Relationship Between Salvage Strategy and Outcomes in Patients With CBF or NPM1-mutated AML and First Molecular Relapse
Year: 2025
Type: conference-abstract
Abstract: Introduction: Patients with Core-Binding Factor (CBF) and NPM1-mutated acute myeloid leukemia (AML) can be monitored by quantitative PCR after having achieved complete remission (CR) to detect molecular relapse with a growing interest in the use of preemptive therapy to prevent overt morphologic relapse. The best salvage strategy, including lower-intensity venetoclax (VEN)-containing regimens and allogeneic hematopoietic cell transplantation (HCT), is however unclear. In this study, we retrospectively analyzed the outcome of CBF or NPM1-mutated AML patients who received preemptive therapy for molecular relapse according to the salvage strategy used. Methods: All CBF and NPM1-mutated AML adults, who had molecular relapse after first-line therapy including induction therapy with daunorubicin/idarubicin and cytarabine followed by standard chemotherapy consolidation, without allogeneic HCT in first CR, were included. Molecular relapse was defined according to ELN recommendations (Heuser M, Blood 2021) as a conversion from MRD negativity to positivity or an increase in MRD copy numbers >1 log between two positive samples. MRD response included patients with MRD negativity and MRD reduction ≥1 log. Results: Between 2010 and 2023, we included 121 adults from 12 centers with CBF (n=28) and NPM1-mutated (n=93) AML who had molecular relapse. The different salvage strategies included upfront allogeneic HCT (n=19), intensive chemotherapy (IC; n=21), venetoclax and azacitidine combination (VEN-AZA; n=70), and other strategies (n=11; including AZA, gemtuzumab ozogamicin, selective inhibitors). Patients receiving upfront allogeneic HCT had lower transcript levels at molecular relapse (median, 1% vs. 4%, 17%, and 14% for IC, VEN-AZA, and other in bone marrow, respectively, P=0.033 and 0% vs. 1%, 2%, and 3% in peripheral blood, respectively, P=0.036) and a longer time to initiation of salvage therapy (72 days vs. 50, 48, and 60 days, respectively, P=0.01) while patients receiving VEN-AZA were older (58 years vs. 51,41, and 44 years for upfront allo, IC, and other, respectively, P<0.001) and more likely to have NPM1-mutated AML (94% vs. 37%, 48%, and 91%, respectively, P<0.001). MRD response was higher in patients undergoing IC (89% [72% MRD negativity, 17% MRD reduction] vs. 72% for VEN-AZA [33% MRD negativity, 39% MRD reduction] vs. 17% for other [17% MRD negativity], P=0.002). With a median follow-up of 3.38 years (interquartile [IQR]: 2.39-4.95) in survivors, there were 27 deaths contributing to the estimates for overall survival (OS). At three years, OS was not statistically different between the four groups (84% [69-100%] for upfront allo vs. 81% [66-100%] for IC vs. 79% [69-90%] for VEN-AZA vs. 64% [41-100%] for other, P=0.31). After multivariable adjustment, age at molecular relapse (hazard ratio [HR]=1.04 [1.00-1.08], P=0.049), male gender (HR=1.37 [1.12-3.33], P=0.007), and transcript levels in blood at initiation of salvage (HR=1.01 [1.00-1.01], P<0.001) were associated with OS. Allogeneic HCT was received by 98 patients (81%) with a cumulative incidence of allogeneic HCT at 12 weeks of 100% for upfront allo, 71% [51-92%] for IC, 73% [50-97%] for VEN-AZA, and 82% [55-100%] for other (P<0.001). In a 190-day landmark analysis, when 75% of transplant recipients had undergone the procedure, three-year OS was statistically significantly higher in those who received allogeneic HCT (82% [73-93%] vs. 70% [57-86%] for those who did not receive HCT at 190 days, P=0.041). In patients who received allogeneic HCT, type of salvage therapy was not statistically associated with post-HCT relapse (11% [0-25%] for upfront allo vs. 13% [0-31%] for IC vs. 19% [7-32%] for VEN-AZA vs. 10% [0-30%] for others, P=0.77), relapse-free survival (90% [77-100%] vs. 80% [62-80%] vs. 71% [58-86%] vs. 60% [36-100%], P=0.2), or OS (90% [77-100%] vs. 86% [70-100%] vs. 86% [77-96%] vs. 70% [47-100%], P=0.42) but with non-relapse mortality (0% vs. 7% [0-15%] vs. 10% [2-18%] vs. 30% [0-60%], P=0.043) at three years. Conclusion: Our data suggests that different salvage strategies are associated with similar outcomes with a similar proportion of patients receiving allogeneic HCT. Allogeneic HCT is associated with increased OS in the context of molecular relapse. Upfront allogeneic HCT may be a valuable option in patients with low transcript levels at molecular relapse and an available donor. Either IC or VEN-AZA can be used as bridge to transplant in other patients.
Source: Blood
Authors: Corentin Orvain, Jules Higue, Pierre Peterlin, Pierre Yves Dumas, Yohan Desbrosses, Emmanuelle Tavernier, Martin Carre, Sabrina Barriere, Audrey Couturier, Thomas Cluzeau, Areti Chantzi, Gaspar Aspas Requena, Eric Delabesse, Anne Bouvier, Audrey Bidet, Florian Renosi, Marie Joelle Mozziconacci, Pascale Flandrin-Gresta, Sylvie Tondeur, Véronèse Lauren, Cedric Pastoret, Berengere Dadone-Montaudie, Sebastien Lachot, Sarah Bertoli, Patrice Chevallier, Hunault-Berger Mathilde, Arnaud Pigneux, Christian Recher
Institutions: Centre Hospitalier Universitaire d'Angers, Institut universitaire du cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Nantes, Centre Hospitalier Universitaire de Bordeaux, Centre Hospitalier Universitaire de Besançon, Institut Paoli-Calmettes, Centre Hospitalier Universitaire de Saint-Étienne, Centre Hospitalier Universitaire de Grenoble, Centre Hospitalier Universitaire de Clermont-Ferrand, Centre Hospitalier Universitaire de Rennes, Centre Hospitalier Universitaire de Nice, Université de Tours, Centre Hospitalier Universitaire de Tours
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417019170
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