Survival Outcomes for Patients with Acute Myeloid Leukemia with Myelodysplasia Related Changes (AML-MRC) in a Real-World, Retrospective Cohort Receiving Intensive Chemotherapy

Introduction

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is defined by the presence of myelodysplasia-related cytogenetic abnormalities (MRC-cyt) or gene mutations (MRC-mut) in the 2022 International Consensus Classification (ICC) guidelines. This replaced previous definitions from the 2016 World Health Organization (WHO) guidelines which included only morphologic, clinical, and cytogenetic criteria. AML with mutated TP53 (AML-TP53) was also recognized as a separate entity, whereas many TP53-mutated (mt) patients were AML-MRC by WHO 2016. Patients with MRC-mut and some with MRC-cyt are classified as adverse (adv)-risk in the European LeukemiaNet (ELN) 2022, unless occurring in the context of favorable (fav)-risk subtypes. However, many validation studies for the AML-MRC cytogenetic and mutation criteria were based on historical induction chemotherapy (IC) cohorts, which may not reflect current practice. We assessed the number of patients reclassified as AML-MRC by 2016 vs. 2022 criteria and defined survival outcomes for AML-MRC and AML-TP53 patients in a recent, real-world cohort of AML patients receiving IC.

Methods

Sequential patients with newly diagnosed AML, excluding acute promyelocytic leukemia, receiving IC were retrospectively identified at a single institution from 2016-2022. Patients received 7+3 (cytarabine 100mg/m², daunorubicin 60mg/m²), CPX-351 (44mg/m²), or other cytarabine-based IC. Cytogenetics and next-generation sequencing were done in a clinical lab; patients without these were excluded. Patients were retrospectively classified as AML-MRC or AML-TP53 by both WHO 2016 and ICC 2022, with hierarchical classification of patients as AML-TP53, MRC-mut, or MRC-cyt. Patients met WHO 2016 clinical criteria if they had morphologic dysplasia or prior MDS or MDS/MPN, without mutated NPM1 or CEBPA. Therapy-related AML was included as a 2016 clinical criteria. Survival analysis was by Kaplan-Meier, between-group comparisons by t-test.

Results

We identified 420 AML patients who received IC. Median age was 58.7 years (yrs) (range 21-77 yrs). IC was 7+3 in 89% (374/420), CPX-351 in 8% (34/420), and other cytarabine-based IC in 3% (12/420); 19% (78/420) received FLT3-inhibitor and 12% (52/420) GO. Overall, 22% (92/420) of the cohort met MRC 2016 criteria and 29% (122/420) met MRC 2022 criteria. Only 15% (63/420) of patients met both MRC 2016 and 2022 criteria. AML-MRC patients were older when considered by 2016 (61.4 vs. 57.9 yrs, P=0.043) or 2022 (60.8 vs. 57.8 yrs, P=0.031) criteria.

MRC 2016 patients had a median overall survival (mOS) of 19.7 months (mo) vs. 46.4 mo (P=0.003). However, 25% (23/92) of MRC 2016 patients had TP53-mt; removing these patients resulted in a mOS of 27.8 mo for MRC 2016 patients vs. 46.4 mo (P=0.200). AML-TP53 per ICC 2022 comprised 5% (23/420) of all patients; these patients had a mOS of 7.0 mo vs. 45.9 mo (P<0.001).

Amongst ICC 2022 AML-MRC patients, 83% (102/122) were MRC-mut (median 2 mt, range 0-5) and 16% (20/122) were MRC-cyt. AML-MRC patients had a mOS of 46.5 mo vs. 33.6 mo in the overall cohort (P=0.940). Comparing the AML-MRC group to ELN 2022 int-risk patients, we observed a mOS of 46.5 mo vs. 25.9 mo (P=0.450). MRC-mut patients had a mOS of 49.5 mo vs. 33.6 mo in the overall cohort (P=0.730). MRC-cyt patients had a mOS of 24.4 mo vs. 33.6 mo in the overall cohort (P=0.340)

Within the MRC-mut group, no difference in mOS was seen for chromatin modifier (P=0.260), splicing (P=0.390), transcription factor (P=0.270) or mixed (P=0.720) mutation patterns. There was no difference for patients with >1 vs. 1 MRC-mut (P=0.660). Among ELN fav-risk patients, 18% (23/129) had a MRC-mut with a mOS of 33.6 mo vs. not reached for those without (P=0.280).

Patients meeting 2016 criteria receiving CPX-351 (26%, 24/92) had a mOS of 36.5 mo vs. other IC regimens (74%, 68/92) at 16.7 mo (P=0.290). Patients meeting 2022 criteria receiving CPX-351 (18%, 19/122) had a mOS of 63.3 mo vs. other IC regimens (84%, 103/122) at 46.5 mo (P=0.930).

Conclusion

Patients with ICC 2022 AML-MRC are a substantively different group than older MRC cohorts. Patients with MRC-defining cytogenetic abnormalities or mutations had comparable mOS to ELN int-risk patients. MRC-defining mutations did not modify mOS for ELN fav-risk patients. Patients with AML-TP53 have dismal outcomes. Further study is needed to clarify risk stratification of AML-MRC in the modern treatment era.

Abou Mourad:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion: Consultancy; Paladin: Honoraria, Speakers Bureau. Cherniawsky:KITE: Honoraria; Astellas: Honoraria. McGinnis:Jazz Pharmaceuticals: Honoraria, Research Funding. Sanford:Pfizer: Research Funding; Astellas: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Research Funding, Speakers Bureau. Song:GSK: Research Funding; BMS: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Toze:Janssen, BeiGene: Honoraria; Abbvia: Research Funding. Stubbins:Takeda: Honoraria; Kite/Gilead: Speakers Bureau; Astellas: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Pfizer: Honoraria.