Clinical Outcomes and Impact of Therapeutic Intervention in Patients (pts) with Acute Myeloid Leukemia (AML) with Recurrence of Measurable Residual Disease (MRD) after Achievement of MRD-Negative Remission

Background: Persistent MRD after frontline therapy is strongly prognostic in pts with AML. However, the clinical impact of MRD recurrence in pts with AML after achieving MRD-negative remission is not established, nor is the utility of therapeutic intervention for these pts.

Methods: We conducted a retrospective analysis of adults with AML in first morphological remission who achieved MRD negativity by multiparameter flow cytometry (MFC), and subsequently had MRD-positive relapse. MRD assessment was performed on bone marrow aspiration samples using 8-color MFC. The objective was to determine the relapse and survival outcomes, including relapse-free survival (RFS) and overall survival (OS), in pts with AML and MRD recurrence while in first morphologic remission, as well as to evaluate the impact of therapeutic intervention in these pts.

Results: Among 1980 frontline pts with non-core-binding factor AML who were treated at MDACC between 8/2011 and 7/2021, 1387 achieved morphological remission, of whom 740 achieved MRD-negative remission. Of the 740 pts, 55 (7.4%) experienced MRD recurrence while in first morphologic remission. The baseline characteristics of the 55 pts included are shown in Table 1. The median time between MRD-negative remission and MRD recurrence was 6.0 months (range, 1.4 to 53.3). At the time of MRD recurrence, 44 pts (80%) were on active therapy and 11 (20%) had completed frontline therapy and were on active surveillance. The median level of MRD at the time of recurrence was 0.7% (range, 0.05% to 4.0%).

The median duration of follow-up from the time of MRD recurrence was 44.3 months (range, 1 to 108). Among pts with MRD recurrence, the median time to morphological relapse was 5.9 months, with a 5-year cumulative incidence of relapse (CIR) of 82%. Notably, the risk of relapse was particularly high in the first 6 months, and 42% of pts relapsed by 3 months. The median RFS and OS after MRD recurrence were 5.5 and 18.1 months, respectively, with a 5-year RFS of 6% and OS of 22% (Figure 1A). Pts with MRD recurrence and adverse-risk cytogenetics had significantly worse RFS (2.8 vs 8.7 months; P=0.006) and OS (7.9 vs 36.1 months; P<0.001) than those without an adverse-risk karyotype. Similarly, ELN cyto-molecular risk was associated with worse RFS (P=0.03) and OS (P=0.01) among pts with MRD recurrence.

At the time of MRD recurrence, 36 pts (65%) continued with the same treatment. Three of these pts eventually converted to MRD-negative, 28 relapsed, and 5 remained in MRD-positive remission at last follow-up. Three pts (5%) received no therapy for MRD-positive disease, all of whom subsequently relapsed. Sixteen pts (29%) changed therapy, 9 of whom proceeded directly to allogeneic stem cell transplant (ASCT) and 7 of whom changed chemotherapy regimen (and 3 of whom eventually proceeded to ASCT). Among these 7 pts who changed chemotherapy at the time of MRD recurrence, 3 converted to MRD-negative and 4 remained MRD-positive.

The median time to therapeutic intervention was 1.1 months (range, 0.1 to 4.3). In a landmark analysis, therapeutic intervention (defined as either transplantation or change in chemotherapy regimen) was associated with significantly better RFS (5-year RFS: 31% vs 5%; P=0.01) and OS (5-year OS: 45% vs 17%; P=0.01; Figure 1B), compared with those who continued their current therapy. The outcomes of pts who continued the same therapy or were monitored at the time of MRD recurrence were dismal, with a 5-year CIR of 96%.

Among the 12 pts who underwent ASCT after MRD recurrence while still in first morphological remission, the median RFS and OS were both 36.1 months, and the 5-year RFS and OS rates were 38% and 42%, respectively. Outcomes were very poor among pts who did not proceed with ASCT in first remission, with 5-year CIR, RFS and OS rates of 96%, 4%, and 17%, respectively. Only one non-transplanted pt was alive and without relapse beyond 2 years; this pt died in MRD-positive remission 61 months after MRD recurrence.

Conclusion: The outcomes of pts with AML who experience MRD recurrence are very poor. Serial MRD monitoring is imperative in pts who achieve MRD-negative remission, and MRD-directed therapies improve outcomes and should be considered for pts who experience MRD recurrence.

Ravandi:Xencor: Research Funding; Prelude: Research Funding; Amgen: Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; Novartis: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Astellas: Consultancy, Honoraria, Research Funding. Kadia:Glycomimetics: Research Funding; Delta-Fly: Research Funding; Regeneron: Research Funding; Astex: Honoraria; Agios: Consultancy; Iterion: Research Funding; Ascentage: Research Funding; cellenkos: Research Funding; Servier: Consultancy; Genentech: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Research Funding; cyclacel: Research Funding; JAZZ: Consultancy, Research Funding; PinotBio: Consultancy; Pfizer: Research Funding; AstraZeneca: Research Funding; BMS: Consultancy, Research Funding; Astellas: Research Funding; Genfleet: Research Funding; Abbvie: Consultancy, Research Funding. DiNardo:LOXO: Research Funding; Novartis: Honoraria; Cleave: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Jazz: Honoraria; Bluebird Bio: Honoraria; Gilead: Honoraria; Foghorn: Honoraria, Research Funding; Forma: Research Funding; ImmuneOnc: Honoraria, Research Funding; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Astex: Research Funding; 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; Astellas: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; GenMab: Membership on an entity's Board of Directors or advisory committees. Issa:Novartis, Kura Oncology: Consultancy; Celgene, Kura Oncology, Syndax, Merck, Novartis: Research Funding. 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. Loghavi:Astellas: Research Funding; Abbvie: Consultancy, Current equity holder in publicly-traded company; Amgen: Research Funding; PeerView: Honoraria; QualWorld: Consultancy; GLG: Consultancy. Konopleva:Sanofi: Other: grant support, Research Funding; Rafael Pharmaceutical: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: Grant support, Research Funding; Calithera: Other: Grant Support, Research Funding; Cellectis: Consultancy, Other: Grant support, Research Funding; Eli Lilly: Consultancy, Patents & Royalties, Research Funding; Reata Pharmaceuticals: Current equity holder in private company, Patents & Royalties; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kisoji: Consultancy, Honoraria; Forty-Seven: Consultancy, Honoraria, Other: Grant support; Amgen: Consultancy; Novartis: Patents & Royalties, Research Funding; Stemline Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grant support, Research Funding; Genentech: Consultancy, Other: grant support, Research Funding; AbbVie: Consultancy, Other: grant support, Research Funding. Yilmaz:Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Jabbour:Takeda: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding. Shpall:NY blood center: Consultancy; Takeda: Patents & Royalties; Affimed: Other: License agreement; Bayer: Honoraria; Navan: Consultancy; axio: Consultancy; adaptimmune: Consultancy; Fibroblasts and FibroBiologics: Consultancy. Popat:Iovance: Consultancy; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Bayer: Research Funding. Kantarjian:Daiichi-Sankyo: Consultancy, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; NOVA Research: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Short:Novartis: Consultancy; Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria; Stemline Therapeutics: Research Funding.