Validation of the Prognostic Risk Signatures for Older Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents and Venetoclax
Authors: Bataller Alex , Bazinet Alexandre , DiNardo Courtney D. , Borthakur Gautam , Short Nicholas J. , Jabbour Elias , Takahashi Koichi , Daver Naval , Issa Ghayas C. , Pemmaraju Naveen , Jain Nitin , Montalban-Bravo Guillermo , Wierda William G. , Garcia-Manero Guillermo , Ravandi Farhad , Kantarjian Hagop M. , Kadia Tapan M. 
Published: December 2023

Introduction: Hypomethylating agents (HMA) with Venetoclax (Ven) is the standard of care for patients with acute myeloid leukemia (AML) ≥ 75 yrs of age or not candidates to intensive treatment. Döhner, et al. (ASH 2022) demonstrated that the European LeukemiaNet (ELN) risk classifications do not accurately predict prognosis in HMA-Ven treated patients. A prognostic risk signature classification (PRSc) was proposed, stratifying patients by RAS, FLT3 and TP53 mutations alone. We report a validation of this PRSc in a large cohort of patients treated with HMA-Ven.

Methods: This unicentric analysis included patients older than 60 years old with newly diagnosed treated with HMA-Ven in different treatment protocols. Responses were assessed with the ELN-2022 criteria. The PRSc allocated patients with [ K/N]- RAS or FLT3-ITD mutations in the intermediate benefit group, patients with TP53 in the lower benefit group, whereas patients with AML lacking these mutations were allocated in the higher benefit group. Cumulative incidence (CI) was calculated for pts achieving remission with death and relapse as competing events.

Results: A total of 179 patients were included, diagnosed between 11/2014 and 12/2021. Median age was 74 yrs old (range, 61-89) and 58% were male. 31% of patients had diploid cytogenetics and 35% had complex karyotype. According to the ELN 2022 risk category, 30 (17%), 15 (8%) and 114 (64%) patients were allocated in the favorable, intermediate and adverse risk group, respectively. According to the PRSc, 75 (42%), 31 (17%) and 54 (30%) were allocated in the higher, intermediate and lower benefit group, respectively. In the PRSc intermediate benefit group, 21 patients had NRAS mutations, 9 patients had KRAS mutation and 7 patients had FLT3-ITD. Patients received treatment with decitabine 10 days with Ven (n=89, 50%), decitabine 5 days with Ven (n=69, 38%), oral decitabine 5 days with Ven (n=14, 8%) and Azacitidine 7 days with Ven (n=7, 4%).

The overall response rate (ORR) was 70% (126/179), including 96 pts (54%) achieving complete remission (CR) rate and 30 (17%) having CR with incomplete hematologic recovery (CRi). The ORR for patients allocated in the ELN 2022 favorable, intermediate and adverse risk was 90% (27/30), 93% (14/15) and 63% (72/114). According to the PRSc, the ORR was 87% (65/75), 55% (17/31) and 59% (32/54) for patients of the higher, intermediate and lower benefit group, respectively. The median number of cycles to best response was 1 (1-8), and 22 patients (12%) underwent allogeneic stem cell transplantation.

After a median follow-up of 35 months, the median overall survival (OS) was 11 months. According to the ELN 2022 classification, the mOS was 44, 13 and 8 months (p&lt;0.001, C-index=0.6). When applying the PRSc, the median OS was 30, 12 and 5 months for higher, intermediate and lower benefit group (p&lt;0.001, C-index=0.66). Median event-free survival (EFS) was 8 months, being 30, 8, and 5 months for ELN 2022 favorable, intermediate and adverse group, respectively (p&lt;0.001, C-index=0.62). When applying the PRSc, the median EFS was 18, 8 and 4 months for higher, intermediate and lower benefit group, respectively (p&lt;0.001, C-index=0.65).

The 2-yr CI of relapse and death was 47% and 22%, respectively. By the ELN 2022 subgroups, the 2-yr CI of relapse was 29%, 43% and 55% for favorable, intermediate and adverse groups, respectively (p=0.1). The 2-yr CI of death was 12%, 21% and 25% for favorable, intermediate and adverse groups, respectively (p=0.4). By the PRSc, the 2-yr CI of relapse was 26%, 70% and 60% for higher, intermediate and lower benefit group, respectively (p=0.004). The 2-yr CI of death was 20%, 6% and 33% for higher, intermediate and lower benefit group, respectively (p=0.1).

Conclusion: The PRSc classification can stratify 3 different groups of patients with distinct outcomes. In the present study the 3 categories defined by the PRSc have very similar survival than the median OS previously reported (27, 12 and 5 months for higher, intermediate and lower benefit group), with a better performance according to the C-index. Signaling mutations ( RAS or FLT3-ITD) as well as TP53 mutations represent a challenge with HMA-Ven, in which novel treatments or combinations are warranted to improve outcomes.