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Genetic analysis involving 2035 patients with a myeloproliferative disorder identified eight genomic subgroups with distinct clinical phenotypes, risk of leukemic transformation, and event-free survival.

Myelofibrosis is a BCR-ABL1–negative myeloproliferative neoplasm characterized by anemia, progressive splenomegaly, extramedullary hematopoiesis, bone marrow fibrosis, constitutional symptoms, leukemic progression, and shortened survival. Constitutive activation of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, and other cellular pathways downstream, leads to myeloproliferation, proinflammatory cytokine expression, and bone marrow remodeling. Transplant is the only curative option for myelofibrosis, but high rates of morbidity and mortality limit eligibility. Several prognostic models have been developed to facilitate treatment decisions. Until the recent approval of fedratinib, a JAK2 inhibitor, ruxolitinib was the only available JAK inhibitor for treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib reduces splenomegaly to some degree in almost all treated patients; however, many patients cannot tolerate ruxolitinib due to dose-dependent drug-related cytopenias, and even patients with a good initial response often develop resistance to ruxolitinib after 2–3 years of therapy. Currently, there is no consensus definition of ruxolitinib failure. Until fedratinib approval, strategies to overcome ruxolitinib resistance or intolerance were mainly different approaches to continued ruxolitinib therapy, including dosing modifications and ruxolitinib rechallenge. Fedratinib and two other JAK2 inhibitors in later stages of clinical development, pacritinib and momelotinib, have been shown to induce clinical responses and improve symptoms in patients previously treated with ruxolitinib. Fedratinib induces robust spleen responses, and pacritinib and momelotinib may have preferential activity in patients with severe cytopenias. Reviewed here are strategies to ameliorate ruxolitinib resistance or intolerance, and outcomes of clinical trials in patients with myelofibrosis receiving second-line JAK inhibitors after ruxolitinib treatment.

Ruxolitinib, an oral inhibitor of Janus kinase (JAK) 1 and 2, was associated with hematocrit control and spleen size reduction in 21% of patients with polycythemia vera who had an inadequate response to or unacceptable side effects from hydroxyurea. Polycythemia vera is a chronic clonal myeloproliferative neoplasm characterized by increased red-cell mass; elevated white-cell and platelet counts are also common. 1 Patients have an increased risk of thrombotic and cardiovascular events 2 and a substantial symptom burden that includes pruritus, fatigue, and night sweats. 3 Splenomegaly often develops as the disease progresses. 4 The main goal of therapy is to prevent thrombotic events while avoiding iatrogenic harm and minimizing the risk of transformation to post–polycythemia vera myelofibrosis or acute myeloid leukemia (AML). 5 , 6 Most patients receive low-dose aspirin and undergo phlebotomy, 7 with a goal of maintaining hematocrit values of less than 45%. Aggressive . . .

About 10% of myeloproliferative neoplasms carry mutations in both TET2 and JAK2 . Clinical presentation, risk of thrombosis, and rates of tumor progression are affected by which gene mutation is acquired first. Cancers evolve as a consequence of the stepwise accumulation of somatic lesions, with competition between subclones and sequential subclonal evolution. 1 , 2 Darwinian selection of variant subclones results in acquisition of biologic attributes required for tumor formation. 3 Genetic interaction is central to this process, but it is unclear how mutated genes interact to generate the phenotypic hallmarks of cancer, and the influence, if any, of the order in which mutations are acquired is unknown. 4 Cooperation between different genetic lesions has been observed in cell-line models of transformation 5 and in mouse models of several cancers. 6 , 7 Moreover, the consequences of an early . . .

Background 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. Methods 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. Results 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. Conclusions 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. Trial registration ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .

An enhanced understanding of the importance of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signalling in multiple disease states has led to an increasing applicability of therapeutic intervention with JAK inhibitors. These agents have revolutionised treatments for a heterogeneous group of disorders, such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven dermatological diseases, exemplifying rapid bench-to-bedside translation. In this Therapeutics paper, we summarise the currently available data concerning the successes and safety of an array of JAK inhibitors and hypothesise on how these fields could develop.

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2 V617F , CALR ins5 or CALR del52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study’s A’herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk. Preclinical studies indicate that myeloproliferative neoplasms (MPN) may be sensitive to the estrogen receptor modulator, tamoxifen. Here, the authors present a phase II clinical trial reporting the efficacy of tamoxifen in MPN and analysis of peripheral haematopoietic stem cells to identify potential predictive signatures of responders.

Background Quality of life and symptom burden of patients with myelofibrosis are well recognized and compounded in those with anemia; however, the effects of transfusion burden or anemia severity on quality of life have not been comprehensively characterized. This post hoc descriptive analysis explored the association between transfusion status or hemoglobin improvement and patient‐reported outcomes (PROs). Methods The analysis used pooled populations across treatment arms from 3 clinical trials (SIMPLIFY‐1, SIMPLIFY‐2, MOMENTUM); sample sizes for each PRO measure were dependent on the trials in which they were administered. Results At both baseline and week 24, transfusion independence was associated with umerically greater mean SF‐36v2 and EORTC QLQ‐C30 scores than transfusion dependence; in the subgroup that was transfusion dependent at baseline, those who achieved transfusion independence at week 24 had greater PRO improvements than those who remained reliant on transfusions. Regardless of transfusion status, patients who achieved a hemoglobin improvement ≥ 1, ≥ 1.5, or ≥ 2 g/dL from baseline also had clinically meaningful improvements in quality of life (assessed via mean EQ‐5D‐5L or SF‐36v2 scores) and symptoms (assessed via PGIC or MPN‐SAF/MFSAF Total Symptom Score) at week 24 compared with those who did not. Conclusions Collectively, these results provide preliminary insights into the associations of transfusion status and anemia severity with quality of life in myelofibrosis; as current PRO measures do not directly evaluate the relationship between symptoms such as fatigue and anemia, development of new measures to more comprehensively capture the patient experience for those with anemia in myelofibrosis may be warranted. Trial Registration NCT01969838, NCT02101268, NCT04173494

Introduction Secondary and idiopathic polycythaemia is far more common than polycythaemia vera. Whilst venesection for polycythaemia vera has a robust evidence base, the data supporting this treatment for secondary and/or idiopathic polycythaemia are limited to small single‐arm studies showing transient improvement in symptoms or physiologic endpoints. As a result the British Society for Haematology Guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis suggests considering venesection in patients with hypoxic lung disease with Hct > 0.56 or to a target Hct < 0.55 in those with idiopathic polycythaemia. We hypothesised that this paucity of evidence results in widespread variation in management of secondary polycythaemia. Methods To assess attitudes and practice in the treatment of secondary and idiopathic polycythaemia we designed an international clinician survey to evaluate current practice and define the point of clinical equipoise at which clinicians would be content to enter patients into a randomised venesection study. This survey was distributed using the wide‐reaching HaemSTAR research network. Results A total of 123 clinicians responded, of which 90 were experienced senior clinicians. 62% reported not routinely offering regular venesection whereas 38% of respondents did. Those considering venesection rose to ∼2/3 of respondents in specific circumstances such as polycythaemia‐related symptoms, previous arterial or unprovoked venous thrombosis. Respondents were more likely to offer venesection to patients with idiopathic‐ compared to androgen‐ or hypoxia‐driven polycythaemia. Of those who would venesect, most would use a threshold Hct ≥ 0.55, with a target Hct < 0.55 but there was significant variability. Conclusions Our survey showed considerable variability in venesection practice for patients with secondary or idiopathic polycythaemia, probably reflecting the paucity of the evidence base. There was widespread support for a trial of venesection vs observation in secondary polycythaemia and this survey has helped to define the threshold Hct at which clinical equipoise exists.