Molecular markers as possible efficacy predictors of targeted therapy for myelofibrosis: single-center study
https://doi.org/10.17650/1818-8346-2023-18-4-115-134
Abstract
Background. Targeted therapy is the most promising in the treatment of myelofibrosis, but it is necessary to search for the reasons limiting its effectiveness. There are known factors negatively affecting the development of myelofibrosis, but data on their negative impact in the context of targeted therapy are scarce.
Aim. Assessing the impact of cytogenetic and genetic abnormalities on the course and therapy results for primary and secondary myelofibrosis during ruxolitinib therapy.
Materials and methods. The prospective study included 106 patients with myelofibrosis in the chronic phase (53 (50 %) men and 53 (50 %) women) who received ruxolitinib at the Moscow City Hematology Center, S.P. Botkin City Clinical Hospital. The median age of patients was 62 (18–84) years. The median disease duration before initiation of ruxolitinib therapy was 79 (1–432) months. Before therapy, genetic studies were performed, including next-generation sequencing. The median duration of ruxolitinib therapy was 33 (1–111) months. The influence of the cytogenetic landscape, driver mutations, allele burden of JAK2 (over time) and CALR, additional mutations on the dynamics of symptoms, spleen size, achievement of hematological response, overall survival, progression-free survival, survival without blast crisis and without progression of myelofibrosis with targeted therapy was assessed.
Results. The studied genetic factors did not have a significant correlation with hemogram parameters. The hematological response in patients with JAK2 and CALR mutations compared favorably with the response in the groups with the MPL mutation and triple negative status (TNS). Higher hematological response rate was obtained in the group with initially low allele burden <50 % of JAK2 or CALR. Significant differences in 5-year overall survival were found between groups of patients with TNS and JAK2 and CALR mutations (p <0.05); with CALR allele burden <50 % and ³50 % before initiation of ruxolitinib therapy (p = 0.01); the presence or absence of positive dynamics of the JAK2 allele burden during treatment (p <0.05); additional mutations assigned to different pathogenicity groups (p <0.05); with different number of pathogenic mutations (1 or ³2), the presence or absence of pathogenic mutations in the ASXL1 (p = 0.002) and SETBP1 (p = 0.00001) genes. The 5-year progression-free survival was significantly different in cohorts of patients with or without positive dynamics of the JAK2 allelic load during treatment (p <0.05); additional mutations assigned to different pathogenicity groups (p <0.05); with a different number of pathogenic mutations (1 or ³2), the presence or absence of a pathogenic mutation of the SETBP1 gene (p = 0.003). Progression-free survival did not correlate with the type of driver mutation or its absence; however, all patients with TNS died from myelofibrosis progression. Significant differences in 5-year blast crisis-free survival were observed between groups with JAK2 and MPL mutations (p = 0.001), JAK2 and TNS (p = 0.002); difference in 5-year survival without progression of fibrosis – between groups with pathogenic and benign (p = 0.031); uncertain and benign (p = 0.001) mutations.
Conclusion. The study identified genetic markers associated with decreased efficacy of ruxolitinib therapy.
Keywords
About the Authors
O. Yu. VinogradovaRussian Federation
Department of Oncology, Hematology and Radiation Therapy, Faculty of Pediatrics, N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284,
1 Samory Mashela St., Moscow 117997,
1 Ostrovityanova St., Moscow 117997
D. I. Shikhbabaeva
Russian Federation
Dzhariyat I. Shikhbabaeva
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284
Yu. N. Kobzev
Russian Federation
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284
A. L. Neverova
Russian Federation
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284
M. M. Pankraskina
Russian Federation
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284
S. G. Malakho
Russian Federation
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284
M. V. Chernikov
Russian Federation
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284
M. A. Murzabekova
Russian Federation
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284
A. G. Popova
Russian Federation
Department of Oncology, Hematology and Radiation Therapy, Faculty of Pediatrics
1 Ostrovityanova St., Moscow 117997
L. B. Egoryan
Russian Federation
Department of Hematology and Transfusiology named after. acad. I.A. Kassirskiy and A.I. Vorobyov
Build. 1, 2/1 Barrikadnaya St., Moscow 125993
A. V. Krechetova
Russian Federation
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284
V. V. Ptushkin
Russian Federation
Department of Oncology, Hematology and Radiation Therapy, Faculty of Pediatrics, N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia;
Department of Hematology and Transfusiology named after. acad. I.A. Kassirskiy and A.I. Vorobyov, Russian Medical Academy of Continuing Professional Education, Ministry of Health of Russia
Build 17, 5 2nd Botkinskiy Proezd, Moscow 125284,
1 Samory Mashela St., Moscow 117997,
1 Ostrovityanova St., Moscow 117997,
Build. 1, 2/1 Barrikadnaya St., Moscow 125993
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Review
For citations:
Vinogradova O.Yu., Shikhbabaeva D.I., Kobzev Yu.N., Neverova A.L., Pankraskina M.M., Malakho S.G., Chernikov M.V., Murzabekova M.A., Popova A.G., Egoryan L.B., Krechetova A.V., Ptushkin V.V. Molecular markers as possible efficacy predictors of targeted therapy for myelofibrosis: single-center study. Oncohematology. 2023;18(4):115-134. (In Russ.) https://doi.org/10.17650/1818-8346-2023-18-4-115-134