Calr Vs. JAK2 Vs. MPL Mutations in the Progression of Philadelphia-Negative Myeloproliferative Neoplasms

Objective: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic disorders characterized by proliferation in one or more myeloid lineages. The classical Philadelphia (Ph) chromosome-negative MPN includes polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). All of these diseases are associated with an increased risk of thrombo-hemorrhagic complications, progression to myelofibrosis or acute leukemia transformation, which remains the primary source of mortality. Mutations in JAK2 (JAK2^V617Fand JAK2 exon 12), MPL (MPL^W515L/K) and CALR have been identified as the driver of MPN, and thus included as the major diagnostic criteria for MPN in the 2008 WHO diagnostic criteria. It has been reported that patients bearing similar JAK2 mutations may present different phenotypes of MPNs. In addition, these gene mutations are involved in heterogeneity in clinical manifestations and different natural histories with progression to post polycythemia vera/essential thrombocytosis myelofibrosis (post-PV/ET MF) and acute myeloid leukemia (AML). The main purpose of the current study is to investigate the effects of recurrent gene mutations (CALR/JAK2/MPL) on the overall survival (OS) and progression with a cohort of 1353 Chinese patients with different subtypes of MPNs.

Methods: In the current study, a cohort of 1353 MPN patients were screened for mutations in JAK2 (exon 12), CALR (exon nine), and MPL exon (ten). MPN patients were divided into seven groups according to the clinical diagnosis and mutations: CALR mutated PMF or ET patients, JAK2 mutated PV, ET or PMF patients, and triple (CALR / JAK2 / MPL) negative PMF or ET patients. Overall survival (OS) was calculated from the time of diagnosis of MPN to death or the last follow-up. Myelofibrosis-free survival (MFS) and leukemia-free survival (LFS) were calculated from the time of diagnosis of PV/ET/PMF to the occurrence of post-ET/PV MF, leukemia, death or the last follow-up.

Results: Multivariate analysis indicates that triple-negative mutation of CALR/JAK2/MPL is an independent risk factor of poor OS (HR = 2.47, 95%CI: 1.17-5.22; p= 0.018) as well as leukemia-free survival (LFS, HR = 2.83, 95%CI: 1.19-6.72; p= 0.013) in patients with PMF, but not those with ET. Compare to JAK2 mutation, CALR mutations do not correlate with significantly better OS (p= 0.59) or LFS (p= 0.748) in PMF patients. Interestingly, CALR mutated ET patients have a trend of worse myelofibrosis-free survival rate (MFS) than triple-negative patients, while similar to that of patients with JAK2 mutation (p= 0.93).The multivariable analyses, including age and sex,reveal that JAK2 mutated PV patients (HR = 2.51, 95%CI: 1.55-4.05; p < 0.001) have a higher risk of fibrotic transformation than ET patientswith the JAK2 mutation.

Conclusion: Triple-negative mutation is a worse prognostic factor in PMF patients; JAK2 mutated PV patients have a worse MFS compared toET patientswith JAK2 mutation.