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225 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 619. Acute Myeloid Leukemias: Disease Burden and Minimal Residual Disease in Prognosis and Treatment: Measurable Residual Disease in AML in 2024 and Beyond
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, Research, AML, Clinical Research, Diseases, Real-world evidence, Biological Processes, Myeloid Malignancies, Molecular biology, Measurable Residual Disease
Saturday, December 7, 2024: 2:30 PM

Carlos Jimenez-Vicente1,2*, Aina Cardus3*, Guillermo Ramil López, MD4,5*, Guadalupe Onate, MD, PhD6*, Iago Arribas, MD7*, Sara Garcia-Avila, MD8*, Lucia Gomez-Perez, MD9*, Daniel Esteban, MD10*, Antonella Sturla11*, Francesca Guijarro, MD12,13*, Mònica López-Guerra14,15*, Sandra Castaño-Díez, MD14,16*, Alexandra Martínez-Roca12,17*, Albert Cortés-Bullich, MD12,18*, Amanda Isabel Perez, MD19*, Ines Zugasti17*, Inés Monge-Escartin20*, Jorge Sierra, MD21, Susana Vives, MD22,23*, Helena Pomares24*, Montserrat Arnan, MD, PhD25*, Josep Nomdedeu26*, Ana Garrido, MD4*, Marta Pratcorona, MD, PhD4,5*, Marina Díaz-Beyá, MD, PhD14,16* and Jordi Esteve, MD, PhD14,27

1Department of Hematology, ICAMS, Hospital Clínic de Barcelona, Barcelona, Spain
2Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS),, Barcelona, Spain
3Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
4Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
5IIB-Sant Pau, Sant Pau Biomedical Research Institute, Barcelona, Spain
6Hematology Department, Hospital Santa Creu i Sant Pau, Barcelona, Spain
7Hematology Department. Institut Català d’Oncologia, Hospital Duran i Reynals. Institut d’Investigació Biomèdica de Bellvitge (IDIBELL). Universitat de Barcelona., L'Hospitalet De Llobregat, Barcelona., Spain
8Hospital del Mar, Barcelona, Spain
9Department of Hematology, Hospital del Mar, Barcelona, Spain
10Hospital Universitari Germans Trias i Pujol - Institut Català d'Oncologia, Badalona, Spain
11Servei d’Hematologia, Institut Català d’Oncologia, Hospital Duran i Reynals, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet, Spain
12Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
13Hematopathology Unit, Pathology Department, Hospital Clínic de Barcelona, Barcelona, Spain
14Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain
15Hematopathology Section, Pathology Department, Hospital Clínic Barcelona, Barcelona, Spain
16Hematology Department, Hospital Clínic de Barcelona, Barcelona, Spain
17Hematology Department, Hospital Clinic de Barcelona, ICMHO, Barcelona, Spain
18Hospital Clínic de Barcelona, Barcelona, Spain
19Department of Hematology, ICAMS, Hospital Clínic de Barcelona, Barcelona, Spain., Barcelona, Spain
20Pharmacy Department, Hospital Clinic De Barcelona, Barcelona, ESP
21Hematology and Hemotherapy Department, Hospital de la Sant Creu i Sant Pau. IIB-Sant Pau and José Carreras Leukemia Research Institutes. Universitat Autónoma de Barcelona, Barcelona, Spain
22Hematology Department, Institut Catala d'Oncologia - Hospital Germans Trias i Pujol, Badalona, Spain
23Hospital Germans Trias i Pujol, Badalona, ESP
24Clinical Hematology Department, ICO-Hospitalet, Hospital Durán i Reynals. IDIBELL, Barcelona., Barcelona, Spain
25Hematology Department. Institut Català d’Oncologia, Hospital Duran i Reynals. Institut d’Investigació Biomèdica de Bellvitge (IDIBELL). Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain
26Hospital de la Santa Creu i Sant Pau, Barcelona, AL, ESP
27Hematology Department, Hospital Clínic Barcelona, ICAMS, Barcelona, Spain

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 <0.001) and Kaplan-Meier landmark analysis at 3 cycles (OS: 27 vs. 10, LFS: 18 vs.7, both p <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 <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 <0.001) and LFS (HR: 0.3 (95%CI: 0.15-0.58), p <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.

Disclosures: Jimenez-Vicente: AbbVie: Other: Travel Grants; AbbVie: Speakers Bureau. Ramil López: Johnson & Johnson's: Other: Travel grant to attend conference; Abbvie: Other: Travel grant to attend conference; Astellas: Other: Travel grant to attend conference. Martínez-Roca: Abbvie: Honoraria, Other: Travel Grant; Pfizer: Honoraria; Kite/Gilead: Honoraria, Other: Travel Grant. Díaz-Beyá: BMS: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy.

*signifies non-member of ASH