancy; Ligand Pharma: Consultancy; Novartis: Other: Research funding to my institution; Aptevo: Consultancy; Redona therapeutics: Consultancy. DeAngelo: Kite: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Gilead: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Autolos: Consultancy; Amgen: Consultancy, Honoraria; Blueprint: Consultancy, Research Funding; Curis: Consultancy; MT Sinai MPN Consortium: Other: DSMB; Fibrogen: Other: DSMB; Daiichi-Sankyo: Other: DSMB; Glycomimetics: Research Funding; AbbVie: Research Funding; Takeda: Consultancy; Bristol-Meyers Squibb: Honoraria. Cutler: Incyte: Consultancy; Syndax: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Rigel: Consultancy; Astellas: Consultancy; Cimeio: Current equity holder in publicly-traded company; Oxford Immune Algorithmics: Current equity holder in private company; Allovir: Other: DSMB; Angiocrine: Other: DSMB. Komrokji: PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Research Funding; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servio: Honoraria; Taiho: Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servio: Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stahl: GSK: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Sierra Oncolgy: Membership on an entity's Board of Directors or advisory committees; Kymera: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH