Type: Oral
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Minimal Residual Disease Detection in AML and Single Cell Investigations
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Diseases, Myeloid Malignancies, Minimal Residual Disease
Methods: In this retrospective chart review study, we selected all newly-diagnosed AML pts treated at our institution between 2010 and 2021 who had achieved a first response (CR, CRi, or MLFS) and had undergone MRD testing by flow cytometry at the time of best response. Pts with core-binding factor AML and acute promyelocytic leukemia, as well as pts who had received prior therapy for antecedent myelodysplastic syndrome, were excluded. We divided pts into 2 cohorts: cohort IA consisting of pts receiving intensive chemotherapy based on intermediate to high-dose cytarabine plus an anthracycline (without venetoclax), and cohort LO + VEN consisting of pts treated with a low-dose cytarabine or hypomethylating agent backbone plus venetoclax. The Kaplan Meier method was used to calculate OS and time-to-relapse (TTR). Pts who underwent stem cell transplantation (SCT) were censored at the time of transplant. Multivariate analysis was performed using a Cox proportional hazards model.
Results:
We identified 635 pts meeting inclusion criteria (385 IA, 250 LO + VEN). Compared to pts treated with IA, pts treated with LO + VEN were significantly older (median age 71.6 vs 52.8 yrs), had a lower rate of true CR (76% vs 89%), had a higher rate of CRi/MLFS (24% vs 11%), were less likely to achieve MRD-negativity (60% MRD(-) vs 71%), and were less likely to have undergone SCT (25% vs 50%). In addition, the LO + VEN cohort was enriched for ELN 2017 adverse risk disease (58% vs 34% in the IA cohort) and adverse risk cytogenetic features such as -5/5q- (19% vs 7%), -7/7q- (17% vs 7%), -17/17p- (12% vs 5%), and complex karyotype (29% vs 16%).
The median OS was 51m, 24.6m, 15.1m, and 9.9m in the IA MRD(-), LO + VEN MRD(-), IA MRD(+), and LO + VEN MRD(+) cohorts, respectively (fig. 1A). The median TTR was 59.9m, 55.9m, 8.9m, and 5.9m in the IA MRD(-), LO + VEN MRD(-), IA MRD(+), and LO + VEN MRD(+) cohorts, respectively (fig. 1B). When comparing the IA MRD(-) cohort to the LO + VEN MRD(-) cohort, the IA-treated patients had superior OS (p=0.002, fig. 1A) but similar TTR (p=0.830, fig. 1B). Similar findings were obtained in the MRD(+) pairs (fig. 1A-B). A subset analysis evaluating only pts aged ≥ 60 yrs (n=297) showed no statistically significant differences in OS or TTR within MRD categories (median OS 28.9m in IA MRD(-) vs 24.6m in LO + VEN MRD(-), p=0.09; median OS 15.1m in IA MRD(+) vs 10.6m in LO + VEN MRD(+), p=0.51; median TTR not reached in IA MRD(-) vs 35.7m in LO + VEN MRD(-), p=0.32; median TTR 9.6m in IA MRD(+) vs 6.0m in LO + VEN MRD(+), p=0.43)
Given the imbalances in patient and disease characteristics between the treatment cohorts, we performed a multivariate analysis on the full cohort to better elucidate the relative prognostic impact of MRD and treatment intensity. By univariate analysis, age, treatment cohort (IA vs LO + VEN), best response (CR/CRi/MLFS), MRD status, and ELN risk were significant predictors for OS and were included in the multivariate model. By multivariate analysis, age (HR 1.02, p=0.026), best response (HR 1.41 for CRi, p=0.066; HR 2.69 for MLFS, p<0.001), MRD-status (HR 1.53 for MRD(+), p=0.007), and ELN category (HR 1.34 for intermediate, p=0.161, HR 1.96 for adverse, p=0.001) remained significant predictors of OS. For TTR, best response (HR 2.15 for CRi, p<0.001; HR 3.78 for MLFS, p<0.001), MRD-status (HR 1.94 for MRD(+), p<0.001), and ELN category (HR 1.79 for intermediate, p=0.014, HR 2.89 for adverse, p<0.001) remained significant. Treatment received was not predictive of either OS or TTR by multivariate analysis.
Conclusions: MRD status is a stronger predictor of OS and TTR than the intensity of therapy received. These data suggest achievement of MRD-negativity should be a major objective of AML therapy.
Disclosures: Kadia: Novartis: Consultancy; Regeneron: Research Funding; Servier: Consultancy; cellenkos: Research Funding; Astellas: Research Funding; Ascentage: Research Funding; Genfleet: Research Funding; Amgen: Research Funding; Astex: Honoraria; Pfizer: Research Funding; Glycomimetics: Research Funding; cyclacel: Research Funding; Delta-Fly: Research Funding; PinotBio: Consultancy; Iterion: Research Funding; Genentech: Consultancy, Research Funding; JAZZ: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy; AstraZeneca: Research Funding. Short: Astellas: Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; AstraZeneca: Consultancy. Borthakur: Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Loghavi: Abbvie: Consultancy, Current equity holder in publicly-traded company; QualWorld: Consultancy; Amgen: Research Funding; Astellas: Research Funding; GLG: Consultancy; PeerView: Honoraria; Guidepoint: Consultancy; Caris: Consultancy; BluePrint Medicine: Consultancy; Daiichi Sankyo: Consultancy. DiNardo: Gilead: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Cleave: Research Funding; Takeda: Honoraria; Bluebird Bio: Honoraria; Novartis: Honoraria; LOXO: Research Funding; ImmuneOnc: Honoraria, Research Funding; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Astex: Research Funding; Forma: Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria. Daver: Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Alvarado: BerGenBio: Research Funding; Daiichi-Sankyo/Lilly: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Sun Pharma: Research Funding. Andreeff: Kintor Pharmaceutical: Research Funding; Breast Cancer Research Foundation: Research Funding; Daiichi-Sankyo Inc.: Consultancy, Research Funding; AstraZeneca: Research Funding; Syndax: Consultancy, Research Funding; Brooklyn ITX: Research Funding; Pinot Bio: Research Funding; Oxford Biomedical UK: Research Funding; Senti Bio: Consultancy, Research Funding; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy; Medicxi: Consultancy; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; Reata: Current holder of stock options in a privately-held company; Chimerix: Current holder of stock options in a privately-held company; Oncolyze: Current holder of stock options in a privately-held company. Jabbour: Takeda: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Amgen: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding. Konopleva: F. Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grant support, Research Funding; AbbVie: Consultancy, Other: grant support, Research Funding; Genentech: Consultancy, Other: grant support, Research Funding; Stemline Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy; Forty-Seven: Consultancy, Honoraria, Other: Grant support; Kisoji: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Current equity holder in private company, Patents & Royalties; Eli Lilly: Consultancy, Patents & Royalties, Research Funding; Cellectis: Consultancy, Other: Grant support, Research Funding; Calithera: Other: Grant Support, Research Funding; Ablynx: Other: Grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceutical: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Novartis: Patents & Royalties, Research Funding. Kantarjian: Takeda: Honoraria; Jazz Pharmaceuticals: Research Funding; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Ravandi: BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Novartis: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; Syos: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Xencor: Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding.