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The recent identification of somatic mutations such as JAK2 V617F that deregulate Janus kinase (JAK)–signal transducer and activator of transcription signaling has spurred development of orally bioavailable small-molecule inhibitors that selectively target JAK2 kinase as an approach to pathogenesis-directed therapy of myeloproliferative disorders (MPD). In pre-clinical studies, these compounds inhibit JAK2V617F-mediated cell growth at nanomolar concentrations, and in vivo therapeutic efficacy has been demonstrated in mouse models of JAK2V617F-induced disease. In addition, ex vivo growth of progenitor cells from MPD patients harboring JAK2 V617F or MPL W515L/K mutations is also potently inhibited. JAK2 inhibitors currently in clinical trials can be grouped into those designed to primarily target JAK2 kinase (JAK2-selective) and those originally developed for non-MPD indications, but that nevertheless have significant JAK2-inhibitory activity (non-JAK2 selective). This article discusses the rationale for using JAK2 inhibitors for the treatment of MPD, as well as relevant aspects of clinical trial development for these patients. For instance, which group of MPD patients is appropriate for initial Phase I studies? Should JAK2 V617F-negative MPD patients be included in the initial studies? What are the likely consequences of ‘off-target’ JAK3 and wild-type JAK2 inhibition? How should treatment responses be monitored?

Calreticulin ( CALR ) mutations were recently described in JAK2 and MPL unmutated primary myelofibrosis (PMF) and essential thrombocythemia. In the current study, we compared the clinical, cytogenetic and molecular features of patients with PMF with or without CALR , JAK2 or MPL mutations. Among 254 study patients, 147 (58%) harbored JAK2 , 63 (25%) CALR and 21 (8.3%) MPL mutations; 22 (8.7%) patients were negative for all three mutations, whereas one patient expressed both JAK2 and CALR mutations. Study patients were also screened for ASXL1 (31%), EZH2 (6%), IDH (4%), SRSF2 (12%), SF3B1 (7%) and U2AF1 (16%) mutations. In univariate analysis, CALR mutations were associated with younger age ( P <0.0001), higher platelet count ( P <0.0001) and lower DIPSS-plus score ( P =0.02). CALR -mutated patients were also less likely to be anemic, require transfusions or display leukocytosis. Spliceosome mutations were infrequent ( P =0.0001) in CALR -mutated patients, but no other molecular or cytogenetic associations were evident. In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of both DIPSS-plus risk and ASXL1 mutation status ( P =0.001; HR 3.4 for triple-negative and 2.2 for JAK2 -mutated). Triple-negative patients also displayed inferior LFS ( P =0.003). The current study identifies ‘CALR – ASXL1 + ’ and ‘triple-negative’ as high-risk molecular signatures in PMF.

Current prognostication in primary myelofibrosis (PMF) is based on the dynamic international prognostic scoring system (DIPSS)-plus, which employs clinical and cytogenetic variables. We recently reported DIPSS-plus independent prognostic significance for calreticulin ( CALR ) (favorable) and ASXL1 (unfavorable) mutations. In the current study, 570 PMF patients were recruited for derivation ( n =277) and validation ( n =293) of a molecular prognostic model based on these two mutations. Survival was the longest in CALR + ASXL1 − (median 10.4 years) and shortest in CALR − ASXL1 + patients (median, 2.3 years; hazard ratio (HR), 5.9; 95% confidence interval (CI), 3.5–10.0). CALR + ASXL1 + and CALR – ASXL1 − patients had similar survival and were grouped together in an intermediate-risk category (median survival, 5.8 years; HR, 2.5; 95% CI, 1.5–4.0). The CALR / ASXL1 mutations-based prognostic model was DIPSS-plus independent ( P <0.0001) and effective in identifying low-/intermediate-1-risk patients with shorter (median, 4 years) or longer (median 20 years) survival and high-/intermediate-2-risk patients with shorter (median, 2.3 years) survival. Multivariable analysis distinguished CALR − ASXL1 + mutational status as the most significant risk factor for survival: HR 3.7 vs 2.8 for age >65 years vs 2.7 for unfavorable karyotype. These observations signify immediate clinical relevance and warrant i) CALR and ASXL1 mutation determination in all patients with PMF and ii) molecular revision of DIPSS-plus.

JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2 / MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase ( n =21), the maximum-tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7–>18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect.

In a recent International Working Group on Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) study, prior arterial events and hypertension were predictors of subsequent arterial thrombosis whereas prior venous events and age ≥65 years predicted venous thrombosis in polycythemia vera (PV). In the current study, we sought to validate the above findings and identify additional predictors of arterial versus venous thrombosis. At a median follow up of 109 months, thrombosis after diagnosis occurred in 128 (22%) patients; 82 (14%) arterial and 57 (10%) venous events. On multivariate analysis, prior arterial events (<0.0001), hyperlipidemia ( p  = 0.03), and hypertension ( p  = 0.02) predicted subsequent arterial events. In comparison, prior venous events ( p  = 0.05), leukocytosis ≥11 × 10 9 /L ( p  = 0.002), and major hemorrhage ( p  = 0.02) were predictors of subsequent venous events. Salient associations with arterial thrombosis included age ≥ 60 years, hypertension, diabetes, hyperlipidemia and normal karyotype whereas age ≤ 60 years, females, palpable splenomegaly and history of major hemorrhage were associated with venous thrombosis. TET2 or ASXL1 mutations did not impact arterial nor venous thrombosis. In conclusion, we identify distinct associations for arterial versus venous thrombosis in PV and confirm that a prior arterial or venous thrombotic event is the most reliable predictor of subsequent events.

Truncation mutations of the receptor cytoplasmic domain for colony-stimulating factor 3 (CSF3R) are frequently seen in severe congenital neutropenia, whereas activating missense mutations affecting the extracellular domain (exon 14) have been described in hereditary neutrophilia and chronic neutrophilic leukemia (CNL). In order to clarify mutational frequency, specificity and phenotypic associations, we sequenced CSF3R exons 14–17 in 54 clinically suspected cases of CNL ( n =35) or atypical chronic myeloid leukemia (aCML; n =19). Central review of these cases confirmed WHO-defined CNL in 12 patients, monoclonal gammopathy (MG)-associated CNL in 5 and WHO-defined aCML in 9. A total of 14 CSF3R mutations were detected in 13 patients, including 10 with CSF3R T618I (exon 14 mutation, sometimes annotated as CSF3R T595I). CSF3R T618I occurred exclusively in WHO-defined CNL with a mutational frequency of 83% (10 of 12 cases). CSF3R mutations were not seen in aCML or MG-associated CNL. CSF3R T618I was also absent among 170 patients with primary myelofibrosis (PMF; n =76) or chronic myelomonocytic leukemia (CMML; n =94). SETBP1 mutational frequencies in WHO-defined CNL, aCML, CMML and PMF were 33, 0, 7 and 3%, respectively. Four CSF3R T618I-mutated cases co-expressed SETBP1 mutations. We conclude that CSF3R T618I is a highly sensitive and specific molecular marker for CNL and should be incorporated into current diagnostic criteria.

JAK2 and MPL mutations are recurrent in myeloproliferative neoplasms (MPNs). A JAK2 mutation, primarily JAK2 V617F, is almost invariably associated with polycythemia vera (PV). However, JAK2 V617F also occurs in the majority of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF) as well as in a much smaller percentage of those with other MPNs. The mechanism(s) behind this one allele-multiple phenotypes phenomenon has not been fully elucidated. The issue is further confounded by the presence of marked variation in JAK2 V617F allele burden among mutation-positive patients. In the current communication, we discuss potential mechanisms for phenotypic diversity among JAK2 V617F-positive MPNs as well as review the current literature in regard to genotype–phenotype correlations (that is clinical correlates and prognostic significance) in the context of both the presence or absence of the mutation (ET and PMF) and its allele burden (PV, ET and PMF).

The impact of calreticulin ( CALR ) mutations on long-term survival in essential thrombocythemia (ET) was examined in 299 patients whose diagnosis predated 2006. Mutational frequencies were 53% for Janus kinase 2 ( JAK2 ), 32% for CALR and 3% for MPL ; the remaining 12% were ‘triple-negative’. We confirmed the association of mutant CALR (vs JAK2 V617F) with younger age ( P =0.002), male sex ( P =0.01), higher platelet count (0.0004), lower hemoglobin ( P <0.0001), lower leukocyte count (0.02) and lower incidence of recurrent thrombosis (0.04). Triple-negative patients were also younger than their JAK2 -mutated counterparts ( P =0.003) and displayed lower hemoglobin ( P =0.003), lower leukocyte count (<0.0001) and lower thrombotic events ( P =0.02). Median follow-up time was 12.7 years and 47% of the patients were followed until death. Survival was the longest for triple-negative and shortest for MPL-mutated patients. Median survival was 19 years for JAK2 and 20 years for CALR-mutated cases ( P =0.32); the corresponding figures for patients of age ⩽65 years were 26 and 32 years ( P =0.56). The two mutational categories were also similar for leukemic ( P =0.28) and fibrotic ( P =0.28) progression rates. The current study is uniquely characterized by its very long follow-up period and provides accurate estimates of long-term survival in ET and complements current information on mutation-specific phenotype and prognosis.