Incidence, risk factors, and survival impact of secondary myelofibrosis in patients with myeloproliferative neoplasms in the real world: A nested case-control study

Abstract

Abstract Myeloproliferative neoplasms (MPN) are a group of diseases characterized by clonal proliferation of hematopoietic stem cells in the bone marrow, mainly including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Some patients with PV/ET will progress to secondary myelofibrosis (post-PV/ET MF), which seriously affects prognosis. Secondary myelofibrosis increases complications such as splenomegaly, cytopenia, and systemic symptoms in patients. Currently, the research on MPN secondary MF is mainly based on clinical trials or single-center retrospective data. The risk factors for secondary MF in MPN remain unclear. This study aims to clarify the risk factors for MPN secondary MF and further explore the risk factors and prognosis of MPN secondary MF by conducting a nested case-control study based on real-world data.This is a real-world database of 2379 patients with myeloproliferative neoplasms.Based on this database, the case group was defined as: patients diagnosed with MPN and who met the WHO criteria for secondary MF after bone marrow biopsy (fibrosis grade≥MF-2), excluding those with primary MF or those with other hematological malignancies; patients in the control group were matched 1:2 based on propensity score, and the baseline conditions of clinical characteristics, gene mutations, and treatment of MPN patients were included. Fine-Gray method was used to calculate the cumulative incidence rate with death as the competing event. Kaplan-Meier survival analysis and multivariate Cox regression analysis were used to determine the risk factors and survival status of patients with secondary bone marrow fibrosis in patients with myeloproliferative neoplasms.The median follow-up time for the 2379 MPN patients was 8 (1-47) years. The proportions of patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) were 54.4%, 34.7%, and 10.9%, respectively. The proportions of patients with JAK2V617Fmutation, JAK2exon12 mutation, CALR mutation, MPLmutation, and triple-negative mutation were 79.6%, 3.2%, 5.9%, 1.5%, and 9.8%, respectively. The incidence of myelofibrosis was 2.45/100 (95% CI [1.15/100, 4.15/100]) person-years. In this study, there were 121 patients in the secondary myelofibrosis group in JAK2V617F mutated MPN, and the control group, which did not have secondary myelofibrosis, was matched with the secondary myelofibrosis group at a ratio of 1:2, totaling 242 patients. By comparing the baseline characteristics of the two groups, the secondary myelofibrosis group had significantly higher levels of hematocrit, monocyte proportion, JAK2V617F allele burden（V617F%）, and the proportion of patients with splenomegaly compared to the control group (P<0.05). The proportion of DTA mutations(44.8% vs 27%，P=0.019), ASXL1mutations(17.2 vs 6.6，P=0.033), and spliceosome-related gene mutations(3.7 vs 1.7，P=0.047) was significantly higher in the secondary myelofibrosis group than in the control group (P<0.05). By comparing the genetic landscape of patients with JAK2V617F mutation in PV, ET, post-PV MF, and post-ET MF, the results showed that the proportions of ASXL1 and DTA mutations in JAK2V617Fmutation PV and ET patients were significantly lower than those in JAK2V617F mutation post-PV MF and post-ET MF patients. Moreover, the V617F%, ASXL1, and DTA mutation loads were significantly lower in JAK2V617F mutation post-PV MF and post-ET MF patients. Multivariate Cox analysis showed that age≥60years (P<0.0001, HR = 3.028, 95% confidence interval [2.75, 5.9]), white blood cell count≥15×109/L (P=0.023, HR = 1.627, 95% confidence interval [1.066, 2.188]), ASXL1 mutation (P = 0.034, HR = 1.114, 95% confidence interval [1.019, 1.326]), V617F%>50% (P=0.001, HR = 3.312, 95% confidence interval [1.205, 5.673]) and splenomegaly (P=0.044, HR = 1.014, 95% confidence interval [1.011, 1.126]) were risk factors for secondary myelofibrosis in patients with myeloproliferative neoplasms.In conclusion, our study systematically revealed the risk of bone marrow fibrosis transformation in the patient population with myeloproliferative neoplasms (MPN) in the real world as we found that age, white blood cell count, splenomegaly, V617F%, and ASXL1mutation are independent adverse prognostic factors for secondary bone marrow fibrosis. For these patients, early intervention is urgently needed to prevent the disease from progressing to the terminal stage.