Measurable residual disease (MRD) assessment as an early end point oftreatment efficacy in acute myeloid leukemia (AML): A pethema studyof 2,623 patients (Pts) treated with intensive therapy

Abstract Background: Despite advances in treatment of AML pts considered fit for intensive therapy, significant unmet medical needs remain. Early end points for survival can accelerate the approval of novel therapies. MRD has been recently accepted as an early end point in other hematological malignancies, but important questions remain unanswered to support its acceptance in AML. Is multiparameter flow cytometry (MFC) more sensitive than the morphological definition of complete remission (CR)? Are MRD kinetics more prognostic than a single assessment? Are there genetic risk groups in whom MRD is not informative? Is the prognostic value of MRD independent of induction and consolidation therapy? Are MRD negative rates achieved with each therapy associated with different survival? Aim: Investigate the potential role of MRD assessed by MFC as an early endpoint for survival in AML pts treated with intensive therapy. Methods: The PETHEMA registry had 2,623 newly-diagnosed AML pts treated in routine practice and clinical trials, who had at least one MRD assessment at first CR using local MFC methods. Pts were mainly treated with 3+7 (n=2,160), followed by 3+7 plus a FLT3 inhibitor (n=137), FLAG-based regimens (n=97). Additional treatments included CPX-351 (n=59), 3+7+Etoposide (n=44), 3+7+GO (n=37), and others (n=89). Pts were stratified into low (CBF, n=348), intermediate-low (CEBPA/NPM1+ and FLT3-, n=392), intermediate-high (MRC 2010 intermediate or normal karyotype with FLT3- and NPM1-, n=738) and high (MRC 2010 high or FLT3+, n=784) genetic risk. Relapse-free (RFS) and overall survival (OS) were landmarked at the time of MRD assessment. Results: Of the 2623 pts in CR1, 1256 (48%) showed MRD ≥0.1% and 532 (20%) had MRD levels ≥0.01% - <0.1%. When compared to pts with <0.01% MRD (n=835, 32%), those with MRD levels ≥0.01% - <0.1% and ≥0.1% showed inferior RFS (medians of 35, 23 and 17, p<.001) and OS (medians of 94, 55 and 33 months, p<.001). Hence, the 0.01% cutoff was selected to define negative vs positive MRD status. Positive MRD was associated with inferior RFS (HR= 1.3, p<.001) and OS (HR= 1.4, p<.001). The respective global odds ratio estimated by the bivariate Plackett Copula model were 8.0 (95% CI, 5-16.7) and 9.8 (95% CI, 5.7-27.8), which indicates a strong correlation between MRD status at CR1 and survival outcomes. Of note, a sub-analysis in pts with ≥2 MRD assessments (n=322) showed that MRD kinetics are more prognostic than a single MRD test. When compared to pts with sustained MRD negativity and those having positive and negative MRD result, pts who were systematically MRD positive showed inferior RFS (median of 61, 48 and 16 months, p<.001) and OS (median 96 vs 105 vs 35 months, p<.001). In multivariate analysis adjusted for genetic risk and the different treatments, MRD status retained independent prognostic value for RFS (HR= 1.3, p<.001) and OS (HR= 1.3, p<.001). MRD status predicted different outcome in pts with genetic high-risk and was borderline significant in those with low-risk. By contrast, there were no differences in intermediate-risk groups, which could be partially associated with MRD-guided intensification. Accordingly, pts who were not transplanted showed different OS according to MRD status. By contrast, MRD status at CR1 was not prognostic in pts undergoing autologous or allogeneic transplant. The association between the treatment effect in MRD and survival was investigated in the three most frequent induction regimens. MRD negative rates were higher after 3+7 plus a FLT3 inhibitor vs 3+7 vs FLAG-based regimens (42% vs 31% vs 29%, p=.02). The higher MRD negative rates preceded longer RFS (median 32 vs 21 vs 14 months, p=.01) and OS (median 58 vs 47 vs 22 months, p=.01) with 3+7 plus a FLT3 inhibitor vs 3+7 vs FLAG-based regimens. Conclusion: MRD assessment by MFC proved to be more sensitive than CR and showed a strong patient-level association with survival. MRD negative rates achieved with each treatment were also associated with differences in survival. While these results qualify MRD as a potential early end point of treatment efficacy in AML pts considered fit for intensive therapy, attention should be paid to genetically-defined intermediate risk groups in whom MRD status may guide treatment decisions that could ameliorate the poor prognosis of positive MRD. MRD kinetics may be required to improve prognostication of such pts, particularly in those who are transplanted.

Authors

Institutions

Publication Details

Journal
Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-5293
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Measurable residual disease (MRD) assessment as an early end point oftreatment efficacy in acute myeloid leukemia (AML): A pethema studyof 2,623 patients (Pts) treated with intensive therapy

Teresa Caballero, Pau Montesinos, Daniel García Belmonte, Olga Salamero et al.
Blood
Acute Myeloid Leukemia Research
article

Measurable residual disease (MRD) assessment as an early end point oftreatment efficacy in acute myeloid leukemia (AML): A pethema studyof 2,623 patients (Pts) treated with intensive therapy

Teresa Caballero, Pau Montesinos, Daniel García Belmonte, Olga Salamero, Esperanza Lavilla, Amparo Sempere, Mar Tormo, Esther Pérez Carbajo, David Martínez‐Cuadrón, José Mariz, Luis Felipe Casado Montero, Leire Burgos, Jorge Labrador, Sebastián Hidalgo, Diana Cuervo, Benjamín Herreros, Marcela Espinoza, Juan Miguel Bergua Burgués, Manuel Pérez‐Encinas, Lorenzo Algarra, Beatriz De Rueda Ciller, Cristina Gil, M. Madrigal, Carmen Couto, Josefina Serrano, Pilar Herrera Puente, Pilar Lloret Madrid, Bruno Paiva, Raimundo García‐Boyero, José Luis López Lorenzo, Eduardo Rodríguez‐Arbolí, Evelyn Acuña‐Cruz, Lara M. Gómez García, Miguel Ángel López, María Teresa Olave Rubio, Claudia Sossa, María‐Belén Vídriales, Maria Jose Sayas Lloris, Teresa Bernal, Mercedes Colorado, Antonio Solana‐Altabella, María Teresa Cedena Romero, Olga Arce‐Fernández, Carmen Botella, Joaquín Sánchez‐García, Manuel Barrios García, Rebeca Rodriguez Veiga, Susana Vives, Sofía Grille, Ágata Almela, María José García, Carmen González, Celina Benavente, Armando Mena Duran, Dolly Viviana Fiallo Suarez, Maria Del Carmen Martinez Chamorro, Carlos Rodríguez‐Medina, María Luz Amigo, M.J. Cremades Romero, Karoll Giovanna Gomez Correcha
article en

Abstract

Abstract Background: Despite advances in treatment of AML pts considered fit for intensive therapy, significant unmet medical needs remain. Early end points for survival can accelerate the approval of novel therapies. MRD has been recently accepted as an early end point in other hematological malignancies, but important questions remain unanswered to support its acceptance in AML. Is multiparameter flow cytometry (MFC) more sensitive than the morphological definition of complete remission (CR)? Are MRD kinetics more prognostic than a single assessment? Are there genetic risk groups in whom MRD is not informative? Is the prognostic value of MRD independent of induction and consolidation therapy? Are MRD negative rates achieved with each therapy associated with different survival? Aim: Investigate the potential role of MRD assessed by MFC as an early endpoint for survival in AML pts treated with intensive therapy. Methods: The PETHEMA registry had 2,623 newly-diagnosed AML pts treated in routine practice and clinical trials, who had at least one MRD assessment at first CR using local MFC methods. Pts were mainly treated with 3+7 (n=2,160), followed by 3+7 plus a FLT3 inhibitor (n=137), FLAG-based regimens (n=97). Additional treatments included CPX-351 (n=59), 3+7+Etoposide (n=44), 3+7+GO (n=37), and others (n=89). Pts were stratified into low (CBF, n=348), intermediate-low (CEBPA/NPM1+ and FLT3-, n=392), intermediate-high (MRC 2010 intermediate or normal karyotype with FLT3- and NPM1-, n=738) and high (MRC 2010 high or FLT3+, n=784) genetic risk. Relapse-free (RFS) and overall survival (OS) were landmarked at the time of MRD assessment. Results: Of the 2623 pts in CR1, 1256 (48%) showed MRD ≥0.1% and 532 (20%) had MRD levels ≥0.01% - <0.1%. When compared to pts with <0.01% MRD (n=835, 32%), those with MRD levels ≥0.01% - <0.1% and ≥0.1% showed inferior RFS (medians of 35, 23 and 17, p<.001) and OS (medians of 94, 55 and 33 months, p<.001). Hence, the 0.01% cutoff was selected to define negative vs positive MRD status. Positive MRD was associated with inferior RFS (HR= 1.3, p<.001) and OS (HR= 1.4, p<.001). The respective global odds ratio estimated by the bivariate Plackett Copula model were 8.0 (95% CI, 5-16.7) and 9.8 (95% CI, 5.7-27.8), which indicates a strong correlation between MRD status at CR1 and survival outcomes. Of note, a sub-analysis in pts with ≥2 MRD assessments (n=322) showed that MRD kinetics are more prognostic than a single MRD test. When compared to pts with sustained MRD negativity and those having positive and negative MRD result, pts who were systematically MRD positive showed inferior RFS (median of 61, 48 and 16 months, p<.001) and OS (median 96 vs 105 vs 35 months, p<.001). In multivariate analysis adjusted for genetic risk and the different treatments, MRD status retained independent prognostic value for RFS (HR= 1.3, p<.001) and OS (HR= 1.3, p<.001). MRD status predicted different outcome in pts with genetic high-risk and was borderline significant in those with low-risk. By contrast, there were no differences in intermediate-risk groups, which could be partially associated with MRD-guided intensification. Accordingly, pts who were not transplanted showed different OS according to MRD status. By contrast, MRD status at CR1 was not prognostic in pts undergoing autologous or allogeneic transplant. The association between the treatment effect in MRD and survival was investigated in the three most frequent induction regimens. MRD negative rates were higher after 3+7 plus a FLT3 inhibitor vs 3+7 vs FLAG-based regimens (42% vs 31% vs 29%, p=.02). The higher MRD negative rates preceded longer RFS (median 32 vs 21 vs 14 months, p=.01) and OS (median 58 vs 47 vs 22 months, p=.01) with 3+7 plus a FLT3 inhibitor vs 3+7 vs FLAG-based regimens. Conclusion: MRD assessment by MFC proved to be more sensitive than CR and showed a strong patient-level association with survival. MRD negative rates achieved with each treatment were also associated with differences in survival. While these results qualify MRD as a potential early end point of treatment efficacy in AML pts considered fit for intensive therapy, attention should be paid to genetically-defined intermediate risk groups in whom MRD status may guide treatment decisions that could ameliorate the poor prognosis of positive MRD. MRD kinetics may be required to improve prognostication of such pts, particularly in those who are transplanted.

BloodVol. 146(Supplement 1)
Instituto Cajal (ES), Hospital Clínico San Carlos (ES), Hospital Universitari i Politècnic La Fe (ES), Universidad Distrital Francisco José de Caldas (CO), Fundación Pethema (ES), Hospital Universitario Virgen Macarena (ES), Hospital General Universitario Morales Meseguer (ES), Hospital de Basurto (ES), Hospital La Luz (ES), Complejo Hospitalario Universitario de Santiago (ES), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Complejo Hospitalario de Salamanca (ES), Marqués de Valdecilla University Hospital (ES), Biogipuzkoa Health Research Institute (ES), Hospital Universitario 12 De Octubre (ES), Instituto Português de Oncologia Francisco Gentil (PT), Hospital Regional Universitario de Málaga (ES), Hospital Universitario Quirónsalud Madrid (ES), Hospital San Pedro de Alcántara (ES), Navarre Institute of Health Research (ES), Hospital Universitario Miguel Servet (ES), Hospital Universitario de Burgos (ES), Hospital Regional de Concepción (CL), Hospital Universitario Reina Sofía (ES), Hospital General Universitari de Castelló (ES), Hospital Universitario Doctor Peset (ES), Vall d'Hebron Hospital Universitari (ES), Hospital General Universitario De Valencia (ES), Hospital Juan Ramón Jiménez (ES), Hospital Universitario Fundación Jiménez Díaz (ES), Clinica Universidad de Navarra (ES), Hospital Clínico Universitario Lozano Blesa (ES), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Hospital General Universitario de Alicante Doctor Balmis (ES), Donostiako Unibertsitate Ospitalea (ES), Fundación Arturo López Pérez (CL), Instituto Nacional del Cáncer (CL), Hospital Universitario Lucus Augusti (ES), Hospital General Universitario de Albacete (ES), Hospital Universitario de Valme (ES), Complejo Hospitalario Torrecárdenas (ES), Foscal Hospital (CO), Hospital Universitario Virgen del Rocío (ES), Hospital Universitari Germans Trias i Pujol (ES), Hospital de Clínicas (UY), Complejo Hospitalario Universitario de Albacete (ES), Clínica Dávila (CL), Hospital Clínico Universitario de Valladolid (ES), INCLIVA Health Research Institute (ES), Hospital Universitario de León (ES), Hospital Universitario Ramón y Cajal (ES), Hospital Universitario Infantil San José (CO), Complejo Hospitalario Universitario de Toledo (ES), Instituto de Investigación Sanitaria La Fe (ES), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Chartered Institute of Management Accountants (GB)
Openalex Percentile: Top 43%
Acute Myeloid Leukemia Research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.