Molecular predictors of anemia response to momelotinib in patients with myelofibrosis: Real-world outcomes from the momgemfin study.
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.
Article Details
Authors (82)
Adrian Segura Diaz
1H. U. Dr. Negrin de Gran Canaria, Las Palmas, Spain
Lucia Perez Lamas
2Hospital Universitario Puerta de Hierro, Majadahonda, Spain
Ruth Stuckey
9Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas, Spain
alberto Alvarez-Larran
3Hospital Clínic, Barcelona, Barcelona, Spain
María Alicia Senin
4Institut Català d'Oncologia, Hospital Duran i Reynals. Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
Elvira Mora Casterá
5Hospital Universitario y Politécnico La Fe, Valencia, Spain
Paula Sastre
3Hospital Clínic, Barcelona, Barcelona, Spain
Maria Laura Fox
6Hospital Universitario Vall d'Hebron, Barcelona, Spain
Irene Pastor Galan
7Hospital Clínico Universitario-INCLIVA, Valencia, Spain
Maria Teresa Gomez Casares
Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain
Gemma Azaceta
8Hospital Clínico Universitario Lozano Blesa de Zaragoza, Zaragoza, Spain
Sara Garrido Paniagua
1Vall d'Hebron Hospital, Department of Hematology, BARCELONA, Spain
Raul Perez Lopez
14Hospital Clínico Universitario Virgen de la Arrixaca, Murcia. Instituto Murciano de Investigación Biosanitaria Pascual Parrilla–IMIB., Murcia, Spain
Diana Margarita Trejos Carvajal
11Hospital General de Castellon, CASTELLON, Spain
Anna Angona
12Hospital Universitario Doctor Josep Trueta - ICO, Barcelona, Spain
Carmen Albo Lopez
2Instituto de Investigacion Sanitaria Galicia-Sur, Vigo, Spain
Pablo Lorente
14Hospital Arnau de Vilanova, Valencia, Spain
Regina Garcia Delgado
15Hospital Universitario Virgen de la Victoria, Malaga, Spain
Míriam Vara Pampliega
10Hospital Universitario de Cruces, Bizkaia, Spain
Juan Antonio Juan Vera Goñi
17Hospital Virgen Macarena, Sevilla, Spain
Dunia De Miguel Llorente
18Hospital Universitario de Guadalajara, Guadalajara, Spain
Angeles Fernández Rodríguez
19HOSPITAL UNIVERSITARIO CENTRAL DE ASTURIAS, OVIEDO, Spain
Alberto Marin Sanchez
20Hospital General Universitario De Albacete, Albacete, Spain
Adriana Hernando Megido
21Hospital Universitario de Cabueñes, GIJÓN, Spain
Gonzalo Carreño
22Hospital Universitario 12 de Octubre, Madrid, Spain
Natalia De Las Heras Rodriguez
23Hospital Universitario de León, León, Spain
Blanca Xicoy
3Hematology Service, Institut Català d'Oncologia. Hospital Germans Trias i Pujol, Institut de Recerca Contra la Leucèmia Josep Carreras, Badalona, Spain
Manuel Perez Encinas
34Hospital Clínico Universitario de Santiago, USC, Santiago de Compostela, Spain
Raquel Mata Serna
26Fundación Jiménez Díaz, Madrid, Spain
Lucia Nuñez Martin-Buitrago
27HOSPITAL GENERAL LA MANCHA CENTRO, Ciudad Real, Spain
Francisca Ferrer Marin
28Morales Meseguer University General Hospital, Regional Center of Blood Donation. CIBERER. UCAM. IMIB-Murcia, Murcia, Spain
Neus Amer Salas
29Hospital Universitario Son Llàtzer, Palma de Mallorca, Spain
Carolina Guillén Rienda
30Clínica Universidad de Navarra, Pamplona, Spain
Patricia Velez
Laura Lamarca Eraso
32Hospital Santa Ana de Motril, Motril, Spain
Sandra Martín
33Hospital Regional Universitario de Málaga, Malaga, Spain
Iryna Luts Khoroz
34Hospital Nuestra Señora del Prado, Talavera de la Reina, Spain
Abel Domingo
35H. Moises Broggi (ICO-H), Barcelona, Spain
Erik De Cabo López
36Hospital del Bierzo, Ponferrada, Spain
Angela Gil
37Hospital Universitario de Guadalajara, Guadalajara, Spain
Sofía Martín-Consuegra Ramos
38Hospital de Alcañiz, TERUEL, Spain
Fernando Marco De Lucas
39Servicio de Hematología, Hospital Universitario Basurto, Bilbao, Spain
Maria José Otero Martinez-Fornes
40Hospital Gómez Ulla, Madrid, Spain
María Luisa Martín Mateos
41Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
Teresa Arquero-Portero
26Fundación Jiménez Díaz, Madrid, Spain
Luis Antonio López Gómez
42Hospital Royo Villanova, Zaragoza, Spain
Angela Martinez Hellin
43HOSPITAL UNIVERSITARIO CLINICO SAN CECILIO, Granada, Spain
Aurelia Tejedor
44Hospital Universitario Santa Lucia, CARTAGENA, Spain
Esther Herrera de Pablo
45hosptial lluís Alcayís, Valencia, Spain
Maria Isabel Mata Vazquez
46Hospital Costa del Sol, Marbella, Spain
Inmaculada Castillo Valero
47HOSPITAL UNIVERSITARIO LA PLANA, VILLARREAL, Spain
Maria Jose Fernández
48Hospital Universitario Doctor Peset, Valencia, Spain
Carlos Aguilar-Franco
49Hospital Santa Barbara, Soria, Spain
Marta Santaliestra
50Hospital Universitari Mútua Terrassa, TARRASA, Spain
Antonio Garcia Menchon
51Hospital Rafael Méndez, Lorca, Spain
Begona Navas Elorza
52Hospital Clinico San Carlos, Madrid, Spain
Maria Antonia Duran
53Hospital Son Espases, Palma de Mallorca, Spain
María Pérez Sala
54Hospital de Elda, ELDA, Spain
Teresa Hernández Santamaría
55HOSPITAL UNIVERSITARIO DONOSTIA, San Sabastian, Spain
Mª Ángeles Muñoz Jarreño
56Hospital del Henares, Madrid, Spain
Julio Davila Valls
57Hospital Universitario Nuestra Senora de Sonsoles, Avila, Spain
Williana Torres Jiménez
58Hospital Virgen de la luz, CUENCA, Spain
Joan Alfons Gonzálvez Fernández
59Hospital General Universitario de Elche, ELCHE, Spain
Teresa Cobo
60Hospital Universitario del Sureste, Madrid, Spain
Aitor Abuin Blanco
61Hospital Clínico de Santiago de Compostela, SANTIAGO DE COMPOSTELA, Spain
Francisco Perez
Maria José Llácer Ferrandis
1Hospital General Universitario Gregorio Marañón, Department of Hematology and Hemotherapy, Madrid, Spain
Paola Beneit Villena
64Hospital San Juan de Alicante, Alicante, Spain
Raisa Peralta
65CLINICA SAN MIGUEL, Pamplona, Spain
Federico Herrera
66Hospital Universitario de Getafe, Getafe, Spain
Eloi Cañamero Giro
67Hospital de Mataró, Barcelona, Spain
Reyes Jimenez Barcenas
68Hospital Serrania de Ronda, Malaga, Spain
Mercedes Gasior Kabat
69Hospital La Paz, Madrid, Spain
Sonia González De Villambrosia
70Hospital Marques de Valdecilla, Santander, Spain
Marina Menéndez Cuevas
71Hospital Rey Juan Carlos, Madrid, Spain
Beatriz Cuevas Ruiz
72HOSPITAL UNIVERSITARIO DE BURGOS, Burgos, Spain
Marta Fonseca-Santos
1University Hospital of Salamanca, Hematology, Salamanca, Spain
Sonia Garcés Piquer
74hospital General de Valencia, Valencia, Spain
Rosalía Delapuerta
75HVA, Valencia, Spain
Alvaro Lorenzo Vizcaya
76Hospital Universitario Lucus Augusti, Lugo, Spain
Juan Carlos Hernandez Boluda
7Hospital Clínico Universitario-INCLIVA, Valencia, Spain
Valentín García Gutiérrez
8Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain