ABSTRACT: Background The BCR-ABL-negative myeloproliferative neoplasms, i.e., polycythemia vera, essential thrombocythemia (ET), and myelofibrosis (MF), are characterized by mutations in JAK2, CALR, or MPL.
Immune thrombocytopenia is associated with persistently deranged fibrosis-related seromarker profiles but low bone marrow fibrosis grades: A 2-year observational study on thrombopoietin receptor agonist treatment.
The discovery of mutations in JAK2, CALR, and MPL have uncovered activated JAK-STAT signaling as a primary driver of MF, supporting a rationale for JAK inhibition.
Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays.
Concurrently, numerous studies dealt with clinical issues; it led to a revised WHO classification; clarified the role of mutated JAK2 and leukocytosis in the pathogenesis of cardiovascular events; allowed the development of risk prognostic scores and tools for monitoring response to therapy; and resulted in completion of Phase III trials with JAK2 inhibitor in myelofibrosis.
Moreover, 4 therapeutic JAK2 inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) have either been approved or are in advanced clinical development for myelofibrosis.
For the current study, the authors explored the relation between specific cytogenetic clones and JAK2(V617F) mutational status in patients with MMM and the effects on treatment response to erythropoietin (Epo).
Treatment of patients with myelofibrosis with the type I JAK (Janus kinase) inhibitor ruxolitinib paradoxically induces JAK2 activation loop phosphorylation and is associated with a life-threatening cytokine-rebound syndrome if rapidly withdrawn.
The in vitro treatment of splenic and peripheral blood MF CD34(+) cells with the JAK1/2/3 inhibitor, AZD1480, reduced the absolute number of CD34(+), CD34(+)CD90(+), and CD34(+)CXCR4(+) cells as well as assayable hematopoietic progenitor cells (HPCs) irrespective of the JAK2 and calreticulin mutational status.
Whether noncanonical and/or concomitant JAK2- and MPL-mutations exist in myelofibrosis (MF) regardless of phenotype-driver mutations is not yet elucidated.
Based on available information about the role of cytokines in the pathogenesis of myelofibrosis, the hypothesis that the clinical efficacy of JAK2-inhibitors could be mainly ascribed to a general down-regulation of cytokine production and cytokine signaling is discussed.
The objective of the current study was to examine the impact of CALR mutation variant stratified driver mutational status on overall (OS), myelofibrosis-free (MFFS), thrombosis-free, and leukemia-free survival (LFS) in ET; 495 patients (median age 58 years; 61% females) with ET were fully annotated for the their driver mutational status: 321 (65%) harbored JAK2, 109 (22%) CALR, and 12 (2%) MPL mutations and 11% were triple-negative.
Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated durable improvements in splenomegaly, symptoms, and overall survival in controlled clinical trials in patients with myelofibrosis.
To identify key features that may help distinguish these 2 entities, we retrospectively studied 21 cases diagnosed as "CMML" with JAK2V617F and bone marrow fibrosis that were identified from a cohort of 610 cases of CMML diagnosed in 2006 to 2016.
We developed a time-dependent assay to mimic ruxolitinib withdrawal in primary JAK2<sup>V617F</sup> and CALR mutant myelofibrosis patient samples and observed notable activation of spontaneous STAT signaling in JAK2<sup>V617F</sup> samples after drug washout.
Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented.
To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia.
However, they often accentuate the anemia and do not reduce the JAK2 allele burden, therefore lacking the potential to modify the natural history of MF.
Depending on the biological background of individual patients, heterozygous and homozygous JAK2V617F ET/PV may preferentially induce myeloid metaplasia with myelofibrosis with a relative suppression of megakaryocytic and erythropoietic myeloproliferation leading to clinical pictures of fibrotic chronic idiopathic myelofibrosis (CIMF) or agnogenic myeloid metaplasia.
RQ-PCR experiments showed increased JAK2 expression in patients with the JAK2V617F mutation, with a significant difference between essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) patients.