Molecular predictors of anemia response to momelotinib in patients with myelofibrosis: Real-world outcomes from the momgemfin study.

Abstract In patients with myelofibrosis (MF), driver mutation status, presence of additional mutations (especially of high-molecular risk, HMR) and adverse karyotype all have prognostic value and, as a result, have been incorporated into recent prognostic models. Published data from several real-world studies on momelotinib-treated (MMB) MF patients confirm its efficacy—particularly in improving anemia and reducing transfusion dependence. The MOMGEMFIN study included 154 MF patients treated with MMB, 76.6% of which had prior JAK inhibitor exposure. At baseline, 70.1% were transfusion-dependent (TD). MMB led to a sustained improvement in anemia, with achievement of transfusion independence (TI) in 48.4% of TD patients at 3 months. However, there is still limited data regarding predictors of response based on patients' mutational profiles. In this context, we present the results of the molecular sub-analysis from the MOMGEMFIN project, which studied the impact of genetic profile on response to (MMB). The main variables analyzed were driver gene mutations and presence of additional mutations, evaluated with next-generation sequencing (NGS) using a myeloid gene panel. HMR were defined as presence of pathogenic/probable pathogenic mutation in ASXL1, EZH2, IDH1/2, SRSF2, U2AF1 genes. NGS data was available in 108 patients prior to MMB start. Sixty-two percent were male, with a median follow-up of 4.95 months. The most frequent driver mutation genotype was JAK2 (63%), followed by CALR (22.7%), triple negative (TN) (6.5%), MPL (5.8%), and unknown (1.9%). Among patients with NGS data, 63.9% harbored additional mutations, the most common being ASXL1 (34.3%), TET2 (14.8%), U2AF1 (11.1%), SRSF2 (8.3%), EZH2 (8.3%), SF3B1 (8.3%), RAS (7.4%), and IDH1/2 (3.7%). Among 122 patients with baseline anemia, no association was observed between anemia response (according to 2024 IWG-ELN criteria) and driver mutations. However, patients with additional mutations showed a trend toward poorer anemia response (>1 g/dL, p=0.013; >1.5 g/dL, p=0.002; Pearson), particularly those with a HMR. Statistical significance was not reached for individual genes, likely due to the small sample size, with the exception of U2AF1. Driver mutations had no significant impact on transfusion independence (TI, according to 2024 IWG-ELN criteria). However, only a third of patients with additional mutations achieved transfusion independence (15/45, 33.3%), compared to 55.6% of patients without an additional mutation (p=0.103). This decreased further to just 16.7% of patients with more than one HRM mutation (p=0.023). The presence of a U2AF1 mutation was significantly associated with not reaching TI (p=0.022). For the group of patients previously treated with JAK inhibitors (n=118), JAK2 mutation was associated with TI (p=0.008), whereas TN and MPL were negative predictors (p=0.067 and p=0.155). This trend was not observed for the JAK inhibitor-naïve group (p=0.053), likely due to the small sample size. Overall survival from the initiation of MMB differed significantly according to driver mutation status (p = 0.023; Log-rank test). Longer survival was observed in patients with JAK2 (mean: 11.7 months) and CALRmutations (mean: 13.7 months), whereas patients with MPL mutations or TN had shorter survival (mean: 7.0 and 7.1 months, respectively). Presence of additional mutation was not significant, but a negative trend was observed with U2AF1 and HMR. JAK2mut patients who had received prior JAK inhibitor treatment also showed superior OS compared to other driver mutations (p=0.042). The positive impact of JAK2mut on OS (p=0.034 Log-rank, JAK2mut vs. JAK2WT) was completely negated if patients also harbored a U2AF1 mutation (n=12 JAK2/U2AF1 co-mutated), with survival significantly reduced from MMB initiation (p=0.037) and from the time of diagnosis (p<0.001). Importantly, TI was associated with improved overall survival, both from diagnosis (p=0.012) and from MMB start (p=0.007). Conclusion These data show that U2AF1mut correlates with a lower probability of TI in MMB treated patients. The JAK2 driver mutation was associated with a better response to MMB with the exception of those with a U2AF1 co-mutation. Transfusion dependence negatively impacted overall survival, consistent with published data.

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Blood
Published
2025-11-03
DOI
https://doi.org/10.1182/blood-2025-3808
Primary Topic
Myeloproliferative Neoplasms: Diagnosis and Treatment
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article
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article

Molecular predictors of anemia response to momelotinib in patients with myelofibrosis: Real-world outcomes from the momgemfin study.

alberto Alvarez-Larran, Francisca Ferrer‐Marín, Patricia Sastre, Fernando Marco De Lucas et al.
Blood
Myeloproliferative Neoplasms: Diagnosis and Treatment
article

Molecular predictors of anemia response to momelotinib in patients with myelofibrosis: Real-world outcomes from the momgemfin study.

alberto Alvarez-Larran, Francisca Ferrer‐Marín, Patricia Sastre, Fernando Marco De Lucas, Inmaculada Castillo Valero, Luis Antonio López Gómez, Ruth Stuckey, Mercedes Gasior Kabat, Aurelia Tejedor, Ángela Gil, Esther Herrera de Pablo, Javier Fernández, Adrián Segura Díaz, Daniel Carvajal, Leonardo Lamas, Eloi Cañamero, Pablo Lorente, Irene Pastor Galan, Wladimiro Jiménez, Maria Isabel Mata Vazquez, Manuel Pérez‐Encinas, Teresa Cobo, Valentín García‐Gutiérrez, Anna Angona, María Laura Fox, Marta Santaliestra, Erik de Cabo, Elvira Mora, Paola Beneit Villena, Carlos Aguilar-Franco, Beatriz Cuevas Ruiz, Raisa Peralta, Sandra Piquer, Sara Garrido Paniagua, Marta Fonseca Santos, Teresa Arquero‐Portero, Alberto Marin Sanchez, Begoña Navas Elorza, Julio Dávila, Reyes Jiménez‐Bárcenas, Sandra Martín, Ángeles Fernández Rodríguez, Raúl Pérez López, Federico Herrera, Natalia De Las Heras Rodríguez, Rosalía Delapuerta, Blanca Xicoy, Juan Carlos Hernández‐Boluda, Regina García Delgado, María José Otero Martínez-Fornes, Sonia González de Villambrosía, Juan Antonio Juan Vera Goñi, Raquel Mata Serna, Ángela Martínez Hellin, Gemma Azaceta, María Luisa Martín Mateos, Francisco Pérez, María Teresa Gómez‐Casares, María Antonia Durán, Álvaro Lorenzo Vizcaya, Simone G. Ramos, Marina Menéndez Cuevas, María José Llácer Ferrandis, Carmen Albo Lopez, María José Fernández, Patricia Vélez, A Domingo, Aitor Abuín Blanco, Gonzalo Carreño, Lucía Núñez Martín-Buitrago, Neus Amer Salas, María Pérez Sala, D. de Miguel Llorente, Míriam Vara Pampliega, María Alicia Senin, Adriana Hernando Megido, Carolina Guillén Rienda, Laura Lamarca Eraso, Iryna Luts Khoroz, Antonio García Menchon, Teresa Hernández Santamaría, Ma Ángeles Muñoz Jarreño
article en

Abstract

Abstract In patients with myelofibrosis (MF), driver mutation status, presence of additional mutations (especially of high-molecular risk, HMR) and adverse karyotype all have prognostic value and, as a result, have been incorporated into recent prognostic models. Published data from several real-world studies on momelotinib-treated (MMB) MF patients confirm its efficacy—particularly in improving anemia and reducing transfusion dependence. The MOMGEMFIN study included 154 MF patients treated with MMB, 76.6% of which had prior JAK inhibitor exposure. At baseline, 70.1% were transfusion-dependent (TD). MMB led to a sustained improvement in anemia, with achievement of transfusion independence (TI) in 48.4% of TD patients at 3 months. However, there is still limited data regarding predictors of response based on patients' mutational profiles. In this context, we present the results of the molecular sub-analysis from the MOMGEMFIN project, which studied the impact of genetic profile on response to (MMB). The main variables analyzed were driver gene mutations and presence of additional mutations, evaluated with next-generation sequencing (NGS) using a myeloid gene panel. HMR were defined as presence of pathogenic/probable pathogenic mutation in ASXL1, EZH2, IDH1/2, SRSF2, U2AF1 genes. NGS data was available in 108 patients prior to MMB start. Sixty-two percent were male, with a median follow-up of 4.95 months. The most frequent driver mutation genotype was JAK2 (63%), followed by CALR (22.7%), triple negative (TN) (6.5%), MPL (5.8%), and unknown (1.9%). Among patients with NGS data, 63.9% harbored additional mutations, the most common being ASXL1 (34.3%), TET2 (14.8%), U2AF1 (11.1%), SRSF2 (8.3%), EZH2 (8.3%), SF3B1 (8.3%), RAS (7.4%), and IDH1/2 (3.7%). Among 122 patients with baseline anemia, no association was observed between anemia response (according to 2024 IWG-ELN criteria) and driver mutations. However, patients with additional mutations showed a trend toward poorer anemia response (>1 g/dL, p=0.013; >1.5 g/dL, p=0.002; Pearson), particularly those with a HMR. Statistical significance was not reached for individual genes, likely due to the small sample size, with the exception of U2AF1. Driver mutations had no significant impact on transfusion independence (TI, according to 2024 IWG-ELN criteria). However, only a third of patients with additional mutations achieved transfusion independence (15/45, 33.3%), compared to 55.6% of patients without an additional mutation (p=0.103). This decreased further to just 16.7% of patients with more than one HRM mutation (p=0.023). The presence of a U2AF1 mutation was significantly associated with not reaching TI (p=0.022). For the group of patients previously treated with JAK inhibitors (n=118), JAK2 mutation was associated with TI (p=0.008), whereas TN and MPL were negative predictors (p=0.067 and p=0.155). This trend was not observed for the JAK inhibitor-naïve group (p=0.053), likely due to the small sample size. Overall survival from the initiation of MMB differed significantly according to driver mutation status (p = 0.023; Log-rank test). Longer survival was observed in patients with JAK2 (mean: 11.7 months) and CALRmutations (mean: 13.7 months), whereas patients with MPL mutations or TN had shorter survival (mean: 7.0 and 7.1 months, respectively). Presence of additional mutation was not significant, but a negative trend was observed with U2AF1 and HMR. JAK2mut patients who had received prior JAK inhibitor treatment also showed superior OS compared to other driver mutations (p=0.042). The positive impact of JAK2mut on OS (p=0.034 Log-rank, JAK2mut vs. JAK2WT) was completely negated if patients also harbored a U2AF1 mutation (n=12 JAK2/U2AF1 co-mutated), with survival significantly reduced from MMB initiation (p=0.037) and from the time of diagnosis (p<0.001). Importantly, TI was associated with improved overall survival, both from diagnosis (p=0.012) and from MMB start (p=0.007). Conclusion These data show that U2AF1mut correlates with a lower probability of TI in MMB treated patients. The JAK2 driver mutation was associated with a better response to MMB with the exception of those with a U2AF1 co-mutation. Transfusion dependence negatively impacted overall survival, consistent with published data.

BloodVol. 146(Supplement 1)
Universitat de Miguel Hernández d'Elx (ES), Hebron University (PS), Universidad Rey Juan Carlos (ES), Universidade de Santiago de Compostela (ES), Hospital Universitario La Paz (ES), Santa Barbara Cottage Hospital (US), University Hospital Complex Of Vigo (ES), Hospital General Universitario Gregorio Marañón (ES), Hospital Clínico San Carlos (ES), Hospital Universitari i Politècnic La Fe (ES), Institut d'Investigació Biomédica de Bellvitge (ES), Hospital Costa del Sol (ES), Hospital Son Llatzer (ES), Josep Carreras Leukaemia Research Institute (ES), Hospital Universitario Virgen Macarena (ES), Hospital General Universitario Morales Meseguer (ES), Hospital Universitari Sant Joan D'Alacant (ES), Galicia Sur Biomedical Foundation (ES), Hospital Virgen de la Luz (ES), Hospital de Basurto (ES), Hospital General Nuestra Señora del Prado (ES), Hospital Universitario de Guadalajara (ES), Hospital Clínico Universitario de Valencia (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), Hospital Universitario Rey Juan Carlos (ES), Hospital Universitario 12 De Octubre (ES), Hospital Royo Villanova (ES), Vall d'Hebron Institut de Recerca (ES), Hospital Universitario de Getafe (ES), Hospital Universitario Puerta de Hierro Majadahonda (ES), Hospital Rafael Méndez (ES), Hospital Regional Universitario de Málaga (ES), Spanish Clinical Research Network (ES), Instituto de Investigación Biosanitaria de Granada (ES), Hospital Clínic de Barcelona (ES), Hospital Universitario de Burgos (ES), Hospital General Universitario de Elche (ES), Hospital General Universitario de Ciudad Real (ES), Hospital Arnau de Vilanova (ES), Hospital El Bierzo (ES), Hospital General Universitari de Castelló (ES), Hospital Universitario Doctor Peset (ES), Hospital Universitario del Sureste (ES), Mother Hospital (IN), Instituto Ramón y Cajal de Investigación Sanitaria (ES), Vall d'Hebron Hospital Universitari (ES), Hospital General Universitario De Valencia (ES), Hospital Universitario Fundación Jiménez Díaz (ES), Mútua Terrassa (ES), Hospital Del Mar (ES), Hospital de Sant Joan Despí Moisès Broggi (ES), Hospital Universitario Central de Asturias (ES), Hospital de Mataró (ES), Clinica Universidad de Navarra (ES), Hospital Clínico Universitario Lozano Blesa (ES), Hospital de Cruces (ES), Centro de Implantología Cirugía Oral y Maxilofacial (ES), Donostiako Unibertsitate Ospitalea (ES), Duran i Reynals Hospital (ES), Hospital Universitario Lucus Augusti (ES), Hospital General Universitario de Albacete (ES), Santa Lucía University General Hospital (ES), Hospital General de Elda (ES), Hospital Universitario De Cabueñes (ES), Hospital Universitario Virgen de la Arrixaca (ES), Hospital Universitario Lluís Alcanyís (ES), Hospital Universitario del Henares (ES), Hospital Universitario Son Espases (ES), Hospital Universitari de Girona Doctor Josep Trueta (ES), Hospital Clínico Universitario Virgen de la Victoria (ES), INCLIVA Health Research Institute (ES), Hospital Universitario de León (ES), Hospital Central de la Defensa Gómez Ulla (ES), Hospital Nuestra Señora de Alarcos (ES), Universidad de Málaga (ES), Universidad de Navarra (ES)
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Myeloproliferative Neoplasms: Diagnosis and Treatment
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