Outcomes and effect of somatic mutations after erythropoiesis stimulating agents in patients with lower-risk myelodysplastic syndromes

Juan Carlos Caballero; Julio Dávila; María López-Pavía; Esperanza Such; Teresa Bernal; Fernando Ramos; Marisa Calabuig; Jesús María Hernández Sánchez; Helena Pomares; Mercedes Sánchez Barba; María Abáigar; Bernardo González; Brayan Merchán; Reyes Sancho-Tello; Marta Callejas; Carolina Muñoz-Novas; Carlos Cerveró; Guillermo Sanz; Jesús María Hernández Rivas; María Díez Campelo

doi:10.1177/20406207231218157

Outcomes and effect of somatic mutations after erythropoiesis stimulating agents in patients with lower-risk myelodysplastic syndromes

Ther Adv Hematol. 2024 Jan 4:15:20406207231218157. doi: 10.1177/20406207231218157. eCollection 2024.

Authors

Juan Carlos Caballero¹, Julio Dávila², María López-Pavía^{3

4

5}, Esperanza Such^{3

4

5}, Teresa Bernal⁶, Fernando Ramos⁷, Marisa Calabuig⁸, Jesús María Hernández Sánchez⁹, Helena Pomares¹⁰, Mercedes Sánchez Barba¹¹, María Abáigar⁹, Bernardo González¹², Brayan Merchán¹³, Reyes Sancho-Tello¹⁴, Marta Callejas¹⁵, Carolina Muñoz-Novas¹⁶, Carlos Cerveró¹⁷, Guillermo Sanz^{3

4

5}, Jesús María Hernández Rivas^{18

19

20}, María Díez Campelo^{21

20}

Affiliations

¹ Hematology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.
² Hematology Department, Hospital Nuestra Señora de Sonsoles, Ávila, Spain.
³ Hematology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
⁴ CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
⁵ Universidad de Valencia, Valencia, Spain.
⁶ Hematology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.
⁷ Hematology Department, Hospital Universitario de León, León, Spain.
⁸ Hematology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain.
⁹ Instituto de Biología Molecular y Celular del Cáncer, Instituto Biosanitario de Salamanca, Centro de Investigación del Cáncer, USAL-CSIC, Salamanca, Spain.
¹⁰ Hematology Department, Hospital Universitario de Bellvitge-Hospital Duran I Reynals, Instituto Catalán de Oncología, L'Hospitalet del Llobregat, Spain.
¹¹ Statistics Department, Universidad de Salamanca, Salamanca, Spain.
¹² Hematology Department, Hospital Universitario de Canarias, La Laguna, Spain.
¹³ Hematology Department, Hospital Universitario Vall d'Hebron, Barcelona, Spain.
¹⁴ Hematology Department, Hospital Arnau de Vilanova, Valencia, Spain.
¹⁵ Hematology Department, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain.
¹⁶ Hematology Department, Hospital Universitario Infanta Leonor, Madrid, Spain.
¹⁷ Hematology Department, Hospital Virgen de la Luz, Cuenca, Spain.
¹⁸ Instituto de Biología Molecular y Celular del Cáncer, Instituto Biosanitario de Salamanca, Centro de Investigación del Cáncer, USAL-CSIC, Salamanca, Spain Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain Instituto Biosanitario de Salamanca, Salamanca, Spain.
¹⁹ Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain Instituto Biosanitario de Salamanca, Salamanca, Spain.
²⁰ Instituto Biosanitario de Salamanca, Salamanca, Spain.
²¹ Hematology Department, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, Salamanca 37007, Spain.

Abstract

Background: Erythropoiesis stimulating agents (ESAs) are the first-line therapy in patients with lower-risk myelodysplastic syndromes (LR-MDS). Some predictive factors for ESAs response have been identified. Type and number of somatic mutations have been associated with prognosis and response to therapies in MDS patients.

Objectives: The objective was to evaluate the outcomes after ESAs in patients with LR-MDS and to address the potential predictive value of somatic mutations in ESAs-treated patients.

Design: Multi-center retrospective study of a cohort of 722 patients with LR-MDS included in the SPRESAS (Spanish Registry of Erythropoietic Stimulating Agents Study) study. Retrospective analysis of 65 patients with next generation sequencing (NGS) data from diagnosis.

Methods: ESAs' efficacy and safety were evaluated in patients receiving ESAs and best supportive care (BSC). To assess the potential prognostic value of somatic mutations in erythroid response (ER) rate and outcome, NGS was performed in responders and non-responders.

Results: ER rate for ESAs-treated patients was 65%. Serum erythropoietin (EPO) level <200 U/l was the only variable significantly associated with a higher ER rate (odds ratio, 2.45; p = 0.036). Median overall survival (OS) in patients treated with ESAs was 6.7 versus 3.1 years in patients receiving BSC (p < 0.001). From 65 patients with NGS data, 57 (87.7%) have at least one mutation. We observed a trend to a higher frequency of ER among patients with a lower number of mutated genes (40.4% in <3 mutated genes versus 22.2% in ⩾3; p = 0.170). The presence of ⩾3 mutated genes was also significantly associated with worse OS (hazard ratio, 2.8; p = 0.015), even in responders. A higher cumulative incidence of acute myeloid leukemia progression at 5 years was also observed in patients with ⩾3 mutated genes versus <3 (33.3% and 10.7%, respectively; p < 0.001).

Conclusion: This large study confirms the beneficial effect of ESAs and the adverse effect of somatic mutations in patients with LR-MDS.

Keywords: erythropoiesis stimulating agents; lower-risk myelodysplastic syndromes; myelodysplastic syndromes; next generation sequencing; somatic mutations.