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.
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.
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.
One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2.
We report here that JAK2(V617F)-associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 x 10(-16); essential thrombocythemia, n = 78, P = 8.2 x 10(-9) and myelofibrosis, n = 41, P = 8.0 x 10(-5)).
This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2V617F-positive essential thrombocythemia.
The detection rate of JAK2(V617F) was 76.2% for PV (homozygous in 14.3%), 46.9% for ET, 80% for myelofibrosis (homozygous in 20%), and 0% for the other conditions.
Primary myelofibrosis or myelofibrotic transformation preceded all 7 JAK2-mutant but only 1 of 9 JAK2 wild-type AMLs (P = .001), implying that JAK2-mutant AML is preceded by mutation(s) that give rise to a "myelofibrosis" phenotype.
When present in a heterozygous state the JAK2-V617F mutation preferentially stimulates megakaryopoiesis and in most cases manifests as essential thrombocythemia (ET), whereas homozygous JAK2-V617F reduces megakaryopoiesis in favor of increased erythropoiesis, resulting in polycythemia vera and/or myelofibrosis.
Concerning myelofibrosis (MF), controversy remains on the relationship between the above JAK2 haplotype and the patients' clinicohematological features and survival.
In conclusion, the size of the mutated clone in chronic phase MPN is different according to genotype with CALR-mutated ET showing a pattern similar to that observed in MF.
In this context, the distinctive role of a positive JAK2(V617F) mutation for the diagnosis of Ph- MPD was underscored, including entities with a low allele burden and the discrimination from reactive disorders (autoimmune myelofibrosis, reactive thrombocytosis).
Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations.
The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013.
JAK2V617F mutations were detected in 6 of the 28 patients with bone marrow fibrosis presenting at the time of diagnosis and 2 of the 7 patients with bone marrow fibrosis developing in the course of disease, significantly higher than the control group patients.
Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.
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.
Novel treatment strategies are under investigation, including targeted inhibition of JAK2(V617F), the activating tyrosine kinase point mutation present in about half of patients with MMM.
Three studies now report an amino acid substitution in the JAK2 kinase in most patients with polycythemia vera as well as in some cases of essential thrombocythemia and chronic idiopathic myelofibrosis.