Jean‐Jacques Kiladjian

Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis.

Within a period of three years, we identified 13 patients in whom pure red-cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We investigated whether there was an immunologic basis for the anemia in these patients.Serum samples from the 13 patients with pure red-cell aplasia were tested for neutralizing antibodies that could inhibit erythroid-colony formation by normal bone marrow cells in vitro. The presence of antierythropoietin antibodies was identified by means of binding assays with the use of radiolabeled intact, deglycosylated, or denatured epoetin.Serum from all 13 patients blocked the formation of erythroid colonies by normal bone marrow cells. The inhibition was reversed by epoetin. Antibodies from 12 of the 13 patients bound only conformational epitopes in the protein moiety of epoetin; serum from the remaining patient bound to both conformational and linear epitopes in erythropoietin. In all the patients, the antibody titer slowly decreased after the discontinuation of treatment with epoetin.Neutralizing antierythropoietin antibodies and pure red-cell aplasia can develop in patients with the anemia of chronic renal failure during treatment with epoetin.

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first- and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.

Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.

Abstract Interferon-α (IFN-α) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-α-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-α-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-α-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6+ to 18+ months, and persisted after pegylated IFN-α-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-α-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.

This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. 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. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.

Ruxolitinib is a Janus kinase (JAK) (JAK1/JAK2) inhibitor that has demonstrated superiority over placebo and best available therapy (BAT) in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies. COMFORT-II was a randomized (2:1), open-label phase 3 study in patients with myelofibrosis; patients randomized to BAT could crossover to ruxolitinib upon protocol-defined disease progression or after the primary end point, confounding long-term comparisons. At week 48, 28% (41/146) of patients randomized to ruxolitinib achieved ⩾35% decrease in spleen volume (primary end point) compared with no patients on BAT (P<0.001). Among the 78 patients (53.4%) in the ruxolitinib arm who achieved ⩾35% reductions in spleen volume at any time, the probability of maintaining response was 0.48 (95% confidence interval (CI), 0.35-0.60) at 5 years (median, 3.2 years). Median overall survival was not reached in the ruxolitinib arm and was 4.1 years in the BAT arm. There was a 33% reduction in risk of death with ruxolitinib compared with BAT by intent-to-treat analysis (hazard ratio (HR)=0.67; 95% CI, 0.44-1.02; P=0.06); the crossover-corrected HR was 0.44 (95% CI, 0.18-1.04; P=0.06). There was no unexpected increased incidence of adverse events with longer exposure. This final analysis showed that spleen volume reductions with ruxolitinib were maintained with continued therapy and may be associated with survival benefits.

Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibitor that has demonstrated rapid reductions in splenomegaly and marked improvement in disease-related symptoms and quality of life in patients with myelofibrosis (MF). The present analysis reports the 3-year follow-up (median, 151 weeks) of the efficacy and safety of Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219 patients with intermediate-2 and high-risk MF. In the ruxolitinib arm, with continued therapy, spleen volume reductions of ≥35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation) were sustained for at least 144 weeks, with the probability of 50% (95% confidence interval [CI], 36-63) among patients achieving such degree of response. At the time of this analysis, 45% of the patients randomized to ruxolitinib remained on treatment. Ruxolitinib continues to be well tolerated. Anemia and thrombocytopenia were the main toxicities, but they were generally manageable, improved over time, and rarely led to treatment discontinuation (1% and 3.6% of patients, respectively). No single nonhematologic adverse event led to definitive ruxolitinib discontinuation in more than 1 patient. Additionally, patients randomized to ruxolitinib showed longer overall survival than those randomized to BAT (hazard ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P = .009).

Purpose Myeloproliferative neoplasm (MPN) symptoms are troublesome to patients, and alleviation of this burden represents a paramount treatment objective in the development of MPN-directed therapies. We aimed to assess the utility of an abbreviated symptom score for the most pertinent and representative MPN symptoms for subsequent serial use in assessing response to therapy. Patients and Methods The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS) was calculated as the mean score for 10 items from two previously validated scoring systems. Questions focus on fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Results MPN-SAF TSS was calculable for 1,408 of 1,433 patients with MPNs who had a mean score of 21.2 (standard deviation [SD], 16.3). MPN-SAF TSS results significantly differed among MPN disease subtypes (P &lt; .001), with a mean of 18.7 (SD, 15.3), 21.8 (SD, 16.3), and 25.3 (SD, 17.2) for patients with essential thrombocythemia, polycythemia vera, and myelofibrosis, respectively. The MPN-SAF TSS strongly correlated with overall quality of life (QOL; r = 0.59; P &lt; .001) and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) functional scales (all P &lt; .001 and absolute r ≥ 0.50 except social functioning r = 0.48). No significant trends were present when comparing therapy subgroups. The MPN-SAF TSS had excellent internal consistency (Cronbach's α = .83). Factor analysis identified a single underlying construct, indicating that the MPN-SAF TSS is an appropriate, unified scoring method. Conclusion The MPN-SAF TSS is a concise, valid, and accurate assessment of MPN symptom burden with demonstrated clinical utility in the largest prospective MPN symptom study to date. This new prospective scoring method may be used to assess MPN symptom burden in both clinical practice and trial settings.

Abstract Myeloproliferative diseases (MPDs) represent the commonest cause of splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT), but their diagnosis is hampered by changes secondary to portal hypertension, while their influence in the outcome of SVT remains unclear. We assessed the diagnostic and prognostic value of JAK2 and MPL515 mutations in 241 SVT patients (104 BCS, 137 PVT). JAK2V617F was found in 45% of BCS and 34% of PVT, while JAK2 exon 12 and MPL515 mutations were not detected. JAK2V617F was found in 96.5% of patients with bone marrow (BM) changes specific for MPD and endogenous erythoid colonies, but also in 58% of those with only one feature and in 7% of those with neither feature. Stratifying MPD diagnosis first on JAK2V617F detection would have avoided BM investigations in 40% of the patients. In BCS, presence of MPD carried significantly poorer baseline prognostic features, required hepatic decompression procedures earlier, but had no impact on 5-year survival. Our results suggest that JAK2V617F testing should replace BM investigations as initial test for MPD in patients with SVT. Underlying MPD is associated with severe forms of BCS, but current therapy appears to offset deleterious effects of MPD on the medium-term outcome.

Abstract Myeloproliferative neoplasms (MPNs) are the most common cause of Budd-Chiari syndrome (BCS) and nonmalignant, noncirrhotic portal vein thrombosis (PVT). In this meta-analysis, we determined the prevalence of MPNs and their subtypes as well as JAK2V617F and its diagnostic role in these uncommon disorders. MEDLINE and EMBASE databases were searched. Prevalence of MPNs, JAK2V617F, and MPN subtypes were calculated using a random-effects model. A total of 1062 BCS and 855 PVT patients were included. In BCS, mean prevalence of MPNs and JAK2V617F was 40.9% (95% CI, 32.9%-49.5%) and 41.1% (95% CI, 32.3%-50.6%), respectively. In PVT, mean prevalence of MPNs and JAK2V617F was 31.5% (95% CI, 25.1%-38.8%) and 27.7% (95% CI, 20.8%-35.8%), respectively. JAK2V617F and MPNs were more frequent in BCS compared with PVT (P = .03 and P = .09, respectively). Polycythemia vera was more prevalent in BCS than in PVT (P = .001). JAK2V617F screening in splanchnic vein thrombosis (SVT) patients without typical hematologic MPN features identified MPN in 17.1% and 15.4% of screened BCS and PVT patients, respectively. These results demonstrate a high prevalence of MPNs and JAK2V617F in SVT patients and show differences in underlying etiology between these disorders. Furthermore, these results validate routine inclusion of JAK2V617F in the diagnostic workup of SVT patients.

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms with variable risk of evolution into post-PV and post-ET myelofibrosis, from now on referred to as secondary myelofibrosis (SMF). No specific tools have been defined for risk stratification in SMF. To develop a prognostic model for predicting survival, we studied 685 JAK2, CALR, and MPL annotated patients with SMF. Median survival of the whole cohort was 9.3 years (95% CI: 8-not reached-NR-). Through penalized Cox regressions we identified negative predictors of survival and according to beta risk coefficients we assigned 2 points to hemoglobin level <11 g/dl, to circulating blasts ⩾3%, and to CALR-unmutated genotype, 1 point to platelet count <150 × 109/l and to constitutional symptoms, and 0.15 points to any year of age. Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) allocated SMF patients into four risk categories with different survival (P<0.0001): low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI: 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI: 3.2-7.9; 126 patients), and high risk (2 years, 95% CI: 1.7-3.9; 75 patients). Finally, we found that the MYSEC-PM represents the most appropriate tool for SMF decision-making to be used in clinical and trial settings.

Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naïve patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naïve patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.

Myelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib. 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved the primary endpoint of 35% or more reduction in spleen volume from baseline assessed by MRI or CT. Furthermore, more than 50% of patients discontinue ruxolitinib treatment after 3-5 years. On the basis of this unmet need, we investigated the efficacy and safety of fedratinib, a JAK2-selective inhibitor, in patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis.This single-arm, open-label, non-randomised, phase 2, multicentre study, done at 31 sites in nine countries, enrolled adult patients with a current diagnosis of intermediate or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis, found to be ruxolitinib resistant or intolerant after at least 14 days of treatment. Other main inclusion criteria were palpable splenomegaly (≥5 cm below the left costal margin), Eastern Cooperative Oncology Group performance status of 2 or less, and life expectancy of 6 months or less. Patients received oral fedratinib at a starting dose of 400 mg once per day, for six consecutive 28-day cycles. The primary endpoint was spleen response (defined as the proportion of patients with a ≥35% reduction in spleen volume as determined by blinded CT and MRI at a central imaging laboratory). We did the primary analysis in the per-protocol population only (patients treated with fedratinib, for whom a baseline and at least one post-baseline spleen volume measurement was available) and the safety analysis in all patients receiving at least one dose of fedratinib. This trial was registered with ClinicalTrials.gov, number NCT01523171.Between May 8, 2012, and Aug 29, 2013, 97 patients were enrolled and received at least one dose of fedratinib. Of 83 assessable patients, 46 (55%, 95% CI 44-66) achieved a spleen response. Common grade 3-4 adverse events included anaemia (37 [38%] of 97 patients) and thrombocytopenia (21 [22%] of 97), with 18 (19%) patients discontinuing due to adverse events. Seven (7%) patients died during the study, but none of the deaths was drug related. Suspected cases of Wernicke's encephalopathy in other fedratinib trials led to study termination.This phase 2 study met its primary endpoint, suggesting that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis might achieve significant clinical benefit with fedratinib, albeit at the cost of some potential toxicity, which requires further evaluation. Fedratinib development in this setting is currently being assessed.Sanofi.

The overall impact of hydroxyurea (HU) or pipobroman treatments on the long-term outcome of patients with polycythemia vera (PV) has not been assessed in randomized studies. We report final analyses from the French Polycythemia Study Group (FPSG) study, which randomly assigned HU versus pipobroman as first-line therapy in 285 patients younger than age 65 years.The full methodology has been described previously. FPSG results were updated with a median follow-up of 16.3 years. Statistical analysis was performed by using competing risks on the intention-to-treat population and according to main treatment received.Median survival was 17 years for the whole cohort, 20.3 years for the HU arm, and 15.4 years for the pipobroman arm (P = .008) and differed significantly from that in the general population. At 10, 15, and 20 years, cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was 6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (P = .004). Cumulative myelofibrosis incidence at 10, 15, and 20 years according to main treatment received was 15%, 24%, and 32% with HU versus 5%, 10%, and 21% with pipobroman (P = .02).Data from this unique randomized trial comparing HU with another cytoreductive drug in PV showed that (1) survival of patients with PV treated with conventional agents differed from survival in the general population, (2) evolution to AML/MDS is the first cause of death, (3) pipobroman is leukemogenic and is unsuitable for first-line therapy, and (4) incidence of evolution to AML/MDS with HU is higher than previously reported, although consideration should be given to the natural evolution of PV.

Background Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. Methods This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. Findings Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8–28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8–6·7). The most common grade 3–4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. Interpretation Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. Funding CTI BioPharma Corp.

Standardized response criteria to interpret and compare clinical trials are needed for approval of new therapeutic agents by regulatory agencies. The European LeukemiaNet (ELN) response criteria for essential thrombocythemia (ET) and polycythemia vera (PV) issued in 2009 have been widely adopted as end points in a number of recent clinical trials. However, evidence exists that they do not predict response or provide clinically relevant measures of benefit for the patients. This article presents revised recommendations for assessing response in ET and PV provided by a working group established by ELN and International Working Group-Myeloproliferative Neoplasms Research and Treatment. New definitions of complete and partial remission incorporate clinical, hematological, and histological response assessments that include a standardized symptom assessment form and consider absence of disease progression and vascular events. We anticipate that these criteria will be adopted widely to facilitate the development of new and more effective therapies for ET and PV.

Background The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment. Methods PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing). Findings Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3–201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4–169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia). Interpretation In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea. Funding AOP Orphan Pharmaceuticals AG.

Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23-0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36-0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .

Background The Janus kinase (JAK) inhibitor ruxolitinib is the only approved therapy for patients with symptomatic myelofibrosis. After ruxolitinib failure, however, there are few therapeutic options. We assessed the efficacy and safety of momelotinib, a JAK 1 and JAK 2 inhibitor, versus best available therapy (BAT) in patients with myelofibrosis who had suboptimal responses or haematological toxic effects with ruxolitinib. Methods In this randomised, phase 3, open-label trial, patients were screened for eligibility from 52 clinical centres in Canada, France, Germany, Israel, Italy, Spain, the UK, and the USA. Patients who had myelofibrosis and previous ruxolitinib treatment for at least 28 days who either required red blood cell transfusions while on ruxolitinib or ruxolitinib dose reduction to less than 20 mg twice a day with at least one of grade 3 thrombocytopenia, anaemia, or bleeding at grade 3 or worse, with palpable spleen of at least 5 cm and without grade 2 or greater peripheral neuropathy were included in the study. Patients were randomly assigned (2:1) to either 24 weeks of open-label momelotinib 200 mg once a day or BAT (which could include ruxolitinib, chemotherapy, steroids, no treatment, or other standard interventions), after which all patients could receive extended momelotinib treatment. Patients were randomly assigned to treatment by an interactive web response system and the randomisation was stratified by transfusion dependence and by baseline total symptom score (TSS). Results were analysed on an intention-to-treat basis. The primary endpoint was a reduction by at least 35% in the spleen volume at 24 weeks compared with baseline. Safety analyses included adverse event monitoring. The trial is registered with ClinicalTrials.gov, number NCT02101268. Findings Between June 19, 2014, and July 28, 2016, 156 patients were recruited to the study; 104 received momelotinib and 52 received BAT. BAT was ruxolitinib in 46 (89%) of 52 patients. 73 (70%) of 104 patients in the momelotinib group and 40 (77%) of 52 patients in the BAT group completed the 24-week treatment phase. Seven (7%) of 104 patients in the momelotinib group and three (6%) of 52 in the BAT group had a reduction in the spleen volume by at least 35% compared with baseline (proportion difference [Cochran–Mantel–Haenszel method], 0·01; 95% CI −0·09 to 0·10), p=0·90). The most common grade 3 or worse adverse events were anaemia (14 [14%] of 104 in the momelotinib group vs seven [14%] of 52 in the BAT group), thrombocytopenia (seven [7%] vs three [6%]), and abdominal pain (one [1%] vs three [6%]). Peripheral neuropathy occurred in 11 (11%) of 104 patients receiving momelotinib (one of which was grade 3) and in no patients in the BAT group. Serious events were reported for 36 (35%) patients in the momelotinib group and 12 (23%) of patients in the BAT group. Deaths due to adverse events were reported for six patients (6%) receiving momelotinib (acute myeloid leukaemia [n=2], respiratory failure [n=2, with one considered possibly related to momelotinib], cardiac arrest [n=1, considered possibly related to momelotinib], and bacterial sepsis [n=1]); and four patients (8%) receiving BAT (lung adenocarcinoma [n=1], myelofibrosis [n=1], and sepsis [n=2]). Interpretation In patients with myelofibrosis previously treated with ruxolitinib, momelotinib was not superior to BAT for the reduction of spleen size by at least 35% compared with baseline. Funding Gilead Sciences, Inc.

Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46–0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13–0.63). Both patients with intermediate-2– or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2–risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544)

Abstract Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.

Myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) is characterized by cytopenias, marrow fibrosis, constitutional symptoms, extramedullary hematopoiesis, splenomegaly, and shortened survival. Constitutive activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in MF leads to cell proliferation, inhibition of cell death, and clonal expansion of myeloproliferative malignant cells. Fedratinib is a selective oral JAK2 inhibitor recently approved in the United States for treatment of adult patients with intermediate-2 or high-risk MF. In mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT5, increased survival, and improved MF-associated disease features, including reduction of white blood cell counts, hematocrit, splenomegaly, and fibrosis. Fedratinib exerts off-target inhibitory activity against bromodomain-containing protein 4 (BRD4); combination JAK/STAT and BRD4 inhibition was shown to synergistically block NF-kB hyperactivation and inflammatory cytokine production, attenuating disease burden and reversing bone marrow fibrosis in animal models of MPNs. In patients, fedratinib is rapidly absorbed and dosed once daily (effective half-life 41 h). Fedratinib showed robust clinical activity in JAK-inhibitor-naïve patients and in patients with MF who were relapsed, refractory, or intolerant to prior ruxolitinib therapy. Fedratinib is effective regardless of JAK2 mutation status. Onset of spleen and symptom responses are typically seen within the first 1-2 months of treatment. The most common adverse events (AEs) with fedratinib are grades 1-2 gastrointestinal events, which are most frequent during early treatment and decrease over time. Treatment discontinuation due to hematologic AEs in clinical trials was uncommon (~3%). Suspected cases of Wernicke's encephalopathy were reported during fedratinib trials in ~1% of patients; thiamine levels should be monitored before and during fedratinib treatment as medically indicated. Phase III trials are ongoing to assess fedratinib effects on long-term safety, efficacy, and overall survival. The recent approval of fedratinib provides a much-needed addition to the limited therapeutic options available for patients with MF.

The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting.195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.Sierra Oncology.

Polycythaemia vera is associated with a reduced quality of life, a high rate of vascular events, and an intrinsic risk of disease evolution. The results of several randomised trials for the treatment of this disorder are now available, and both a new ropegylated formulation of interferon alfa-2b (ropeginterferon alfa-2b; 2018) and ruxolitinib (2015) have been approved in Europe. European LeukemiaNet (ELN) investigators have therefore deemed it appropriate to provide recommendations for the use of these drugs in clinical practice. An expert panel of 14 senior haematologists from ELN centres that had actively participated in previous ELN projects or relevant randomised trials, chaired by a member of the ELN Steering Committee, developed a list of clinical questions, and a methodologist established three patient, intervention, comparator, outcome (PICO) questions and systematically reviewed the evidence. Recommendations were approved by six Delphi consensus rounds and two virtual meetings (on Jan 26, 2021, and June 24, 2021). The expert panel recommended that patients with polycythaemia vera who are younger than 60 years and have not had previous thrombotic events should start cytoreductive drug therapy if at least one of the following criteria are fulfilled: strictly defined intolerance to phlebotomy, symptomatic progressive splenomegaly, persistent leukocytosis (>15 × 109 white blood cells per L), progressive leukocytosis (at least 100% increase if baseline count is <10 × 109 cells per L or at least 50% increase if baseline count is >10 × 109 cells per L), extreme thrombocytosis (>1500 × 109 platelets per L), inadequate haematocrit control requiring phlebotomies, persistently high cardiovascular risk, and persistently high symptom burden. Recombinant interferon alfa, either in the form of ropeginterferon alfa-2b or pegylated interferon alfa-2a, is the recommended cytoreductive treatment for these patients. The expert panel suggested that either interferon alfa or ruxolitinib should be considered for patients who are being treated with hydroxyurea but require a therapy change.

Standard therapy for myelofibrosis comprises Janus kinase inhibitors (JAKis), yet spleen response rates of 30%-40%, high discontinuation rates, and a lack of disease modification highlight an unmet need. Pelabresib (CPI-0610) is an investigational, selective oral bromodomain and extraterminal domain inhibitor (BETi).MANIFEST (ClinicalTrails.gov identifier: NCT02158858), a global, open-label, nonrandomized, multicohort, phase II study, includes a cohort of JAKi-naïve patients with myelofibrosis treated with pelabresib and ruxolitinib. The primary end point is a spleen volume reduction of ≥ 35% (SVR35) at 24 weeks.Eighty-four patients received ≥ 1 dose of pelabresib and ruxolitinib. The median age was 68 (range, 37-85) years; 24% of patients were intermediate-1 risk, 61% were intermediate-2 risk, and 16% were high risk as per the Dynamic International Prognostic Scoring System; 66% (55 of 84) of patients had a hemoglobin level of < 10 g/dL at baseline. At 24 weeks, 68% (57 of 84) achieved SVR35, and 56% (46 of 82) achieved a total symptom score reduction of ≥ 50% (TSS50). Additional benefits at week 24 included 36% (29 of 84) of patients with improved hemoglobin levels (mean, 1.3 g/dL; median, 0.8 g/dL), 28% (16 of 57) with ≥ 1 grade improvement in fibrosis, and 29.5% (13 of 44) with > 25% reduction in JAK2V617F-mutant allele fraction, which was associated with SVR35 response (P = .018, Fisher's exact test). At 48 weeks, 60% (47 of 79) of patients had SVR35 response. Grade 3 or 4 toxicities seen in ≥ 10% patients were thrombocytopenia (12%) and anemia (35%), leading to treatment discontinuation in three patients. 95% (80 of 84) of the study participants continued combination therapy beyond 24 weeks.The rational combination of the BETi pelabresib and ruxolitinib in JAKi-naïve patients with myelofibrosis was well tolerated and showed durable improvements in spleen and symptom burden, with associated biomarker findings of potential disease-modifying activity.

V617F JAK2 mutation is a reliable molecular marker of polycythemia vera (PV), potentially useful to monitor the effect of treatments in this disease. In a phase 2 study of pegylated (peg) IFN-α–2a in PV, we performed prospective sequential quantitative evaluation of the percentage of mutated JAK2 allele (%V617F) by real-time polymerase chain reaction (PCR). The %V617F decreased in 24 (89%) of 27 treated patients, from a mean of 49% to a mean of 27% (mean decrease of 44%; P < .001), and no evidence for a plateau was observed. In one patient, mutant JAK2 was no longer detectable after 12 months. In 3 patients homozygous for the mutation, reappearance of 50% of wild-type allele was observed during treatment. The results seem to confirm the hypothesis that IFN-α preferentially targets the malignant clone in PV and show that %V617F assessment using a quantitative method may provide the first tool to monitor minimal residual disease in PV. This trial was registered at www.clinicaltrials.gov as #NCT00241241.

European experts were convened to develop a definition of response to treatment in polycythemia vera (PV) and essential thrombocythemia (ET). Clinicohematologic (CH), molecular, and histologic response categories were selected. In ET, CH complete response (CR) was: platelet count less than or equal to 400 × 109/L, no disease-related symptoms, normal spleen size, and white blood cell count less than or equal to 10 × 109/L. Platelet count less than or equal to 600 × 109/L or a decrease greater than 50% was partial response (PR). In PV, CH-CR was: hematocrit less than 45% without phlebotomy, platelet count less than or equal to 400 × 109/L, white blood cell count less than or equal to 10 × 109/L, and no disease-related symptoms. A hematocrit less than 45% without phlebotomy or response in 3 or more of the other criteria was defined as PR. In both ET and in PV, molecular CR was a reduction of any molecular abnormality to undetectable levels. Molecular PR was defined as a reduction more than or equal to 50% in patients with less than 50% mutant allele burden, or a reduction more than or equal to 25% in patients with more than 50% mutant allele burden. Bone marrow histologic response in ET was judged on megakaryocyte hyperplasia while on cellularity and reticulin fibrosis in PV. The combined use of these response definitions should help standardize the design and reporting of clinical studies.

Most patients with polycythemia vera and half with idiopathic myelofibrosis and essential thrombocythemia have an acquired V617F mutation in JAK2. Using sensitive polymerase chain reaction (PCR)–based methods, we genotyped 152 patients with idiopathic myelofibrosis to establish whether there were differences in presentation and outcome between those with and those without the mutation. Patients positive for V617F had higher neutrophil and white cell counts (P = .02) than did patients negative for V617F, but other diagnostic features were comparable between the 2 groups. Patients positive for V617F were less likely to require blood transfusion during follow-up (P = .03). Despite this, patients positive for V617F had poorer overall survival, even after correction for confounding factors (P = .01).

Abstract Although approximately 95% of patients with polycythemia vera (PV) harbor the V617F mutation in JAK2 exon 14, several mutations in exon 12 have been described in the remaining patients. We conducted a European collaborative study to define the molecular and clinical features of patients harboring these mutations. Overall, 106 PVs were recruited and 17 different mutations identified. Irrespective of the mutation, two-thirds of patients had isolated erythrocytosis, whereas the remaining subjects had erythrocytosis plus leukocytosis and/or thrombocytosis. Compared with JAK2 (V617F)-positive PV patients, those with exon 12 mutations had significantly higher hemoglobin level and lower platelet and leukocyte counts at diagnosis but similar incidences of thrombosis, myelofibrosis, leukemia, and death. In a multivariable analysis, age more than 60 years and prior thrombosis predicted thrombosis. These findings suggest that, despite the phenotypical difference, the outcome of JAK2 exon 12 mutations-positive PV is similar to that of JAK2 (V617F)-positive PV.

Abstract IFNα has been used to treat malignant and viral disorders for more than 25 years. Its efficacy is likely the consequence of its broad range of biologic activities, including direct effects on malignant cells, enhancement of anti-tumor immune responses, induction of proapoptotic genes, inhibition of angiogenesis, and promotion of the cycling of dormant malignant stem cells. Because of the recent development of “targeted” therapies, the use of IFN has been dramatically reduced over the last decade. The increasing awareness of the multistep pathogenesis of many malignancies has suggested, however, that such an approach using target-specific agents is not universally effective. These observations have resulted in a number of recent clinical trials utilizing IFNα in patients with chronic myeloid leukemia (CML), systemic mast cell disease, hypereosinophilic syndrome and the Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) with promising outcomes. These reports provide evidence that IFNα, alone or in combination with other agents, can induce surprisingly robust molecular response rates and possibly improve survival. Although IFNα at present remains an experimental form of therapy for patients with myeloid malignancies, these promising results suggest that it may become again an important component of the therapeutic arsenal for this group of hematologic malignancies.

Abstract Essential thrombocythemia, a myeloproliferative neoplasm, is associated with increased platelet count and risk of thrombosis or hemorrhage. Cytoreductive therapy aims to normalize platelet counts despite there being only a minimal association between platelet count and complication rates. Evidence is increasing for a correlation between WBC count and thrombosis, but prospective data are lacking. In the present study, we investigated the relationship between vascular complications and 21 887 longitudinal blood counts in a prospective, multicenter cohort of 776 essential thrombocythemia patients. After correction for confounding variables, no association was seen between blood counts at diagnosis and future complications. However, platelet count outside of the normal range during follow-up was associated with an immediate risk of major hemorrhage (P = .0005) but not thrombosis (P = .7). Elevated WBC count during follow-up was correlated with thrombosis (P = .05) and major hemorrhage (P = .01). These data imply that the aim of cytoreduction in essential thrombocythemia should be to keep the platelet count, and arguably the WBC count, within the normal range. This study is registered at the International Standard Randomized Controlled Trials Number Registry (www.isrctn.org) as number 72251782.

Myeloproliferative disorders (MPD) are reported in 25-65% of patients with splanchnic vein thrombosis (SVT). Diagnostic criteria for MPD have not been fully established in this context. Using clusters of abnormal megakaryocytes in bone marrow (BM) biopsy as a reference standard for Philadelphia negative MPD, we assessed the relevance of other criteria currently recommended for the diagnosis of MPD in SVT (128 consecutive SVT patients). First, usual criteria were compared with BM results: endogenous erythroid colony formation (EEC) was strongly correlated with BM results; splenomegaly, blood cell count, total red cell volume, erythropoietin level and cytogenetic were much less accurate. Then, patients were assigned to three groups according to the combination of BM and EEC findings (group I: both present; group II: both absent; group III: other patients); clinical presentation and outcome were compared in each group. At a mean follow-up of 6.09 +/- 6.6 years, progression to a severe form of MPD occurred in 7 of 31 group I patients (23%), in 1 of 34 group III patients (3%) and 0 of 63 group II patients. The combination of marked splenomegaly and platelet count >200 x 10(9)/l was restricted to groups I and III. In conclusion, in patients with SVT, BM findings and EEC allowed the diagnosis of MPD at risk of aggravation. Marked splenomegaly in association with platelet counts >200 x 10(9)/l constitute a simple index with high specificity but low sensitivity.

Abstract Transformation of Philadelphia (Ph)–negative myeloproliferative neoplasms (MPNs) to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) is associated with poor response to chemotherapy and short survival. Fifty-four patients with Ph-negative MPN (including 21 essential thrombocythemia [ET], 21 polycythemia vera [PV], 7 primary myelofibrosis, and 5 unclassified MPN) who had progressed to AML (n = 26) or MDS (n = 28) were treated with azacitidine in a patient-named program. Overall response rate was 52% (24% complete response [CR], 11% partial response [PR], 8% marrow CR or CR with incomplete recovery of cytopenias, 9% hematologic improvement) and median response duration was 9 months. Prognostic factors were for overall response the underlying MPN (71% vs 33% responses in ET and PV, respectively; P = .016); prognostic factors for CR achievement were the underlying MPN (14% CR for PV vs 43% for ET; P = .040) and World Health Organization classification at transformation (36% vs 12% CR in MDS and AML, respectively, P = .038). Recurrence of chronic phase features of the initial MPN was observed in 39% of the responders. Median overall survival was 11 months. Azacitidine gives encouraging results in Ph-negative MPN having progressed to AML or MDS, but response duration is short, and consolidation treatments have to be evaluated.

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal disorders involving hematopoietic stem and progenitor cells and are associated with myeloproliferation, splenomegaly and constitutional symptoms. Similar signs and symptoms can also be found in patients with chronic inflammatory diseases, and inflammatory processes have been found to play an important role in the pathogenesis and progression of MPNs. Signal transduction pathways involving JAK1, JAK2, STAT3 and STAT5 are causally involved in driving both the malignant cells and the inflammatory process. Moreover, anti-inflammatory and immune-modulating drugs have been used successfully in the treatment of MPNs. However, to date, many unresoved issues remain. These include the role of somatic mutations that are present in addition to JAK2V617F, CALR and MPL W515 mutations, the interdependency of malignant and nonmalignant cells and the means to eradicate MPN-initiating and -maintaining cells. It is imperative for successful therapeutic approaches to define whether the malignant clone or the inflammatory cells or both should be targeted. The present review will cover three aspects of the role of inflammation in MPNs: inflammatory states as important differential diagnoses in cases of suspected MPN (that is, in the absence of a clonal marker), the role of inflammation in MPN pathogenesis and progression and the use of anti-inflammatory drugs for MPNs. The findings emphasize the need to separate the inflammatory processes from the malignancy in order to improve our understanding of the pathogenesis, diagnosis and treatment of patients with Philadelphia-negative MPNs.

Key Points Pegylated IFNα induces hematologic and molecular remission in CALR-mutated ET patients. The analysis of additional mutations highlights the presence of subclones with variable evolutions during IFNα therapy.

Inhibition of Janus-kinase 1/2 (JAK1/2) is a mainstay to treat myeloproliferative neoplasms (MPN). Sporadic observations reported the co-incidence of B-cell non-Hodgkin lymphomas during treatment of MPN with JAK1/2 inhibitors. We assessed 626 patients with MPN, including 69 with myelofibrosis receiving JAK1/2 inhibitors for lymphoma development. B-cell lymphomas evolved in 4 (5.8%) of 69 patients receiving JAK1/2 inhibition compared with 2 (0.36%) of 557 with conventional treatment (16-fold increased risk). A similar 15-fold increase was observed in an independent cohort of 929 patients with MPN. Considering primary myelofibrosis only (N = 216), 3 lymphomas were observed in 31 inhibitor-treated patients (9.7%) vs 1 (0.54%) of 185 control patients. Lymphomas were of aggressive B-cell type, extranodal, or leukemic with high MYC expression in the absence of JAK2 V617F or other MPN-associated mutations. Median time from initiation of inhibitor therapy to lymphoma diagnosis was 25 months. Clonal immunoglobulin gene rearrangements were already detected in the bone marrow during myelofibrosis in 16.3% of patients. Lymphomas occurring during JAK1/2 inhibitor treatment were preceded by a preexisting B-cell clone in all 3 patients tested. Sequencing verified clonal identity in 2 patients. The effects of JAK1/2 inhibition were mirrored in Stat1−/− mice: 16 of 24 mice developed a spontaneous myeloid hyperplasia with the concomitant presence of aberrant B cells. Transplantations of bone marrow from diseased mice unmasked the outgrowth of a malignant B-cell clone evolving into aggressive B-cell leukemia-lymphoma. We conclude that JAK/STAT1 pathway inhibition in myelofibrosis is associated with an elevated frequency of aggressive B-cell lymphomas. Detection of a preexisting B-cell clone may identify individuals at risk.

According to the 2008 World Health Organization (WHO) classification, classical Philadelphia chromosome/BCR-ABL negative chronic myeloproliferative neoplasms (MPNs) include polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) [1.Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, Lyon2008Google Scholar]. The reported worldwide annual incidence rate of MPNs ranges from 0.44 to 5.87/105, with the lowest incidence being reported in Japan and Israel [2.Moulard O. Mehta J. Fryzek J. et al.Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union.Eur J Haematol. 2014; 92: 289-297Crossref PubMed Scopus (147) Google Scholar]. These great ranges may reflect racial/geographic differences as well as differences in study design, diagnostic criteria and methods of reporting, among others. The estimated incidence rate in Europe is 0.4–2.8 × 105/year for PV, 0.38–1.7 × 105/year for ET and 0.1–1 × 105/year for PMF [2.Moulard O. Mehta J. Fryzek J. et al.Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union.Eur J Haematol. 2014; 92: 289-297Crossref PubMed Scopus (147) Google Scholar]. There are few reliable estimates of the prevalence [2.Moulard O. Mehta J. Fryzek J. et al.Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union.Eur J Haematol. 2014; 92: 289-297Crossref PubMed Scopus (147) Google Scholar, 3.Titmarsh G.J. Duncombe A.S. McMullin M.F. et al.How common are myeloproliferative neoplasms? A systematic review and meta-analysis.Am J Hematol. 2014; 89: 581-587Crossref PubMed Scopus (123) Google Scholar]. The last is likely to be rising due to earlier diagnosis and trends towards prolonged survival [4.Cervantes F. Dupriez B. Passamonti F. et al.Improving survival trends in primary myelofibrosis: an international study.J Clin Oncol. 2012; 30: 2981-2987Crossref PubMed Scopus (95) Google Scholar]. The reported median age at diagnosis ranges from 65–74 years for PV, 64–73 years for ET, and 69–76 years for PMF [2.Moulard O. Mehta J. Fryzek J. et al.Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union.Eur J Haematol. 2014; 92: 289-297Crossref PubMed Scopus (147) Google Scholar]. To achieve the most accurate diagnosis possible, the 2008 WHO classification is recommended. It is based upon standardised morphological features, ideally using specimens obtained before treatment, and is integrated with haematological, molecular and clinical diagnostic criteria (Table 1). For full details and images of classical morphological features, the reader is referred to the WHO publication [1.Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, Lyon2008Google Scholar]. European consensus-based criteria for grading of cellularity and bone marrow (BM) fibrosis should be followed (Table 2) [6.Thiele J. Kvasnicka H.M. Facchetti F. et al.European consensus on grading bone marrow fibrosis and assessment of cellularity.Haematologica. 2005; 90: 1128-1132PubMed Google Scholar].Table 1The WHO diagnostic criteria for Philadelphia chromosome-negative chronic myeloproliferative neoplasms [1.Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, Lyon2008Google Scholar]Polycythaemia vera (PV)Essential thrombocythaemia (ET)Primary myelofibrosis (PMF)Major criteria1. Haemoglobin>18.5 g/dl (men)>16.5 g/dl (women)or a any other evidence of increased red cell volume1. Platelet count ≥450 × 109/l1. Megakaryocyte proliferation and atypiab accompanied by either reticulin and/or collagen fibrosis, or c2. Megakaryocyte proliferation with large and mature morphology2. Presence of JAK2V617F or JAK2 exon 12 mutation3. Not meeting WHO criteria for CML, PV, PMF, MDS or other myeloid neoplasm2. Not meeting WHO criteria for CML, PV, MDS or other myeloid neoplasm4. Demonstration of JAK2V617F orother clonal marker orno evidence of reactive thrombocytosis3. Demonstration of JAK2V617F orother clonal marker orno evidence of reactive BM fibrosisMinor criteria1. BM trilineage myeloproliferation1. Leukoerythroblastosis2. Sub-normal sEPO level2. Increased serum LDH level3. Endogenous erythroid colony growth3. Anaemia4. Palpable splenomegalyaHb or HCT >99th percentile of reference range for age, sex or altitude of residence or red cell mass >25% above mean normal predicted or Hb >17 g/dl (men)/>15 g/dl (women) if associated with a sustained increase of ≥2 g/dl from baseline that cannot be attributed to correction of iron deficiency.bSmall to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering.cIn the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (i.e. pre-fibrotic PMF).PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria. ET diagnosis requires meeting all four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria.Note: mutations in calreticulin (CALR) will be included as major diagnostic criteria for ET and PMF in the upcoming (2015) revised WHO classification [5.Tefferi A. Thiele J. Vannucchi A.M. Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms.Leukemia. 2014; 28: 1407-1413Crossref PubMed Scopus (172) Google Scholar].BM, bone marrow; WHO, World Health Organization; CML, chronic myelogenous leukaemia; MDS, myelodysplastic syndromes; LDH, lactate dehydrogenase; sEPO, serum erythropoietin; Hb, haemoglobin; HCT, haematocrit. Open table in a new tab Table 2European consensus on the grading of myelofibrosis (MF) [6.Thiele J. Kvasnicka H.M. Facchetti F. et al.European consensus on grading bone marrow fibrosis and assessment of cellularity.Haematologica. 2005; 90: 1128-1132PubMed Google Scholar]Republished with permission. Obtained from the Haematologica Journal website http://www.haematologica.org.MF—0 Scattered linear reticulin with no intersection (cross-overs) corresponding to normal bone marrowMF—1 Loose network of reticulin with many intersections, especially in perivascular areasMF—2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosisMF—3 Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosisFibre density should be assessed in haematopoietic (cellular) areas. Open table in a new tab aHb or HCT >99th percentile of reference range for age, sex or altitude of residence or red cell mass >25% above mean normal predicted or Hb >17 g/dl (men)/>15 g/dl (women) if associated with a sustained increase of ≥2 g/dl from baseline that cannot be attributed to correction of iron deficiency. bSmall to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering. cIn the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation and often decreased erythropoiesis (i.e. pre-fibrotic PMF). PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria. ET diagnosis requires meeting all four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria. Note: mutations in calreticulin (CALR) will be included as major diagnostic criteria for ET and PMF in the upcoming (2015) revised WHO classification [5.Tefferi A. Thiele J. Vannucchi A.M. Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms.Leukemia. 2014; 28: 1407-1413Crossref PubMed Scopus (172) Google Scholar]. BM, bone marrow; WHO, World Health Organization; CML, chronic myelogenous leukaemia; MDS, myelodysplastic syndromes; LDH, lactate dehydrogenase; sEPO, serum erythropoietin; Hb, haemoglobin; HCT, haematocrit. Fibre density should be assessed in haematopoietic (cellular) areas. In PV, classical BM features are a moderate to overt increase in age-matched cellularity, due to a trilineage proliferation (panmyelosis) of erythroid and granulocytic precursors and megakaryocytes in variable proportions. Megakaryocytes are characterised by a pleomorphic appearance due to the variability in sizes, from small to giant cells, without gross abnormalities of maturation. There may be minimal (grade 1) reticulin fibrosis, which is very rarely grade 2. In ET, age-adjusted cellularity is normal or sometimes slightly increased; there is no left-shifted neutrophil granulopoiesis. Any case with a mild to moderate panmyelosis is suspicious for early PV rather than ET. Megakaryocytes have increased in number and are randomly distributed within the BM, with scattered forms or a few loose clusters. Large to giant mature megakaryocytes with extensively folded (staghorn-like) nuclei and mature cytoplasm are in the majority. Gross disturbances of the histologic topography or extensive dense clustering of megakaryocytes should not be detectable. There is no substantial increase of reticulin fibres. The WHO classification suggests that these features clearly distinguish ET from pre-fibrotic/early PMF; however, minor diagnostic criteria should also be present in order to assign this diagnosis (Table 1). In the initial phases of PMF, the BM is often hypercellular with prominent granulocytic and megakaryocytic proliferation, frequently with a reduction of erythroid precursors. If reticulin fibrosis is present, grade 1 is allocated. Megakaryopoiesis is characterised by the extensive formation of loose to dense clusters of megakaryocytes, with abnormal localisation toward the endosteal borders. Megakaryocyte anomalies include a high degree of cellular atypia (from small to giant forms), abnormal nuclear folding and an aberrant nuclear cytoplasmic ratio created by large, bulbous and hyperchromatic cloud-shaped nuclei. Naked (bare) megakaryocytic nuclei are often visible. Overall, the megakaryocytes in PMF show a more pronounced degree of atypia than in other MPN subtypes. The more advanced fibro-osteosclerotic phases of PMF are characterised by grade ≥2 reticulin deposition, and the appearance of coarse bundles of collagen fibres. Additional features include endophytic bone formation (osteosclerosis) associated with extension of adipose tissue. Dilated marrow sinuses with intraluminal haematopoiesis, especially made up of megakaryocytes, are often seen. The morphological hallmark of post-polycythaemia vera myelofibrosis (PPV-MF) and post-essential thrombocythaemia myelofibrosis (PET-MF) is overt reticulin and collagen fibrosis of the BM. Cellularity varies, but hypocellularity is common. Clusters of megakaryocytes (often with hyperchromatic and abnormal nuclei) are prominent, while erythropoiesis and granulopoiesis are decreased. Osteosclerosis may occur. However, these findings must be integrated with other features to achieve a diagnosis (Table 3).Table 3Diagnostic criteria for post-polycythaemia vera myelofibrosis (PPV-MF) and post-essential thrombocythaemia myelofibrosis (PET-MF) according to the International Working Group for Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) [7.Barosi G. Mesa R.A. Thiele J. et al.Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment.Leukemia. 2008; 22: 437-438Crossref PubMed Scopus (375) Google Scholar]Reprinted by permission from Macmillan Publishers Ltd.: Leukemia [7.Barosi G. Mesa R.A. Thiele J. et al.Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment.Leukemia. 2008; 22: 437-438Crossref PubMed Scopus (375) Google Scholar], copyright 2008.PPV-MFPET-MFRequired criteria (both required):1. Documentation of a previous diagnosis of PV as defined by the 2008 WHO criteria2. Bone marrow fibrosis grade 2–3 (on a 0–3 scale) or grade 3–4 (on a 0–4 scale)1. Documentation of a previous diagnosis of ET as defined by the 2008 WHO criteria2. Bone marrow fibrosis grade 2–3 (on a 0–3 scale) or grade 3–4 (on a 0–4 scale)Additional criteria (≥2 required):Anaemia or sustained loss of requirement for phlebotomy in the absence of cytoreductive therapyAnaemia and a Hb ≥2 g/dl decrease from baseline Hb levelLeukoerythroblastic peripheral blood pictureLeukoerythroblastic peripheral blood pictureIncreasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm from the LCM, or the appearance of a newly palpable splenomegalyIncreasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm from the LCM, or the appearance of a newly palpable splenomegalyDevelopment of ≥1 of the constitutional symptoms (>10% weight loss in 6 months, night sweats, unexplained fever >37.5°C)Development of >1 of the constitutional symptoms (>10% weight loss in 6 months, night sweats, unexplained fever >37.5°C)Increased lactate dehydrogenaseWHO, World Health Organization; LCM, left costal margin; Hb, haemoglobin; PV, polycythaemia vera; ET, essential thrombocythaemia. Open table in a new tab WHO, World Health Organization; LCM, left costal margin; Hb, haemoglobin; PV, polycythaemia vera; ET, essential thrombocythaemia. Although a number of clinicopathological studies have demonstrated that a reliable morphological differentiation can be achieved with high consensus rates [8.Thiele J. Kvasnicka H.M. Müllauer L. et al.Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification.Blood. 2011; 117: 5710-5718Crossref PubMed Scopus (132) Google Scholar, 9.Gianelli U. Bossi A. Cortinovis I. et al.Reproducibility of the WHO histological criteria for the diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms.Mod Pathol. 2014; 27: 814-822Crossref PubMed Scopus (34) Google Scholar, 10.Madelung A.B. Bondo H. Stamp I. et al.World Health Organization-defined classification of myeloproliferative neoplasms: morphological reproducibility and clinical correlations—the Danish experience.Am J Hematol. 2013; 88: 1012-1016Crossref PubMed Scopus (41) Google Scholar], both the reproducibility and the clinical usefulness of the WHO classification of MPNs remain controversial issues, especially concerning the distinction between ET and pre-fibrotic/early myelofibrosis (MF) as well as initial cases of PV from ET or even PMF [11.Thiele J. Kvasnicka H.M. The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis.Curr Hematol Malig Rep. 2009; 4: 33-40Crossref PubMed Scopus (69) Google Scholar, 12.Barbui T. Thiele J. Vannucchi A.M. Tefferi A. Problems and pitfalls regarding WHO-defined diagnosis of early/prefibrotic primary myelofibrosis versus essential thrombocythemia.Leukemia. 2013; 27: 1953-1958Crossref PubMed Scopus (60) Google Scholar]. To avoid incorrect classification, comprehensive evaluation and, if necessary, re-evaluation of patients are suggested. This also ensures that the patient is not unnecessarily diagnosed as ‘MPN-unclassified’. MPNs are characterised by somatic recurrent mutations and are included as the main criteria in the 2008 WHO classification (Table 1), for which a further revision is expected in the future due to the newly discovered calreticulin (CALR) mutations [5.Tefferi A. Thiele J. Vannucchi A.M. Barbui T. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms.Leukemia. 2014; 28: 1407-1413Crossref PubMed Scopus (172) Google Scholar]. These mutations include the Janus kinase (JAK) 2V617F mutation, found in ≥95% of PV and ∼60% of ET and PMF patients. 3%–5% of ET and 5%–8% of PMF patients have point mutations at codon 515 of the gene encoding the thrombopoietin receptor MPL (W>L, K or A). Abnormalities (deletions/duplications/substitutions) located in exon 12 of JAK2 are detected exclusively in 2%–4% of PV. About 60%–80% of JAK2 and MPL un-mutated patients with ET and PMF have mutations in the exon 9 of CALR. Therefore, virtually all patients with PV have a mutation in JAK2. Conversely, 10%–15% of ET and PMF patients remain molecularly uncharacterised, and are operationally defined as ‘triple negative’ for the three phenotypic driver mutations. The presence of any of these mutations excludes reactive forms of erythrocytosis, thrombocytosis and MF, but does not indicate a specific MPN subtype. These mutations can be found using methods such as conventional sequencing, qualitative and quantitative polymerase chain reaction (PCR) and high-resolution melting analysis (may have a sensitivity of 1% and higher). Whole blood or purified granulocytes are harvested and tested; the latter is preferred in cases with low mutation burden, as is often the case with JAK2 exon12 mutations. Genotyping should be obtained at diagnosis. It is not recommended to measure the mutation burden serially during follow-up or to assess response to treatment, except following allogeneic stem-cell transplantation (alloSCT) and, possibly, interferon (IFN) treatment. In such instances, a detection limit of JAK2V617F allele burden of ≤0.1% is recommended [13.Jovanovic J.V. Ivey A. Vannucchi A.M. et al.Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European LeukemiaNet/MPN&MPNr-EuroNet (COST action BM0902) study.Leukemia. 2013; 27: 2032-2039Crossref PubMed Scopus (84) Google Scholar]. Accurate differentiation among the three unique MPN subtypes as well as the exclusion of reactive conditions (in mutation-negative patients only) and disorders such as myelodysplasia and chronic myeloid leukaemia (CML) are critical for appropriate prognosis and therapy decision making. It is not acceptable to use the generic diagnostic label ‘MPN’ alone [I, A]. The 2008 WHO diagnostic criteria for MPN outlined in Table 1 should be followed strictly [1.Swerdlow S.H. Campo E. Harris N.L. et al.WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. International Agency for Research on Cancer, Lyon2008Google Scholar]. Any patient with suspected MPN should be tested for the three driver mutations [I, B]. A simplified diagnostic algorithm is presented in Figure 1. A diagnosis of PPV-MF or PET-MF is made using the criteria described by the International Working Group for Myeloproliferative Neoplasm Research and Treatment (IWG-MRT) (Table 3). Any patient newly diagnosed with MPN should be categorised at baseline according to the risks associated with the disease [I, B]. It must be realised that the prognostic scoring systems used for risk-adapted therapy in PV and ET are based on the likelihood of patients developing thrombotic complications. These complications are the leading cause of morbidity and mortality in PV and ET patients. Scores predicting for overall survival in PV and ET are also available, yet considering the long survival of these disorders, they do not currently impact treatment decisions [14.Passamonti F. Thiele J. Girodon F. et al.A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment.Blood. 2012; 120: 1197-1201Crossref PubMed Scopus (188) Google Scholar, 15.Tefferi A. Rumi E. Finazzi G. et al.Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study.Leukemia. 2013; 27: 1874-1881Crossref PubMed Scopus (430) Google Scholar]. The recommended prognostic scoring system for PV and ET is based upon two variables: age >60 years and previous history of thrombosis. These variables separate patients into low- or high-risk categories (Table 4). In ET, an intermediate-risk group is sometimes advocated. However, this group is variably defined and there is no clear evidence of how to manage patients in this category. Thrombocytosis (>1000 × 109/l) is a risk factor for haemorrhage, and advocates caution for the use of aspirin. Extreme thrombocytosis (>1500 × 109/l) is regarded as an indication for therapy in ET, and less frequently in PV. Improved risk stratification is desirable, but any new risk stratification should be robust, easily measurable and ideally validated in a prospective manner.Table 4Risk stratification and risk-adapted therapy in polycythaemia vera (PV) and essential thrombocythaemia (ET) [16.Barbui T. Barosi G. Birgegard G. et al.Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.J Clin Oncol. 2011; 29: 761-770Crossref PubMed Scopus (631) Google Scholar, 17.Marchioli R. Finazzi G. Landolfi R. et al.Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.J Clin Oncol. 2005; 23: 2224-2232Crossref PubMed Scopus (524) Google Scholar]Risk categoryRisk variablesTherapyPVETLow•Age <60 years•No thrombosis history•Phlebotomy, and•Correction of CV risk factors, and•Low-dose aspirina•Correction of CV risk factors, and•Low-dose aspirinaHigh•Age ≥60 yearsand /or•Thrombosis history•Cytoreduction, and•Correction of CV risk factors, and•Low-dose aspirina•Phlebotomy if required•Cytoreduction, and•Correction of CV risk factors, and•Low-dose aspirinaaDepending on the thrombosis type, oral anti-coagulation instead of low-dose aspirin.CV, cardiovascular. Open table in a new tab aDepending on the thrombosis type, oral anti-coagulation instead of low-dose aspirin. CV, cardiovascular. Since the median survival in PMF is ∼6 years, ranging from <2 to >10 years, the relevant end point for current prognostic scoring systems in PMF is represented by survival (Table 5). The International Prognostic Scoring System (IPSS) [18.Cervantes F. Dupriez B. Pereira A. et al.New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.Blood. 2009; 113: 2895-2901Crossref PubMed Scopus (945) Google Scholar] is used at the time of diagnosis to outline four risk categories (low, intermediate-1, intermediate-2 and high risk), with median survival of 135, 95, 48 and 27 months, respectively. The ‘dynamic’ IPSS (DIPSS) [19.Passamonti F. Cervantes F. Vannucchi A.M. et al.A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment).Blood. 2010; 115: 1703-1708Crossref PubMed Scopus (672) Google Scholar], which utilises the same variables as the IPSS, is employed during follow-up. A refinement is represented by DIPSS-plus score [20.Gangat N. Caramazza D. Vaidya R. et al.DIPSS Plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.J Clin Oncol. 2011; 29: 392-397Crossref PubMed Scopus (711) Google Scholar] that incorporates thrombocytopaenia, transfusion requirements and abnormal cytogenetics (Table 5). The role of CALR [21.Rumi E. Pietra D. Pascutto C. et al.Clinical effect of driver mutations of JAK2, CALR or MPL in primary myelofibrosis.Blood. 2014; 124: 1062-1069Crossref PubMed Scopus (298) Google Scholar] and other mutations (i.e. EZH2, ASXL1, SRSF2, IDH1/2 mutations), comprising a high-molecular risk category in PMF [22.Vannucchi A.M. Lasho T.L. Guglielmelli P. et al.Mutations and prognosis in primary myelofibrosis.Leukemia. 2013; 27: 1861-1869Crossref PubMed Scopus (552) Google Scholar], has been underscored but has yet to be incorporated in an updated prognostic score. Appropriate risk stratification in PMF has relevance for risk-adapted therapy, particularly for alloSCT. These scores are commonly used for PPV-MF and PET-MF. It should be underlined that they have not been validated in such a context, and their appropriateness has been questioned [23.Hernández-Boluda J.C. Pereira A. Gómez M. et al.The International Prognostic Scoring System does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis.Haematologica. 2014; 99: e55-e57Crossref PubMed Scopus (47) Google Scholar].Table 5Risk stratification in primary myelofibrosis (MF)VariableIPSS [18.Cervantes F. Dupriez B. Pereira A. et al.New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.Blood. 2009; 113: 2895-2901Crossref PubMed Scopus (945) Google Scholar]DIPSS [19.Passamonti F. Cervantes F. Vannucchi A.M. et al.A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment).Blood. 2010; 115: 1703-1708Crossref PubMed Scopus (672) Google Scholar]DIPSS-plus [20.Gangat N. Caramazza D. Vaidya R. et al.DIPSS Plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status.J Clin Oncol. 2011; 29: 392-397Crossref PubMed Scopus (711) Google Scholar]Age >65 years✓✓✓Constitutional symptoms✓✓✓Haemoglobin (Hb) <10 g/dl✓✓✓Leukocyte count >25 × 109/l✓✓✓Circulating blasts >1%✓✓✓Platelet count <100 × 109/l✓RBC transfusion need✓Unfavourable karyotypea✓1 point each1 point each but Hb = 2Calculated by the DIPSS score (Int 1 = 1, Int 2 = 2, High = 3) plus one additional point for each of the three additional variablesRisk groupPointsMedian survival (years)PointsMedian survival (years)PointsMedian survival (years)Low011.30n.r.015.4Intermediate-117.91–214.216.5Intermediate-224.03–442–32.9High≥32.35–61.5≥41.3aUnfavourable karyotype includes +8, –7/7q–, i(17q), inv(3), –5/5q–, 12p–, 11q23 rearrangements.IPSS, International Prognostic Scoring System; DIPSS, dynamic International Prognostic Scoring System; RBC, red blood cell; Int, intermediate; n.r., not reached. Open table in a new tab aUnfavourable karyotype includes +8, –7/7q–, i(17q), inv(3), –5/5q–, 12p–, 11q23 rearrangements. IPSS, International Prognostic Scoring System; DIPSS, dynamic International Prognostic Scoring System; RBC, red blood cell; Int, intermediate; n.r., not reached. Treatment aims are to reduce the risk of thrombosis and haemorrhage, control symptoms and perhaps reduce the risk of progression (Figure 2). Cure is not presently possible, except in selected MF patients who are successfully receiving alloSCT. All patients should be informed regarding the disease course, and vascular risk factors such as smoking should be aggressively managed. PV therapy should address both short- and long-term objectives (Figure 2A). In the short-term, therapeutic aims are to reduce the risk of occurrence and recurrence of thrombosis. The long-term objective is to reduce the risk of evolution to MF, myelodysplastic syndrome (MDS) and/or acute myeloid leukaemia (AML) [16.Barbui T. Barosi G. Birgegard G. et al.Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.J Clin Oncol. 2011; 29: 761-770Crossref PubMed Scopus (631) Google Scholar]. Risk stratification (Table 4) aims at selecting the patients with a low risk of vascular events. PV is associated with elevated haematocrit (HCT); with these patients, phlebotomy is carried out to control the HCT and low-dose aspirin is used, as it may delay the need for cytoreductive therapy. Phlebotomy can be an emergency therapy at diagnosis, in patients presenting with very high HCT and clinical signs of hyperviscosity, as well as a long-term maintenance therapy to control the HCT [I, A]. The optimal target of HCT levels for reducing vascular events was a matter of debate, but, a recent multicentre, randomised clinical trial (CYTO-PV) showed that the HCT should be maintained strictly below 45% to efficiently reduce the risk of thrombotic events [I, A] [24.Marchioli R. Finazzi G. Specchia G. et al.Cardiovascular events and intensity of treatment in polycythemia vera.N Engl J Med. 2013; 368: 22-33Crossref PubMed Scopus (506) Google Scholar]. Low-dose aspirin is the second cornerstone of PV therapy [I, A]. It has been shown in the European Collaboration on Low-dose Aspirin in Polycythaemia Vera (ECLAP) study, a large European double-blind, placebo-controlled, randomised trial, to significantly reduce a primary combined end point, including: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and major venous thromboembolism [25.Landolfi R. Marchioli R. Kutti J. et al.Efficacy an

Reliable detection of JAK2-V617F is critical for accurate diagnosis of myeloproliferative neoplasms (MPNs); in addition, sensitive mutation-specific assays can be applied to monitor disease response. However, there has been no consistent approach to JAK2-V617F detection, with assays varying markedly in performance, affecting clinical utility. Therefore, we established a network of 12 laboratories from seven countries to systematically evaluate nine different DNA-based quantitative PCR (qPCR) assays, including those in widespread clinical use. Seven quality control rounds involving over 21,500 qPCR reactions were undertaken using centrally distributed cell line dilutions and plasmid controls. The two best-performing assays were tested on normal blood samples (n=100) to evaluate assay specificity, followed by analysis of serial samples from 28 patients transplanted for JAK2-V617F-positive disease. The most sensitive assay, which performed consistently across a range of qPCR platforms, predicted outcome following transplant, with the mutant allele detected a median of 22 weeks (range 6-85 weeks) before relapse. Four of seven patients achieved molecular remission following donor lymphocyte infusion, indicative of a graft vs MPN effect. This study has established a robust, reliable assay for sensitive JAK2-V617F detection, suitable for assessing response in clinical trials, predicting outcome and guiding management of patients undergoing allogeneic transplant.

Recombinant IFN-α (rIFN-α) induces complete hematologic remissions in patients with myeloproliferative neoplasms (MPNs), but its use has been limited by side effects owing to the relatively high doses used. Now, low-dose rIFN-α is stressed, starting relatively early in the course of the MPNs. In polycythemia vera, this has resulted in a significant clinical, hematologic, morphologic and molecular response manifested by reduction in the JAK2V617F allele burden, sustained even after discontinuation of recombinant IFN. In essential thrombocythemia, platelet count reduction is prompt and durable without treatment for varying periods. In hypercellular primary myelofibrosis, rIFN-α has restored normal blood counts, reduced splenomegaly and induced morphologic marrow remissions. This article highlights our current use of rIFN-α in MPNs.

The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% confidence interval [CI]: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; P = .0148). This observation suggests that ruxolitinib may modify the natural history of PMF.

Abstract Anemia of lower-risk myelodysplastic syndromes (MDSs) and primary myelofibrosis (PMF) generally becomes resistant to available treatments, leading to red blood cell (RBC) transfusions, iron overload, shortened survival, and poor quality of life. The transforming growth factor-β superfamily, including activins and growth differentiation factors (GDFs), is aberrantly expressed in lower-risk MDSs and PMF. Luspatercept (and sotatercept), ligand traps that particularly inhibit GDF11, lead to RBC transfusion independence in 10% to 50% of lower-risk MDSs resistant to available treatments, and have started to be used in PMF.

PURPOSE Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086 ). PATIENTS AND METHODS Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety. RESULTS Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias. CONCLUSION In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway.

We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.

Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p < 0.0001) and multivariate (HR = 0.311; p < 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib's pro-erythropoietic mechanism of action, and potentially informing treatment decision-making.

In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The impact of pacritinib on transfusion independence (TI) has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated. Because it has been previously postulated that inhibition of activin A receptor, type 1 (ACVR1)/activin receptor-like kinase-2 improves anemia in patients with myelofibrosis via suppression of hepcidin production, we assessed the relative inhibitory potency of pacritinib compared with other JAK2 inhibitors against ACVR1. Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [IC50] = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 > 1000; Cmax:IC50 < 0.01). Pacritinib's inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production. Among patients on PERSIST-2 who were not transfusion independent at baseline based on Gale criteria, a significantly greater proportion achieved TI on pacritinib compared with those treated on best available therapy (37% vs 7%, P = .001), and significantly more had a ≥50% reduction in transfusion burden (49% vs 9%, P < .0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition.

We investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations.This first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily [QD]) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety.A total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 dose-limiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment-related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively.Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation.

Natural Killer (NK) cells are critical in host defense against malignant transformation and are potent antileukemic cytotoxic effectors. In the present study, we investigated the peripheral NK function in patients with myelodysplastic syndromes (MDS). We demonstrated that the peripheral NK cell population was quantitatively normal in MDS patients. Furthermore, NK cells displayed an expression of the activating natural cytotoxicity receptors (NCR) NKp46 and NKp30 as well as NKG2D similar to that observed in donors, but exert a highly decreased constitutive cytolytic activity compared to resting normal NK cells. Although activation with IL-2 resulted in the upregulation of NKp46 expression by MDS-NK cells, their cytolytic function remained deeply altered as compared to activated donor NK cells. In addition, MDS NK cells did not proliferate in vitro, and displayed an increased rate of apoptosis in response to IL-2 stimulation although the spontaneous apoptosis was not significantly increased. Interestingly, a proportion of peripheral MDS-NK cells were derived from the MDS clone as the cytogenetic anomaly found in bone marrow karyotype was also detected in 20–50% of circulating NK cells. In conclusion, NK cells' cytolytic function and proliferative capacities in response to activation by cytokines are profoundly altered in MDS.

Summary Patients with myelofibrosis ( MF ) have significant debilitating symptoms, physical disabilities, and poor health‐related quality of life ( HRQoL ). Here, we report post‐hoc analyses of the impact of ruxolitinib, a potent and selective JAK 1 and JAK 2 inhibitor, on disease‐related symptoms and HRQoL in MF patients from the large phase 3 COMFORT ‐ II study ( N = 219). During the follow‐up period of 48 weeks, HRQoL and MF ‐associated symptoms improved from baseline for ruxolitinib‐treated patients but remained the same or worsened for best available therapy ( BAT )‐treated patients. Based on the E uropean Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items ( EORTC QLQ ‐ C 30), treatment‐induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 ( P &lt; 0·05) up to week 48 ( P &lt; 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/ QoL and Functional Assessment of Cancer Therapy‐Lymphoma ( FACT ‐Lym) summary scores versus BAT at most time points ( P &lt; 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT ‐General, FACT ‐Lym trial outcome index, and FACT ‐Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF .

The Philadelphia negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are associated with substantial vascular and transformative complications. Standard therapy for high-risk disease, particularly in patients that have failed initial therapy, remains controversial. Non-pegylated interferon has previously been shown to be effective in controlling erythrocytosis, thrombocytosis and thrombotic complications, but was found to have poor tolerability and excessive adverse effects. Recently, pegylated interferon alpha-2a was introduced and found to be better tolerated and less toxic than standard interferon. In addition, in recent phase II trials, pegylated interferon alpha-2a therapy was found to induce both hematologic and molecular remissions. We retrospectively analyzed 118 myeloproliferative patients who underwent pegylated interferon alpha-2a treatment. Responses were evaluated by ELN, IWG-MET and EUMNET standardized criteria sets and adverse effects were analyzed.

Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

In this report, two patients with essential thrombocythemia and somatic mutations in the gene encoding calreticulin but no mutations in the Janus kinase 2 gene had a response to interferon alfa therapy.

Myeloproliferative neoplasm-related myelofibrosis is associated with cytopenic or proliferative phases, splenomegaly and constitutional symptoms. Few effective treatments are available and small series suggested that interferon could be an option for myelofibrosis therapy. We performed a retrospective study of pegylated-interferon α-2a (Peg-IFNα-2a) therapy in myelofibrosis. Sixty-two patients treated with Peg-IFNα-2a at 17 French and Belgian centres were included. Responses were determined based on the criteria established by the International Working Group for Myelofibrosis Research and Treatment. Mean follow-up was 26 months. Sixteen of 25 anaemic patients (64%) (eight concomitantly receiving recombinant erythropoietin) achieved a complete response and transfusion-independence was obtained in 5/13 patients (38·5%). Constitutional symptoms resolved in 82% of patients. All five leucopenic patients normalized their leucocyte counts, whereas a normal platelet count was obtained in 5/8 thrombocytopenic patients. Splenomegaly was reduced in 46·5% of patients, and complete resolution of thrombocytosis and leucocytosis were observed in 82·8% and 68·8% of patients, respectively. Side effects (mostly haematological) were mainly of grade 1-2. The only factor independently associated with treatment failure was a spleen enlargement of more than 6 cm below the costal margin. In conclusion, Peg-IFNα-2a induced high response rates with acceptable toxicity in a large proportion of patients with primary and secondary myelofibrosis, especially in early phases.

In patients with polycythemia vera (PV), an elevated JAK2 p.V617F allele burden is associated with indicators of more severe disease (e.g., leukocytosis, splenomegaly, and increased thrombosis risk); however, correlations between allele burden reductions and clinical benefit in patients with PV have not been extensively evaluated in a randomized trial. This exploratory analysis from the multicenter, open-label, phase 3 Randomized Study of Efficacy and Safety in Polycythemia Vera With JAK Inhibitor INCB018424 Versus Best Supportive Care trial evaluated the long-term effect of ruxolitinib treatment on JAK2 p.V617F allele burden in patients with PV. Evaluable JAK2 p.V617F-positive patients randomized to ruxolitinib (n = 107) or best available therapy (BAT) who crossed over to ruxolitinib at week 32 (n = 97) had consistent JAK2 p.V617F allele burden reductions throughout the study. At all time points measured (up to weeks 208 [ruxolitinib-randomized] and 176 [ruxolitinib crossover]), mean changes from baseline over time in JAK2 p.V617F allele burden ranged from -12.2 to -40.0% (ruxolitinib-randomized) and -6.3 to -17.8% (ruxolitinib crossover). Complete or partial molecular response was observed in 3 patients (ruxolitinib-randomized, n = 2; ruxolitinib crossover, n = 1) and 54 patients (ruxolitinib-randomized, n = 33; ruxolitinib crossover, n = 20; BAT, n = 1), respectively. Among patients treated with interferon as BAT (n = 13), the mean maximal reduction in allele burden from baseline was 25.6% after crossover to ruxolitinib versus 6.6% before crossover. Collectively, the data from this exploratory analysis suggest that ruxolitinib treatment for up to 4 years provides progressive reductions in JAK2 p.V617F allele burden in patients with PV who are resistant to or intolerant of hydroxyurea. The relationship between allele burden changes and clinical outcomes in patients with PV remains unclear.

Abstract Thromboembolic events are the main cause of mortality in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) but their underlying mechanisms are largely unrecognized. The Janus kinase 2 (JAK2)V617F mutation is the most frequent genetic alteration leading to MPN. Usually found in haematopoietic progenitors and stem cells, this mutation has also been described in endothelial cells (ECs) of MPN patients. In this study, we have questioned the impact of the JAK2V617F mutation on EC phenotype and functions. We developed an induced pluripotent stem cells strategy to compare JAK2 mutant and wild-type ECs. Transcriptomic assays showed that several genes and pathways involved in inflammation, cell adhesion and thrombotic events were over-represented in JAK2V617F ECs and expression levels of von Willebrand factor and P-selectin (CD62P) proteins were increased. Finally, we found that leucocytes from MPN patients adhere more tightly to JAK2V617F ECs. Our results show that JAK2V617F ECs have a pro-inflammatory and pro-thrombotic phenotype and were functionally pro-adherent.

Evaluation of Anagrelide (Xagrid®) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia patients treated with cytoreductive therapy. The primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: anagrelide (Xagrid®) (n=804), other cytoreductive therapy (n=2666), or anagrelide + other cytoreductive therapy (n=141). The median age was 56 vs. 70 years for anagrelide vs. other cytoreductive therapy. Event rates (patients with events/100 patient-years) were 1.62 vs. 2.06 for total thrombosis and 0.15 vs. 0.53 for venous thrombosis. Anagrelide was more commonly associated with hemorrhage (0.89 vs. 0.43), especially with anti-aggregatory therapy (1.35 vs. 0.33) and myelofibrosis (1.04 vs. 0.30). Other cytoreductive therapies were more associated with acute leukemia (0.28 vs. 0.07) and other malignancies (1.29 vs. 0.44). Post hoc multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age ≥65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age ≥65, time since diagnosis, and platelet count increase. Safety analysis reflected published data, and no new safety concerns for anagrelide were found. Live births occurred in 41/54 pregnancies (76%). clinicaltrials.gov Identifier: 00567502.

Cytoreductive therapy is beneficial in patients with essential thrombocythemia (ET) at high risk of thrombosis. However, its value in those lacking high-risk features remains unknown. This open-label, randomized trial compared hydroxycarbamide plus aspirin with aspirin alone in patients with ET age 40 to 59 years and without high-risk factors or extreme thrombocytosis.Patients were age 40 to 59 years and lacked a history of ischemia, thrombosis, embolism, hemorrhage, extreme thrombocytosis (platelet count ≥ 1,500 × 109/L), hypertension, or diabetes requiring therapy. In all, 382 patients were randomly assigned 1:1 to hydroxycarbamide plus aspirin or aspirin alone. The composite primary end point was time to arterial or venous thrombosis, serious hemorrhage, or death from vascular causes. Secondary end points were time to first arterial or venous thrombosis, first serious hemorrhage, death, incidence of transformation, and patient-reported quality of life.After a median follow-up of 73 months and a total follow-up of 2,373 patient-years, there was no significant difference between the arms in the likelihood of patients reaching the primary end point (hazard ratio, 0.98; 95% CI, 0.42 to 2.25; P = 1.0). The incidence of significant vascular events was low, at 0.93 per 100 patient-years (95% CI, 0.61 to 1.41). There were also no differences in overall survival; in the composite end point of transformation to myelofibrosis, acute myeloid leukemia, or myelodysplasia; in adverse events; or in patient-reported quality of life.In patients with ET age 40 to 59 years and lacking high-risk factors for thrombosis or extreme thrombocytosis, preemptive addition of hydroxycarbamide to aspirin did not reduce vascular events, myelofibrotic transformation, or leukemic transformation. Patients age 40 to 59 years without other clinical indications for treatment (such as previous thrombosis or hemorrhage) who have a platelet count < 1,500 × 109/L should not receive cytoreductive therapy.

Purpose Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. Patients and Methods Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). Results The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). Conclusion The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.

RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26%; P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 109/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence.

Introduction: Approximately two-thirds of patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis (MF) have anemia, many of whom require red blood cell (RBC) transfusions. In this heavily transfused population there are severely limited treatment options; effective treatment for anemia in MF is a critically unmet medical need. Luspatercept is a first-in-class erythroid maturation agent which binds to select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. Here we report the interim results of the ongoing open-label, phase 2 trial evaluating luspatercept in patients with MF and anemia. Methods: Seventy-four patients with MF and anemia were enrolled, including 41 not receiving concomitant ruxolitinib at study entry who received either no RBC transfusions (n = 20; Cohort 1) or 2-4 RBC U/28 d in the 12 wks prior to treatment (n = 21; Cohort 2). Thirty-three enrolled patients were receiving a stable dose of ruxolitinib for at least 16 wks, of which 14 were not receiving RBC transfusions (Cohort 3A) and 19 were (Cohort 3B). Patients in Cohorts 3A and 3B received a median dose of ruxolitinib of 20 mg/d (range, 5-50 mg/d) for a median of 41 and 43 wks, respectively. Patients received luspatercept every 21 d at a starting dose of 1.0 mg/kg in doses escalating up to 1.75 mg/kg. The primary endpoint in patients not receiving transfusions was a hemoglobin (Hb) increase ≥ 1.5 g/L at every assessment from baseline for ≥ 12 consecutive wks, within the first 24 wks on study. In patients receiving RBC transfusions, the primary endpoint was RBC transfusion-independence (RBC-TI) for ≥ 12 consecutive wks, within the first 24 wks on study. Additional endpoints included proportion of patients achieving mean Hb increase ≥ 1.5 g/dL in Cohorts 1 and 3A, and ≥ 50% decrease in RBC transfusions (minimum 4 RBC U decrease from baseline) in Cohorts 2 and 3B, with both responses lasting ≥ 12 consecutive wks, within 24 wks of study entry. Intent-to-treat (ITT) data were analyzed as of May 10, 2019. Results: Median age was 71 y (range, 50-88 y) and 42 (57%) were male. Median interval from MF diagnosis to study entry was 3.3 y (range, 19 d-13.5 y). Seven patients were Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, 58 were intermediate-2, and 8 were high risk. Median Hb concentration at study entry was 8.8 g/dL (range, 6.7-9.8 g/dL) for Cohort 1 and 8.6 g/dL (range, 6.7-9.1 g/dL) for Cohort 3A. Patients in Cohort 2 received a median of 2.7 RBC U/28 d (range, 1-5 U/28 d) and patients in Cohort 3B received a median of 2.3 RBC U/28 d (range, 2-4 U/28 d). Patients received a median of 8 cycles of luspatercept (range, 1-24 cycles). Efficacy data are displayed in the Table, per ITT data. Two of twenty (10%) and 3/14 (21%) patients in Cohorts 1 and 3A, respectively, achieved an absolute Hb increase ≥ 1.5 g/dL at every measurement from baseline over any consecutive 12 wks. Two of twenty-one (10%) and 6/19 (32%) patients in Cohorts 2 and 3B, respectively, achieved RBC-TI over any consecutive 12 wks. Median duration of Hb response was 20 wks (range, 12-27 wks) in Cohort 1 and 12 wks (range, 12-13 wks) in Cohort 3A. Median duration of RBC-TI was 23 wks (range, 16-31 wks) in Cohort 2 and 32 wks (range, 12-65 wks) in Cohort 3B. Three (15%) and 8 (57%) patients in Cohorts 1 and 3A, respectively, achieved a mean Hb increase of ≥ 1.5 g/dL. Eight (38%) and 10 (53%) patients in Cohorts 2 and 3B, respectively, achieved a ≥ 50% reduction in RBC transfusion burden from baseline. Ruxolitinib exposure remained stable throughout the 24-wk treatment period in both Cohorts 3A and 3B. There was no difference in spleen size between responders and non-responders. Four (5%) patients had grade 3-4 treatment-related adverse events (AEs). There were no treatment-related deaths. Treatment-related AEs occurring in ≥ 3% of patients were hypertension (11%), bone pain (8%), and diarrhea (4%). Seven (9%) patients had ≥ 1 AE resulting in treatment discontinuation; 23 (31%) remain on study. Conclusions: The initial results from this ongoing study suggest clinically significant activity of luspatercept in patients with MF-associated anemia, including those receiving concomitant ruxolitinib. A minority of AEs were grade 3-4 in severity, consistent with previous studies in MDS and beta-thalassemia. Disclosures Gerds: CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding. Vannucchi:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Gotlib:Celgene Corporation: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Promedior: Consultancy, Research Funding; Kartos: Consultancy, Honoraria, Research Funding; CTI Biopharma: Research Funding. Ribrag:BMS: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees. Mead:Celgene: Consultancy, Research Funding; CTI: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Consultancy; Pfizer: Consultancy. Harrison:Sierra Oncology: Honoraria; Gilead: Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Promedior: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau. Mesa:Shire: Honoraria; Promedior: Research Funding; Genotech: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; LaJolla: Consultancy; AbbVie: Research Funding; NS Pharma: Research Funding; CTI: Research Funding; Gilead Sciences: Research Funding; Samus: Research Funding; Baxalta: Consultancy; Galena Biopharma: Consultancy; Celgene Corporation: Research Funding; Sierra Oncology: Consultancy; PharmaEssentia: Research Funding; Genentech: Consultancy; Pfizer: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Incyte: Other: travel, accommodations, expenses, Research Funding. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. Gale:Celgene Corporation: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Pariseau:Celgene Corporation: Employment. Gerike:Celgene Corporation: Employment. Zhang:Celgene Corporation: Employment, Equity Ownership. Linde:Abbott Laboratories, Inc.: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership. Reynolds:Acceleron Pharma: Employment, Equity Ownership. Verstovsek:Gilead: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Roche: Research Funding; Incyte: Research Funding. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

We have previously described the safety and efficacy of pegylated interferon-α2a therapy in a cohort of 62 patients with myeloproliferative neoplasm-associated myelofibrosis followed in centers affiliated to the French Intergroup of Myeloproliferative neoplasms. In this study, we report their long-term outcomes and correlations with mutational patterns of driver and non-driver mutations analyzed by targeted next generation sequencing. The median age at diagnosis was 66 years old, the median follow-up since starting pegylated interferon was 58 months. At the time of analysis, 30 (48.4%) patients were alive including 16 still being treated with pegylated interferon. The median survival of patients with intermediate and high-risk prognostic Lille and dynamic International Prognostic Scoring System scores treated with pegylated interferon was increased in comparison to that of historical cohorts. In addition, overall survival was significantly correlated with the duration of pegylated interferon therapy (70 versus 30 months after 2 years of treatment, P<10-12). JAK2V617F allele burden was decreased by more than 50% in 58.8% of patients and two patients even achieved complete molecular response. Next-generation sequencing analyses performed in 49 patients showed that 28 (57.1%) of them carried non-driver mutations. The presence of at least one additional mutation was associated with a reduction of both overall and leukemia-free survival. These findings in a large series of patients with myelofibrosis suggest that pegylated interferon therapy may provide a survival benefit for patients with intermediate- or high-risk Lille and dynamic International Prognostic Scoring System scores. It also reduced the JAK2V617F allele burden in most patients. These results further support the use of pegylated interferon in selected patients with myelofibrosis.

Although it is well known that myeloproliferative neoplasms occur in younger patients, few large cohorts of such patients have been reported. Thus, our knowledge about circumstances of diagnosis, outcome and treatment is limited, especially for children and young adults. We therefore performed a systematic review of cases, published since 2005, concerning patients aged below 20 years at the time of diagnosis of essential thrombocythemia or polycythemia vera. We identified 396 cases of essential thrombocythemia and 75 of polycythemia vera. The median age at diagnosis was 9.3 and 12 years, respectively, and females constituted 57.6% and 45% of the groups, respectively. Half of the patients were asymptomatic at diagnosis. The proportion of so-called triple negativity was high: 57% in essential thrombocythemia and 73% in polycythemia vera. The incidence of thrombosis during the follow-up was 9.3% in patients with polycythemia vera and less, 3.8%, in those with essential thrombocythemia. Venous events were predominant (84.2%), with hemorrhagic episodes being rarer (

Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors.INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system. Safety and tolerability were monitored by clinical and laboratory assessments. Progression-free survival and overall survival were reported using Kaplan-Meier survival analysis. Immunogenicity was studied by ELISpot, Luminex, and Flow Cytometry.Twenty-six patients were treated with INVAC-1 administered at three dose levels (100, 400, and 800 μg). Vaccination was well tolerated and no dose-limiting toxicity was reported. One treatment-related grade 3 SAE was reported. Fifty-eight percent of patients experienced disease stabilization. PFS was 2.7 months, median OS was 15 months, and 1-year survival was reached for 65% of patients. INVAC-1 vaccination stimulated specific anti-hTERT CD4 T-cell response as well as cytotoxic CD8 T-cell response. No evidence of peripheral vaccine-induced immunosuppression was observed.INVAC-1 vaccination was safe, well tolerated, and immunogenic when administered intradermally at the three tested doses in patients with relapsed or refractory cancers. Disease stabilization was observed for the majority of patients (58%) during the treatment period and beyond.See related commentary by Slingluff Jr, p. 529.

Abstract Purpose: This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53–MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers. Patients and Methods: Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12.5–350 mg) and 2A (days 1–14; 28-day cycle; dose 1–20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1–7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1. Results: Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% [95% confidence interval (CI), 2.2–27.4] in solid tumors and 4.2% (95% CI, 0.1–21.1), 20% (95% CI, 4.3–48.1), and 22.2% (95% CI, 8.6–42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively. Conclusions: A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.

Thrombocytopenia is common in patients with myelofibrosis (MF) and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (platelet counts <50×109/L). Pacritinib, a novel JAK2/interleukin-1 receptor-associated kinase 1 inhibitor, has been studied in two phase III trials (PERSIST-1 and PERSIST- 2), both of which enrolled patients with MF and severe thrombocytopenia. In order to better characterize treatment outcomes for this population with advanced disease, we present a retrospective analysis of efficacy and safety data in the 189 patients with severe thrombocytopenia treated in the PERSIST studies. The proportion of patients in the pacritinib group meeting efficacy endpoints was greater than in the BAT group for ≥35% spleen volume reduction (23% vs. 2%, P=0.0007), ≥50% modified Total Symptom Score reduction (25% vs. 8%, P=0.044), and self-reported symptom benefit ("much" or "very much" improved; 25% vs. 8%, P=0.016) at the primary analysis time point (week 24). The adverse event profile of pacritinib was manageable, and dose modification was rarely required. There was no excess in bleeding or death in pacritinib-treated patients. These results indicate that pacritinib is a promising treatment for patients with MF who lack safe and effective therapeutic options due to severe thrombocytopenia.

Background: In myelofibrosis (MF), patients with cytopenias have posed a therapeutic challenge, as the first two approved JAK2 inhibitors exacerbate anemia and thrombocytopenia. In contrast, newer JAK2 inhibitors, have been associated with hematologic stability and, in some cases, anemia benefit. For example, patients treated with the newly approved JAK2/IRAK1 inhibitor pacritinib were more likely to achieve clinical improvement in hemoglobin compared to best available therapy (BAT) in the Phase 3 PERSIST-2 study. This effect may be the result of enhanced erythropoiesis via IRAK1 inhibition by pacritinib. Similarly, it has been postulated that inhibition of activin A receptor, type I (ACVR1), which mediates hepcidin production, is able to overcome the JAK2 inhibitor class effect on anemia and result in improvement in transfusion independence (TI). The impact of pacritinib on TI has not previously been described, nor has a mechanism been elucidated by which pacritinib improves anemia. Here, we show that pacritinib is a potent ACVR1 inhibitor with a clinically important impact on TI in patients with MF. Methods: Patients treated on PERSIST-2 were included in this analysis provided they were not TI at baseline and had enrolled ³12 weeks prior to study termination. All patients had platelet counts ≤100x109/L as an enrollment criterion. The percentage of patients who became TI was compared between pacritinib 200 mg BID and BAT through week 24. The subgroup of BAT that received erythroid support (erythropoiesis stimulating agents, danazol, thalidomide or analogs, or corticosteroids) was also analyzed. TI was defined using both Gale criteria (absence of RBC transfusions over a 12-week period) and criteria employed in the pivotal studies of momelotinib ("SIMPLIFY criteria": absence of RBC transfusions and no hemoglobin <8 g/dL). The inhibitory activity of pacritinib, momelotinib, fedratinib, and ruxolitinib against ACVR1 was assessed using a HotSpot assay (Reaction Biology Corporation). The half maximal inhibitory concentration (IC50) was calculated using 3-fold serial dilutions starting at 10µM. Results: Baseline characteristics of patients who were not TI (SIMPLIFY criteria) were similar between pacritinib (n=42) and BAT (n=44), including median hemoglobin (8.7 vs. 8.6 g/dL), median platelet count (43 vs. 41 x109/L), and percentage who received prior JAK2 inhibitor therapy (55% vs. 57%). Among patients with JAK2V617F, most patients in both treatment groups had <50% allele burden (75% [27/36] vs. 74% [26/35]). A significantly greater proportion of pacritinib-treated patients achieved TI compared to BAT (24% vs. 5%, P=0.013 based on SIMPLIFY criteria; 37% vs. 7%, P=0.001 based on Gale criteria), as shown in Figure 1A. The TI conversion rate for patients who received erythroid support therapies as BAT (8% with SIMPLIFY criteria; 9% with Gale criteria) was similar to the overall BAT group. The effect size for pacritinib was maintained among patients who had not received ruxolitinib within 30 days prior to treatment initiation, suggesting that conversion to TI was related to a pacritinib treatment effect rather than to a rebound effect of prior ruxolitinib. TI conversion rates were higher on pacritinib compared to BAT in patients with platelet counts <50x109/L and in those with low and with high JAK2V617F allele burden. Pacritinib-treated patients achieved TI throughout the study through week 24 (Figure 1B). To evaluate possible mechanisms of erythropoietic benefit, we measured ACVR1 inhibition and found that the IC50 of pacritinib against ACVR1 was 16.7 nM, which is 12.7-fold lower than the maximum concentration (Cmax) achieved clinically with pacritinib 200 mg BID. Momelotinib inhibited ACVR1 with a mean IC50 of 52.5 nM, which is 3.2 times lower than the clinical Cmax. Neither fedratinib nor ruxolitinib were potent ACVR1 inhibitors (Figure 2). Discussion: Pacritinib exhibited four-fold higher potency for ACVR1 compared to momelotinib and is associated with a clinically and statistically significant improvement in transfusion requirement in patients with MF. In contrast, JAK2 inhibitors that do not inhibit ACVR1 tend to worsen anemia. Further studies are needed to establish the mechanisms underlying the benefits of pacritinib in anemic patients, including the role of IRAK1 and ACVR1 inhibition. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Background In the PEGASUS trial, the complement C3 inhibitor, pegcetacoplan, showed superiority to eculizumab in improving haematological outcomes in adult patients with paroxysmal nocturnal haemoglobinuria and suboptimal response to eculizumab at 16 weeks. The aim of the open-label period was to evaluate the long-term efficacy and safety of pegcetacoplan through to 48 weeks. Methods PEGASUS was a phase 3, randomised, open-label, active-comparator controlled trial conducted in 44 centres in Australia, Belgium, Canada, France, Germany, Japan, Russia, South Korea, Spain, the UK, and the USA. Eligible participants were aged 18 years or older, had paroxysmal nocturnal haemoglobinuria, and had a haemoglobin concentration of less than 10·50 g/dL after 3 months or longer of stable eculizumab treatment. After a 4-week run-in with eculizumab plus pegcetacoplan, patients were randomly assigned (1:1) by interactive response technology to pegcetacoplan (1080 mg subcutaneously twice weekly) or eculizumab (according to their regimen at enrolment) for 16 weeks and could continue to the open-label period (32 weeks of pegcetacoplan monotherapy [pegcetacoplan-to-pegcetacoplan] or 28 weeks of pegcetacoplan monotherapy [eculizumab-to-pegcetacoplan]). Randomisation was stratified by platelet count and number of previous blood transfusions. The primary endpoint was change from baseline in haemoglobin at week 16, which has previously been reported. The outcomes of the open-label period (week 16 to week 48) are reported here. At 48 weeks, efficacy (including mean haemoglobin concentration and quality of life measured on the Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scale) was assessed in the intention-to-treat population and safety was assessed per protocol. This trial was registered with ClinicalTrials.gov, NCT03500549, and has been completed. Findings Between June 14, 2018, and Nov 14, 2019, 80 patients were randomly assigned to receive treatment with pegcetacoplan (41 patients) or eculizumab (39 patients). Most participants were women (49 [61%]) and 31 (39%) were men; 12 (15%) were Asian, two (3%) were Black, 49 (61%) were White, and 17 (21%) were another race or did not report their race. The open-label period had 77 participants (38 pegcetacoplan-to-pegcetacoplan, 39 eculizumab-to-pegcetacoplan). Patients in the pegcetacoplan-to-pegcetacoplan group maintained high mean haemoglobin concentrations between 16 weeks (11·54 g/dL [SD 1·96]) and 48 weeks (11·30 g/dL [1·77]; p=0·14). Patients in the eculizumab-to-pegcetacoplan group had significantly greater mean haemoglobin concentrations at 48 weeks (11·57 g/dL [2·21]) versus 16 weeks (8·58 g/dL [0·96]; p<0·0001). Clinically meaningful improvements in FACIT-Fatigue scores were observed at 48 weeks, with a mean change from baseline for all patients receiving pegcetacoplan monotherapy of 9·89 points (SD 9·63), for patients in the pegcetacoplan-to-pegcetacoplan group mean 10·14 points (9·06), and for patients in the eculizumab-to-pegcetacoplan group mean 9·62 points (10·34). During the entire study period, 13 (16%) of 80 patients discontinued treatment (three [7%] of 41 through to week 16 due to breakthrough haemolysis, and ten [13%] of 77 due to severe treatment-emergent adverse events) and 18 patients (eight pegcetacoplan-to-pegcetacoplan, ten eculizumab-to-pegcetacoplan) had at least one serious treatment-emergent adverse event during the open-label period, four were considered to be related to pegcetacoplan treatment. The most common treatment-emergent adverse events (in ≥10% patients) among both pegcetacoplan-treated groups during the open-label period were injection site reactions (in 20 [26%] of 77 patients), haemolysis (15 [19%]), nasopharyngitis (12 [16%]), and diarrhoea (ten [13%]). No treatment-related deaths occurred throughout the duration of the study. Interpretation The durability of improved haematological outcomes and favourable safety profile over 48 weeks of treatment suggests that pegcetacoplan has the potential to improve treatment benefit and alter treatment goals in patients with paroxysmal nocturnal haemoglobinuria. Funding Apellis Pharmaceuticals.

Myelofibrosis (MF) is a myeloproliferative disorder that exhibits considerable biological and clinical heterogeneity. At the two ends of the disease spectrum are the myelodepletive or cytopenic phenotype and the myeloproliferative phenotype. The cytopenic phenotype has a high prevalence in primary MF (PMF) and is characterized by low blood counts. The myeloproliferative phenotype is typically associated with secondary MF (SMF), mild anemia, minimal need for transfusion support, and normal to mild thrombocytopenia. Differences in somatic driver mutations and allelic burden, as well as the acquisition of non-driver mutations further influences these phenotypic differences, prognosis, and response to therapies such as JAK2 inhibitors. The outcome of patients with the cytopenic phenotype are comparatively worse and frequently pose a challenge to treat given the inherent exacerbation of cytopenias. Recent data indicate that an innate immune deregulated state that hinges on the myddosome-IRAK-NFκB axis favors the cytopenic myelofibrosis phenotype and offers opportunity for novel treatment approaches. We will review the biological and clinical features of the MF disease spectrum and associated treatment considerations.

7002 Background: MMB, an oral JAK1/2 and ACVR1/ALK2 inhibitor, showed clinical activity on MF symptoms, RBC transfusion requirements (anemia), and spleen volume in the SIMPLIFY trials. This pivotal phase 3 study of MF patients (pts) previously treated with a JAK inhibitor (JAKi) tested MMB vs DAN on key symptom, anemia, and spleen volume endpoints at 24 weeks (wks). Methods: Eligibility: Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) ≥10; Hgb &lt;10 g/dL; prior JAKi for ≥90 days, or ≥28 days if RBC transfusions ≥4 units in 8 wks or Gr 3/4 thrombocytopenia, anemia, or hematoma; palpable spleen ≥5 cm. Stratification: TSS, palpable spleen, and RBC units transfused. JAKi taper and washout was ≥21 days. Randomization: 2:1 to MMB 200 mg QD plus DAN placebo or DAN 600 mg QD plus MMB placebo for 24 wks, after which pts could receive open-label MMB. Assessments: Pt reported symptoms using a daily eDiary and spleen volume by MRI or CT. The primary endpoint was TSS response (≥50% reduction from baseline [BL]) rate at wk 24. Secondary endpoints, assessed sequentially at wk 24, were RBC transfusion independence (TI) rate, splenic response rate (SRR; ≥25% reduction in volume from BL), change from BL in TSS, SRR (≥35% reduction from BL) and rate of zero transfusions since BL. Results: 94 of 130 (72%) MMB pts and 38 of 65 (58%) DAN pts completed the 24-wk randomized treatment (RT) phase. Median BL TSS were 28 (MMB) and 26 (DAN), Hgb were 8.1 (MMB) and 7.9 (DAN) g/dL, and platelets were 97 (MMB) and 94 (DAN) x10 9 /L. BL TI was 13% (MMB) and 15% (DAN). Prior JAKi was ruxolitinib in 195 pts (100%) and fedratinib in 9 pts (5%). All primary and key secondary endpoints were met (Table). Most common Gr ≥3 TEAEs in the RT phase of the study were thrombocytopenia (MMB, 22%; DAN, 12%) and anemia (MMB, 8%; DAN, 11%). Gr ≥3 infections occurred in 15% of MMB and 17% of DAN pts. Peripheral neuropathy occurred in 5 (4%) of MMB (all Gr ≤2) and 1 (2%) of DAN (Gr ≤2) pts in the RT phase, and none discontinued study drug. Overall, TEAEs led to study drug discontinuation in 18% of MMB and 23% of DAN pts in RT phase. A trend toward improved OS up to wk 24 was seen with MMB vs DAN (HR=0.506, p=0.0719). Conclusions: In symptomatic and anemic MF pts, MMB was superior to DAN for symptom responses, transfusion requirements, and spleen responses with comparable safety and favorable survival. MMB may address a critical unmet need, particularly in MF pts with anemia. Clinical trial information: NCT04173494. [Table: see text]

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov).Myelofibrosis (MF) is a rare type of blood cancer that interferes with the process of blood cell production by the bone marrow. In patients with MF, the bone marrow becomes overactive, leading to scarring and subsequently a lack of healthy blood cells being produced. The main symptoms of MF include anemia, fatigue, weakness and pain or discomfort in the abdomen. MF is associated with a shortened life expectancy. The current go-to treatment for MF is ruxolitinib. However, ruxolitinib has shown limited efficacy in improving clinical symptoms long term; so, new safe and effective treatments are needed. Pelabresib is a novel drug currently in clinical development for treating MF. The aim of this article is to describe the design of the ongoing, global phase III MANIFEST-2 study. MANIFEST-2 is evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with MF.

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 109 /l, based on outcomes from the phase 3, placebo-controlled JAKARTA trial in JAK-inhibitor-naïve MF, and the phase 2, single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 109 /l ("Low-Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low-Platelets cohort and patients with baseline platelet counts ≥100 × 109 /l ("High-Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low- and High-Platelets cohorts. Fedratinib was generally well-tolerated in both platelet-count cohorts. New or worsening thrombocytopaenia was more frequent in the Low-Platelets (44%) versus the High-Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low-Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients.

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0-70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%-73%] vs. 57% [95% CI, 49%-64%]; hazard ratio, 1.53; 95% CI, 1.01-2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue. Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments. Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment. Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

Momelotinib is the first inhibitor of Janus kinase 1 (JAK1) and JAK2 shown to also inhibit activin A receptor type 1 (ACVR1), a key regulator of iron homeostasis, and has demonstrated improvements in splenomegaly, constitutional symptoms, and anemia in myelofibrosis (MF). This long-term analysis pooled data from 3 randomized phase 3 studies of momelotinib (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), representing MF disease from early (JAK inhibitor-naive) to late (JAK inhibitor-experienced) stages. Patients in the control arms (danazol in MOMENTUM, ruxolitinib in SIMPLIFY-1, and best available therapy in SIMPLIFY-2) could cross over to receive momelotinib at the end of the 24-week randomized period, and all patients could continue momelotinib treatment after the completion of these studies via an extended access protocol (XAP). Across these studies, 725 patients with MF received momelotinib; 12% remained on therapy for ≥5 years, with a median treatment exposure of 11.3 months (range, 0.1-90.4 months). The most common nonhematologic treatment-emergent adverse event (AE) occurring in ≥20% of patients was diarrhea (any grade, 27% and grade ≥3, 3%). Any-grade thrombocytopenia, anemia, and neutropenia occurred in 25%, 23%, and 7% of patients, respectively. The most common reason for momelotinib discontinuation was thrombocytopenia (4% discontinuation rate). The incidence of AEs of clinical importance (eg, infections, malignant transformation, peripheral neuropathy, and hemorrhage) did not increase over time. This analysis of one of the largest randomized trial databases for a JAK inhibitor to date in MF demonstrated a consistent safety profile of momelotinib without long-term or cumulative toxicity. These trials were registered at www.clinicaltrials.gov as: MOMENTUM (#NCT04173494), SIMPLIFY-1 (#NCT01969838), SIMPLIFY-2 (#NCT02101268), and XAP (#NCT03441113).

Despite recent discoveries made in myeloproliferative disorders other than chronic myelogenous leukemia, which it is hoped will result in earlier diagnosis, and better evaluation and management of patients, hematological evolution to myelofibrosis, acute leukemia, and myelodysplastic syndromes (AL/MDS) remain major causes of long-term mortality in polycythemia vera (PV) and essential thrombocythemia (ET) patients. Evaluation of long-term leukemogenic risk of currently available drugs, therefore, is crucial. We report updated results of three French prospective trials of hydroxyurea and pipobroman in PV and ET patients with a median follow-up longer than 10 years. The results show that the incidence of AL/MDS is higher than previously reported with no evidence of a plateau (with ~40% of AL/MDS cases occurring after the 12th year of follow-up). Although hydroxyurea currently remains the first choice in the treatment of high-risk PV and ET patients, the use of nonleukemogenic drugs, such as interferon α (IFN-α) or anagrelide, should be assessed more widely in randomized trials using accurate diagnostic criteria and taking into account the presence of the JAK2 mutation, given that they may have an impact on disease evolution.

The moderate effect of most palliative treatments in primary and secondary myelofibrosis in addition to the restricted possibilities of allogeneic stem cell transplantation has encouraged physicians to look for alternative treatments (Kröger & Mesa, 2008; Hasselbalch, 2009). Since 1987, several studies have suggested that interferons (alpha or beta that are either pegylated or not) may be beneficial in the treatment of myelofibrosis (Parmeggiani et al, 1987; Kiladjian et al, 2008a). Given the efficacy of pegylated interferon α-2a (Peg-IFN α-2a) on biological and molecular parameters in polycythemia vera (PV) patients (Kiladjian et al, 2008b), we undertook a multicentre retrospective study in order to evaluate the impact of this treatment on the clinical and biological parameters inherent to myelofibrosis. From December 2006 to July 2008, all of the patients who were treated with Peg-IFN α-2a for myelofibrosis (according to the World Health Organization 2007 classification) were analysed in seven French GEM (Groupe d’Etudes des Myélofibroses) and FIM (France Intergroupe des Syndromes Myéloprolifératifs) centres (Tefferi et al, 2007). All of the tests were performed during routine visits and informed oral consent was obtained from each patient. The clinical and biological records included a spleen palpation examination and a complete blood count (haemoglobin, leucocyte and platelet counts). In addition, every patient was locally assessed for the presence of the JAK2V617F mutation with each centre using its own method. Fourteen patients in this study were pre-treated prior to analysis, the majority of whom were pre-treated with hydroxycarbamide. We analysed the response according to the European Myelofibrosis Network (EUMNET) criteria for response in myelofibrosis patients (Barosi et al, 2005). Notably, all of the patients were at least 18 years old. A total of 18 patients (10 females, eight males, aged 36–77 years) who were treated with Peg-IFN α-2a for myelofibrosis were identified. Nine of these patients were aged over 70 years. Fifteen patients had secondary myelofibrosis (10 post-PV and five post-essential thrombocythaemia), 14 patients carried the JAK2V617F mutation. All of these data are summarised in Table I. The median leucocyte count was 22·7 × 109/l (range 2·9 × 109/l to 78·4 × 109/l). Nine patients had leucocytosis. Interestingly, five of these patients were characterised as achieving a ‘complete response’ and four of these patients were characterised as obtaining a ‘partial response’. A single patient with leucopenia normalised his leucocyte count. The median platelet count was 461 × 109/l (range 35 × 109/l to 949 × 109/l). Eleven patients were diagnosed with thrombocytosis; 10 of these 11 patients achieved a ‘complete response’ and one out of three thrombocytopenic patients normalised their platelet count. The median level of haemoglobin was determined to be 112 g/l (range 80–15 g/l). Among the three transfusion-dependent patients, two became transfusion-independent. In addition, four of the five other anaemic patients normalised their haemoglobin level (Hb > 100 g/l). Furthermore, splenomegaly was palpable in 12 patients with a median mass size of 11 cm below the left costal margin (range 2–22 cm). Complete disappearance of splenomegaly was observed in only two cases. Since 1987, several reports have indicated significant heterogeneity in the response of myelofibrosis to treatment with recombinant IFN (α, β and γ) (Parmeggiani et al, 1987; Kiladjian et al, 2008a). The first available treatments required daily injections and were poorly tolerated, with only a few ‘major’ or ‘complete responses’ observed. More recent reports have indicated that IFN-α is most frequently used in myelofibrotic patients (Kiladjian et al, 2008a). However, the use of Peg-IFN (α-2b) was reported only once and was found to produce poor results, with only one patient out of 11 achieving a ‘complete response’ (Jabbour et al, 2007). In a recent report, Peg-IFN α-2a induced haematological and even molecular responses in polycythaemic patients (Kiladjian et al, 2008b). Herein we report the results from what we believe to be the first study using the Peg-IFN α-2a in patients with primary and secondary myelofibrosis and our results favour a true efficacy, because all of the patients except two responded to achieve either ‘complete remission’ (six patients) or ‘major responses’ (two patients, 44% of patients). Only two patients stopped treatment because of the loss of efficacy or symptomatic phase of the disease. Peg-IFN acts more specifically and rapidly (3 months) on proliferative patterns (leucocytosis and thrombocytosis). Interestingly, anaemia improved in 80% of the patients after 6 months of treatment. Also, splenomegaly appeared insensitive to Peg-IFN α-2a treatment. We conclude that Peg-IFN is efficient and safe and should be considered when treating both young and old patients with myelofibrosis regardless of whether or not the JAK2V617F mutation is present. In order to ascertain these preliminary results, a randomised trial must be performed.

<h3>Background and Aims</h3> Myeloproliferative neoplasms (MPN) are the leading cause of splanchnic vein thrombosis (SVT). Janus kinase 2 gene (<i>JAK2</i>)<i>^V617F</i> mutations are found in 80 to 90% of patients with SVT and MPN. Mutations of the calreticulin (<i>CALR</i>) gene have also been reported. However, as their prevalence ranges from 0 to 2%, the utility of routine testing is questionable. This study aimed to identify a group of patients with SVT at high risk of harboring <i>CALR</i> mutations and thus requiring this genetic testing. <h3>Methods</h3> <i>CALR</i>, <i>JAK2^V617F</i> and thrombopoietin receptor gene (<i>MPL</i>) mutations were analysed in a test cohort that included 312 patients with SVT. Criteria to identify patients at high risk of <i>CALR</i> mutations in this test cohort was used and evaluated in a validation cohort that included 209 patients with SVT. <h3>Results</h3> In the test cohort, 59 patients had <i>JAK2^V617F</i>, five had <i>CALR</i> and none had <i>MPL</i> mutations. Patients with <i>CALR</i> mutations had higher spleen height and platelet count than patients without these mutations. All patients with <i>CALR</i> mutations had a spleen height ⩾16cm and platelet count >200×10⁹/L. These criteria had a positive predictive value of 56% (5/9) and a negative predictive value of 100% (0/233) for the identification of <i>CALR</i> mutations. In the validation cohort, these criteria had a positive predictive value of 33% (2/6) and a negative predictive value of 99% (1/96). <h3>Conclusion</h3> <i>CALR</i> mutations should be tested in patients with SVT, a spleen height ⩾16cm, platelet count >200×10⁹/L, and no <i>JAK2^V617F</i>. This strategy avoids 96% of unnecessary <i>CALR</i> mutations testing. <b>Lay summary:</b> Mutations of the <i>CALR</i> gene are detected in 0 to 2% of patients with SVT, thus the utility of systematic <i>CALR</i> mutation testing to diagnose MPN is questionable. This study demonstrates that <i>CALR</i> mutations testing can be restricted to patients with SVT, a spleen height ⩾16cm, a platelet count >200×10⁹/L, and no <i>JAK2^V617F</i>. This strategy avoids 96% of unnecessary <i>CALR</i> mutations testing.

Abstract Ruxolitinib (RUXO) is a JAK inhibitor recently approved in France in patients (pts) with myelofibrosis (MF) because of its efficacy on splenomegaly and constitutional symptoms. Although no prospective safety data are available, many centers have started to use RUXO before HSCT to improve general performance status and decrease splenomegaly (influencing the engraftment). This academic study (ClinicalTrials.gov: NCT01795677) was designed to assess the impact of RUXO in pts with MF candidates for HSCT. Primary objective is the achievement of a disease-free survival at 1 year post HSCT &gt; 50%. A total of 53 pts should be transplanted in order to reach this endpoint. Secondary objectives include: probability to be transplanted in pts with donor, overall survival, non-relapse mortality, hematological response, rate of pre-HSCT splenectomy, quality of life and MF-associated symptoms (through questionnaires). Inclusion criteria are: pts with MF, &lt; 70 years, with either an intermediate or high risk MF according to Lille or IPSS score, or poor prognostic cytogenetics: complex karyotype, abnormalities of chromosomes 5, 7 or 17. Pts with platelets &lt; 50 G/L, blasts ≥ 20% or previously treated with RUXO are excluded. After inclusion, RUXO is started at 15 mg BID in pts with platelets &gt; 100 G/L or 10 mg BID in pts with platelets &lt; 100 G/L and the search for a donor is started. If a donor is identified (related or unrelated HLA matched), the patient should be transplanted within 4 months. Pts without donors are prospectively followed on RUXO therapy in a parallel group. Conditioning regimen (CR) consists in melphalan and fludarabine, started after RUXO tapering and discontinuation. In May 2013, as some unexpected severe adverse events (SAE) were reported, investigators decided to stop enrollment of pts and to amend the protocol with new prophylactic measures. Twenty-three pts have been enrolled between Dec 2012 and May 2013 (1 pt excluded for inclusion criteria violation). Median age was 59 years (45-67). MF was primary in 19 and post essential thrombocytemia or polycythemia vera in 3 pts. All pts had splenomegaly (median: 23 cm). 12 pts had the JAK2V617F mutation. Cytogenetics were normal in 7, abnormal in 10 (poor prognostic in 2), missing or failed in 5 pts, respectively. Lille score was low in 5, intermediate (int) in 13 and high in 4 pts, resp. Age adjusted dynamic IPSS was low in 1, int-1 in 7, int-2 in 9, and high in 5 pts, respectively. Median follow-up was 149 days (69-229). Response after 2 months of RUXO was assessable in 16 pts: 50% partial remissions (- 25% in spleen size and improvement of constitutional symptoms) and 50% had stable disease. 8 pts have been transplanted (3 splenectomies before HSCT), 8 are waiting for HSCT, 4 pts have no donor identified yet and 2 pts were excluded from HSCT because of onset of comorbidities. Tolerance of RUXO was generally good and 3 SAEs were reported: febrile pancytopenia (n=2), multiple cranial nerve injury (n=1). The other SAEs (n=10) were reported within 21 days after RUXO discontinuation. Among the 10 pts who stopped RUXO, 7 had SAEs: multiple SAEs in 4, life-threatening in 7 and fatal in 2 pts, resp. Unexpected SAEs occurring after RUXO withdrawal included febrile cardiogenic shocks before HSCT not due to coronaropathy in 2 pts, and tumor lysis syndrome (TLS) with acute renal failure during CR in 1 pt. The 2 deaths were due to severe acute grade III-IV graft-versus-host disease refractory to steroids. The protocol was amended in May 2013 with TLS prophylaxis, modification of RUXO tapering with a shorter duration (10 days) systematically associated with steroids (0.5 mg/kg/day) and slight CR change (started with melphalan instead of ending). Despite this amendment, 2 other pts experienced TLS (but without renal failure) and 1 patient had a cardiogenic shock 9 days after HSCT. After review of the data with the Data Safety Monitoring Board, ethics committee and health authorities, the protocol is continued for the 22 pts already enrolled, but new inclusions are on hold until safety is confirmed. This preliminary report of the first prospective study assessing the impact of RUXO before HSCT in MF pts aims at highlighting unexpected SAEs, namely TLS (n=3) and cardiogenic shocks (n=3), that should be carefully considered in other prospective trials and clinical practice. According to the study design, all included pts should be transplanted before Oct 2013, and more information will be available for Dec 2013. Disclosures: Robin: NOVARTIS: gives ruxolitinib and a financial support for the JAK ALLO study Other. Kiladjian:Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees.

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P

Abstract Objectives Polycythemia vera ( PV )‐related symptoms may not be adequately controlled with conventional therapy. This current analysis of the RESPONSE trial evaluated the effects of ruxolitinib compared with standard therapy on quality of life (QoL) and symptoms in patients with PV who were hydroxyurea resistant/intolerant. Methods In the previously reported primary analysis, ruxolitinib achieved the primary composite endpoint of hematocrit control and ≥35% reduction in spleen volume at Week 32. The current analysis evaluated patient‐reported outcomes using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 ( EORTC QLQ ‐C30), the Myeloproliferative Neoplasm Symptom Assessment Form ( MPN ‐ SAF ), the Pruritus Symptom Impact Scale ( PSIS ), and the Patient Global Impression of Change ( PGIC ). Results Compared with standard therapy, ruxolitinib was associated with greater improvements in global health status/QoL, functional subscales, and individual symptom scores of the EORTC QLQ ‐C30. At Week 32, more patients in the ruxolitinib arm (44%) achieved a ≥10‐point improvement in global health status/QoL vs. standard therapy (9%). Improvements in MPN ‐ SAF symptom scores were consistent with improvements in EORTC QLQ ‐C30, PSIS , and PGIC scores. Conclusions Ruxolitinib provides clinically relevant improvements in QoL and ameliorates symptom burden in patients with PV who are hydroxyurea resistant/intolerant.

Ruxolitinib is an oral Janus-activated kinase 1 (JAK1)/JAK2 inhibitor approved for the treatment of patients with myelofibrosis based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of the three clinical outcomes: (a) splenomegaly, (b) disease-related symptoms, and (c) survival. Ruxolitinib was strongly recommended for improving symptomatic or severe (>15 cm below the costal margin) splenomegaly in patients with an International Prognostic Scoring System (IPSS)/dynamic IPSS risk intermediate 2 or high. Ruxolitinib was also strongly recommended for improving systemic symptoms in patients with an MPN10 score >44, refractory severe itching, unintended weight loss not attributable to other causes or unexplained fever. Because of weak evidence, the panel does not recommend ruxolitinib therapy for improving survival. Also, the recommendations given above do not necessarily apply to patients who are candidates for allogeneic stem cell transplant.

Abstract Myeloproliferative neoplasms (MPNs) are the most frequent underlying causes of splanchnic vein thromboses (SVTs). MPN patients with SVTs (MPN-SVT) often have a unique presentation including younger age, female predominance, and low Janus kinase 2 (JAK2) mutation allele burden. This study aimed at identifying risk factors for adverse hematologic outcomes in MPN-SVT patients. We performed a retrospective study of a fully characterized cohort of MPN-SVT patients. The primary outcome was the incidence of evolution to myelofibrosis, acute leukemia, or death. Eighty patients were included in the testing cohort. Median follow-up was 11 years. Most of the patients were women with a mean age of 42 years and a diagnosis of polycythemia vera. The primary outcome was met in 13% of the patients and was associated with a JAK2V617F allele burden ≥50% (odds ratio [OR], 14.7) and presence of additional mutations in genes affecting chromatin/spliceosome (OR, 9). We identified high-risk patients (29% of the cohort) as those harboring at least 1 molecular risk factor: JAK2-mutant allele burden ≥50%, presence of chromatin/spliceosome/TP53 mutation. High-risk patients had worse event-free survival (81% vs 100%; P = .001) and overall survival at 10 years (89% vs 100%; P = .01) than low-risk patients. These results were confirmed in an independent validation cohort of 30 MPN-SVT patients. In conclusion, molecular profiling identified MPN-SVT patients with dismal outcome. In this high-risk population, a disease-modifying therapy should be taken into consideration to minimize the probability of transformation.

Abstract Classical BCR-ABL–negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon α (IFNα) has demonstrated some efficacy in inducing molecular remission in MPNs. To determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in patients with MPN by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured the clonal architecture of early and late hematopoietic progenitors (84 845 measurements) and the global variant allele frequency in mature cells (409 measurements) several times per year. Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSCs. Our data support the hypothesis that IFNα targets JAK2V617F HSCs by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSCs and increases with high IFNα dose in heterozygous JAK2V617F HSCs. We also found that the molecular responses of CALRm HSCs to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and a high dose of IFNα correlates with worse outcomes. Our work indicates that the long-term molecular efficacy of IFNα implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNα dose.

Marcault et al report the impact of NFE2 mutations on the prognosis of patients with myeloproliferative neoplasms (MPNs) in a study of over 700 patients for whom sequential next-generation sequencing was available. NFE2 mutations were reported in 9.1% of patients and predicted for increased transformation and decreased survival. Since histone deacetylase (HDAC) inhibitors decrease NFE2 levels, patients with NFE2 mutations may benefit from HDAC inhibitors.

Abstract Background: MLN FGFR1 comprise rare hematologic neoplasms belonging to the World Health Organization major category of fusion tyrosine kinases typically associated with eosinophilia. MLN FGFR1 may present with chronic or blast phase (CP or BP) involvement of bone marrow (BM) and/or BP involvement of extramedullary disease (EMD) sites. Diagnosis requires t(8;13)(p11;q12) or another translocation involving chromosome band 8p11 that results in constitutive activation of FGFR1. Hydroxyurea, multikinase inhibitors with anti-FGFR1 activity (eg, midostaurin, ponatinib), or intensive multi-agent chemotherapy often lead to partial (PR) or short-lived complete responses (CR); complete cytogenetic responses (CCyRs) are rare. Given the poor prognosis of MLN FGFR1 and the potential for transformation to BP, a primary goal is to achieve deep responses to bridge patients (pts) to allogeneic hematopoietic stem cell transplant (HSCT). Pemigatinib is a selective and potent inhibitor of FGFR1-3 approved in the US, EU, and Japan for the treatment of adults with previously treated, unresectable, locally advanced, or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement. This is an analysis of data from the ongoing FIGHT-203 study of pemigatinib in adults with MLN FGFR1 (NCT03011372). Methods: FIGHT-203 is a phase 2, multicenter trial enrolling pts ≥18 years of age with MLN FGFR1. Initially, pts had to have received ≥1 prior therapy; the starting dosing was pemigatinib 13.5 mg daily (2 wks; 1 wk off). With amendments, pts without prior therapy were also eligible and the starting dose was changed to 13.5 mg daily on a continuous schedule. The primary endpoint is CR rate; secondary endpoints include rates of overall response (ORR [CR + PR]), CCyR or partial CyR (PCyR), and safety. All primary and secondary endpoints were investigator-assessed according to protocol-defined criteria including modified response criteria for MDS/MPN and modified Lugano criteria for EMD. CCyR and PCyR were defined as 100% or ≥50% reduction in 8p11-rearranged metaphases or cells, respectively, on karyotyping or fluorescence in situ hybridization. Responses were also adjudicated retrospectively by a Central Review Committee (CRC) with CRC-defined criteria based on local lab and radiologic results and central histopathology review; local and central (given priority) cytogenetic results were used by the CRC. Results: At data cutoff (Dec 31, 2020), 34 pts were enrolled and treated (safety population). The average age was 61.2 (range, 36-78) years and 59% were female. The average number of prior therapies was 1.6 (range, 0-6); 3 pts had prior HSCT; 5 were treatment-naive. The longest duration of pemigatinib exposure was 192.4 wks with median dosing duration of 29.3 wks; pts completed a median of 10.0 (range, 2-65) cycles. At data cutoff, treatment was ongoing in 18 pts (53%); reasons for treatment discontinuation (n, %) include bridging to HSCT (6, 18%), progressive disease (5, 15%), adverse event (3, 9%), physician decision (1, 3%), and patient decision (1, 3%). One pt did not have a FGFR1 rearrangement and was excluded from efficacy analysis . Among 33 pts with MLN FGFR1 evaluable for efficacy, the most common FGFR1 fusion partner genes were 13q12/ZMYM2 (45.5%) and 22q11/BCR (24.2%) (Table 1). Response rates by disease categories are shown in Table 2. Two pts had treated MLN FGFR1with a persistent cytogenetic abnormality only (no morphologic disease). Among the 31 pts with BM and/or EMD involvement, CR rates per investigator and CRC assessments were 64.5% and 77.4%, respectively. Among the 33 pts evaluable for CyR, CCyR rates were 72.7% and 75.8%, respectively. Median durations of CR have not been reached. The most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (68%), alopecia (59%), diarrhea (50%), stomatitis (44%), and anemia (35%). Grade ≥3 TEAEs in ≥10% of pts were anemia (18%), and pain in extremity and stomatitis (both 12%). Conclusions: Pemigatinib is the first therapy to demonstrate durable and high rates of CR and CCyR in pts with MLN FGFR1, most of whom had progressed on prior therapies including intensive chemotherapy or HSCT. The safety profile was consistent with FGFR inhibition with no unexpected toxicities. These results suggest that pemigatinib may offer a long-term treatment option for pts with MLN FGFR1 ineligible for HSCT or may facilitate bridging to HSCT in eligible pts. Figure 1 Figure 1. Disclosures Gotlib: PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; Allakos: Consultancy; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiladjian: Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Vannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reiter: Abbvie: Membership on an entity's Board of Directors or advisory committees; Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding. Shomali: Blueprint Medicines: Consultancy; Incyte: Consultancy, Research Funding. George: Blueprint Medicines: Consultancy; Celgene: Consultancy; Incyte Corporation: Consultancy; Bristol Meyers Squibb: Consultancy. Patel: Astellas: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Incyte: Consultancy. Colucci: Incyte: Current Employment, Current holder of stock options in a privately-held company. Walker: Incyte: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Zhen: Incyte: Current Employment, Current holder of stock options in a privately-held company. Verstovsek: Genentech: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Gilead: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. OffLabel Disclosure: Drug - Pemigatinib (INCB054828), a selective and potent inhibitor of fibroblast growth factor receptors 1, 2 and 3. Purpose - To evaluate the efficacy and safety of pemigatinib in patients with myeloid/lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) rearrangement.

Imetelstat, a first-in-class telomerase inhibitor, demonstrated meaningful clinical benefit including a robust symptom response rate and potential overall survival benefit in IMbark, a phase II study in intermediate-2 or high-risk myelofibrosis (MF) patients who have relapsed after or are refractory to JAK inhibitors. We describe the rationale and design for the phase III trial, IMpactMF (NCT04576156), an open-label evaluation of imetelstat versus best available therapy, excluding JAK inhibitors, in MF patients refractory to JAK inhibitor. Imetelstat 9.4 mg/kg is administered as an intravenous infusion every 21 days. Primary objective is to assess overall survival. Secondary objectives include symptom and spleen responses, progression-free survival, clinical response assessment, bone marrow fibrosis reduction, safety and pharmacokinetics. Biomarker, cytogenetics and mutation analyses will be performed.Imetelstat is a new type of treatment being studied in patients with myelofibrosis (MF). Encouraging clinical benefits were seen in a phase II clinical trial of imetelstat in higher risk MF. This article discusses the ongoing phase III trial, called IMpactMF. IMpactMF is comparing imetelstat to best available therapy (BAT) in MF patients not responding to a specific type of treatment, a JAK inhibitor. Imetelstat is an intravenous infusion, given every 21 days. This study will determine if patients who receive imetelstat live longer than patients who are given BAT. It will also collect information on additional outcomes, including safety. Trial Registration Number: NCT04576156 (ClinicalTrials.gov).

Abstract Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age &amp;lt; 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.

Myeloproliferative neoplasms (MPNs) are the most common etiologies of primary splanchnic vein thrombosis, present in almost forty percent of patients with Budd-Chiari syndrome or portal vein thrombosis. Diagnosis of MPNs can be difficult in these patients because key characteristics, such as elevated blood cell counts and splenomegaly, are confounded by portal hypertension or bleeding complications. In recent years, diagnostic tools have improved to provide more accurate diagnosis and classification of MPNs. Although bone marrow biopsy findings remain a major diagnostic criterion, molecular markers are playing an increasing role not only in diagnosis but also in better estimating prognosis. Therefore, though screening for JAK2V617F mutation should be the starting point of the diagnostic workup performed in all patients with splanchnic vein thrombosis, a multidisciplinary approach is needed to accurately diagnose the subtype of myeloproliferative neoplasm, recommend the useful additional tests (bone marrow biopsy, search for an additional mutation using targeted next-generation sequencing), and suggest the best treatment strategy. Indeed, providing a specific expert care pathway for patients with splanchnic vein thrombosis and underlying myeloproliferative neoplasm is crucial to determine the optimal management to reduce the risk of both hematological and hepatic complications.

Patients with polycythemia vera (PV) are at significant risk of thromboembolic events (TE). The PV-AIM study used the Optum® de-identified Electronic Health Record dataset and machine learning to identify markers of TE in a real-world population. Data for 82,960 patients with PV were extracted: 3852 patients were treated with hydroxyurea (HU) only, while 130 patients were treated with HU and then changed to ruxolitinib (HU-ruxolitinib). For HU-alone patients, the annualized incidence rates (IR; per 100 patients) decreased from 8.7 (before HU) to 5.6 (during HU) but increased markedly to 10.5 (continuing HU). Whereas for HU-ruxolitinib patients, the IR decreased from 10.8 (before HU) to 8.4 (during HU) and was maintained at 8.3 (after switching to ruxolitinib). To better understand markers associated with TE risk, we built a machine-learning model for HU-alone patients and validated it using an independent dataset. The model identified lymphocyte percentage (LYP), neutrophil percentage (NEP), and red cell distribution width (RDW) as key markers of TE risk, and optimal thresholds for these markers were established, from which a decision tree was derived. Using these widely used laboratory markers, the decision tree could be used to identify patients at high risk for TE, facilitate treatment decisions, and optimize patient management.

Abstract Classical myeloproliferative neoplasms (MPNs) are characterized by the proliferation of myeloid cells and the risk of transformation into myelofibrosis or acute myeloid leukemia (AML) and TP53 mutations in MPN patients are linked to AML. However, JAK2V617F has been reported to impact the TP53 response to DNA damage, suggesting potential overlapping role of TP53 inactivation in MPN. We established a mouse model showing that JAK2V617F/Vav-Cre/Trp53 −/− mice displayed a similar phenotype to JAK2V617F/Vav-Cre mice, but their proliferation was outcompeted in competitive grafts. RNA-Seq revealed that half of the genes affected by JAK2V617F were affected by p53-inactivation, including the interferon pathway. To validate this finding, mice were repopulated with a mixture of wild-type and JAK2V617F (or JAK2V617F/Vav-Cre/Trp53 −/− ) cells and treated with pegylated interferonα. JAK2V617F-reconstituted mice entered complete hematological remission, while JAK2V617F/Vav-Cre /Trp53 −/− -reconstituted mice did not, confirming that p53 loss induced interferon-α resistance. KEGG and Gene Ontology analyses of common deregulated genes showed that these genes were mainly implicated in cytokine response, proliferation, and leukemia evolution, illustrating that in this mouse model, the development of MPN is not affected by TP53 inactivation. Taken together, our results show that many genetic modifications induced by JAK2V617F are influenced by TP53, the MPN phenotype may not be. Trp53 loss alone is insufficient to induce rapid leukemic transformation in steady-state hematopoiesis in JAK2V617F MPN, and Trp53 loss may contribute to interferon resistance in MPN.

Comparative clinical characteristics, molecular landscape and prognosis scoring for primary (PMF) and secondary myelofibrosis (SMF).