Prognostic Value of the Measurable Residual Disease (MRD) in AML Treatment with Venetoclax in Combination with Hypomethylating Agents: Validation of the ELN 2021 MRD Recommendations
Authors: Jimenez-Vicente Carlos , Cardus Aina , Ramil López Guillermo , Onate Guadalupe , Arribas Iago , Garcia-Avila Sara , Gomez-Perez Lucia , Esteban Daniel , Sturla Antonella , Guijarro Francesca , López-Guerra Mònica , Castaño-Díez Sandra , Martínez-Roca Alexandra , Cortés-Bullich Albert , Perez Amanda Isabel , Zugasti Ines , Monge-Escartin Inés , Sierra Jorge , Vives Susana , Pomares Helena , Arnan Montserrat , Nomdedeu Josep , Garrido Ana , Pratcorona Marta , Díaz-Beyá Marina , Esteve Jordi 
Published: December 2024

Introduction
Measurable residual disease (MRD) assessment has become a crucial prognostic tool in patients diagnosed with acute myeloid leukemia (AML) undergoing intensive chemotherapy. While its prognostic impact is well-documented in these patients, its value among those treated with venetoclax-based low-intensity combinations remains less certain. Some studies have individually validated the efficacy of flow cytometry (MFC) (Pratz K et al, JCO, 2022) and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in patients with AML with mutated NPM1 (Othman J et al, Blood, 2024) in this context.
Methods
This multicenter, retrospective study aims to validate the prognostic value of MRD in patients treated with low-intensity venetoclax combinations, unfit for consolidation with further strategies, following the ELN-MRD 2021 recommendations. Patients were treated in 5 centers belonging to the Spanish CETLAM Group from March 2019 to January 2024. MRD was measured following the updated ELN 2021 recommendations (Heuser M, et al. Blood 2021), using RT-qPCR for patients with NPM1 mutated AML, and an eight-color MFC panel for the rest of the patients. Impact of MRD results on leukemia-free survival (LFS) and overall survival (OS) was estimated considering MRD response as a time-dependent variable using the Mantel-Byar test and with a corresponding landmark analysis. Multivariate analysis (MVA) was performed using Cox's proportional hazards model, including relevant variables related to treatment success.
Results
Initially, 251 patients were included. The overall response rate (CR/CRi/MLFS/PR), including partial response (PR), was 66% (166 patients). Patients who achieved a PR (21 patients, 8.3%) or underwent allogeneic hematopoietic stem cell transplantation (28 patients, 11.5%) were excluded of the study. Additionally, MRD assessment during follow-up was not performed in 29 patients who achieved a response, reducing the final cohort size to 89 patients. The median age of the cohort was 73 years (range 48-85), with 52.8% being male.
Patients received venetoclax combined with hypomethylating agents (VenHMA) as frontline therapy (ND) (74.1%) or in a relapsed/refractory (R/R) (25.9%) status. AML with myelodysplasia-related features was the most frequent diagnosis (42.7%, including specific gene mutations (n = 32) and cytogenetic abnormalities (n = 6)), followed by AML with mutated NPM1 (37.1%) and AML with mutated TP53 (11.2%). According to the ELN 2022 risk classification, 24.7% of the patients were classified in the favorable risk group, 19.1% in the intermediate, and 56.1% had an adverse risk. Additionally, 18 patients had adverse cytogenetic risks, including 6 patients presenting complex karyotypes.
Regarding morphological complete response (CR/CRi/MLFS), median cycles to any response were 1 (range 1-8). Median follow-up was 11.5 months (range 2-52), with a OS and LFS of 18 (range 13.3-24.3) and 10.2 (range 8.2-14.8) months respectively.
MRD response rate was 43.6%. Median number of cycles to MRD response were 3 (range 1-11). MRD response rates at 2, 4, and 6 cycles were 20.2%, 33.7% and 42.7% respectively. Responders who achieved a negative MRD were more frequently younger than 70 years old (p = 0.02) and NPM1 mutated (p = 0.003), with no other clinical nor biological differences found between the two cohorts.
Mantel-Byar test (OS: 27 vs. 11 months, LFS: 21 vs. 9, both p &lt;0.001) and Kaplan-Meier landmark analysis at 3 cycles (OS: 27 vs. 10, LFS: 18 vs.7, both p &lt;0.001) showed that MRD negativity was prognostic for OS and LFS. The MVA analysis considering the most relevant characteristics related to VenHMA treatment [age &lt;70 years (vs. younger), NPM1, FLT3-ITD, N/KRAS/PTPN11/CSF3R, adverse cytogenetic risk (vs. other), ND (vs. R/R) and CR (vs. CRi)] further confirmed MRD response as an independent prognostic value for OS (HR: 0.27 (95%CI: 0.12-0.59), p &lt;0.001) and LFS (HR: 0.3 (95%CI: 0.15-0.58), p &lt;0.001) in patients responding to VenHMA.
Conclusion
MRD response, evaluated accordingly to the ELN-MRD 2021 recommendations, holds significant prognostic value for both OS and LFS in patients treated with VenHMA in real-life clinical practice. These findings underscore the importance of MRD monitoring in guiding treatment follow-up and improving subsequent treatment decisions in low-intensity venetoclax-based therapies.