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Janus kinase inhibitor approved by the US Food and Drug Administration for the treatment of myelofibrosis. In November 2011, ruxolitinib (Jakafi; Incyte/Novartis), a small-molecule inhibitor of Janus kinases, was approved by the US Food and Drug Administration for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis.

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.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, anemia, extramedullary hematopoiesis, and splenomegaly. Patients with MF are at risk for reduced survival versus the general population and often experience burdensome signs and symptoms that reduce quality of life. The oral Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib was initially approved by the US Food and Drug Administration in 2011 for the treatment of patients with intermediate or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF, based on efficacy and safety findings from the randomized, controlled, phase 3 COMFORT trials. Over a decade later, ruxolitinib continues to be the standard of care in higher-risk MF, and dose optimization and management remain crucial for safely maximizing clinical benefits of ruxolitinib. This review summarizes the safety profile of ruxolitinib in patients with MF in the COMFORT trials leading up to approval and in the subsequent JUMP, ROBUST, EXPAND, and REALISE trials; in pooled analyses; and in postmarketing analyses in the 10 years following approval. There is a focus on the occurrence of common hematologic and nonhematologic adverse events, with guidance provided on the management of patients with anemia or thrombocytopenia, including dosing strategies based on findings from the REALISE and EXPAND trials. Finally, to ensure a greater understanding of the safety profile of ruxolitinib, practical considerations are discussed.

The authors report on the clinical activity of a new oral inhibitor of Janus kinase 2 (JAK2) in patients with myelofibrosis. The drug improved a wide range of symptoms promptly, controlled them for >1 year, and appeared to inhibit disease progression to acute leukemia. Myelofibrosis is manifested as primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–polycythemia vera myelofibrosis and is characterized by clinical signs (e.g., progressive anemia, bone marrow fibrosis, and splenomegaly) and a constellation of debilitating symptoms (fatigue, weakness, bone pain, a hypercatabolic state, and weight loss). 1 Survival in myelofibrosis is related to the number of risk factors and ranges from 2 to 4 years among patients with two or more risk factors (intermediate-2 or high risk) to 8 to 11 years among patients with no risk factors or one risk factor (intermediate-1 or low risk) (see Table 1A in the Supplementary Appendix, available with . . .

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 .

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, 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 . . .

Nucleophosmin ( NPM1 ) is the most commonly mutated gene in acute myeloid leukemia (AML) resulting in aberrant cytoplasmic translocation of the encoded nucleolar protein (NPM1c + ). NPM1c + maintains a unique leukemic gene expression program, characterized by activation of HOXA / B clusters and MEIS1 oncogene to facilitate leukemogenesis. However, the mechanisms by which NPM1c + controls such gene expression patterns to promote leukemogenesis remain largely unknown. Here, we show that the activation of HOXBLINC , a HOXB locus-associated long non-coding RNA (lncRNA), is a critical downstream mediator of NPM1c + -associated leukemic transcription program and leukemogenesis. HOXBLINC loss attenuates NPM1c + -driven leukemogenesis by rectifying the signature of NPM1c + leukemic transcription programs. Furthermore, overexpression of HoxBlinc ( HoxBlinc Tg) in mice enhances HSC self-renewal and expands myelopoiesis, leading to the development of AML-like disease, reminiscent of the phenotypes seen in the Npm1 mutant knock-in ( Npm1 c/+ ) mice. HoxBlinc Tg and Npm1 c/+ HSPCs share significantly overlapped transcriptome and chromatin structure. Mechanistically, HoxBlinc binds to the promoter regions of NPM1c + signature genes to control their activation in HoxBlinc Tg HSPCs, via MLL1 recruitment and promoter H3K4me3 modification. Our study reveals that HOXBLINC lncRNA activation plays an essential oncogenic role in NPM1c + leukemia . HOXBLINC and its partner MLL1 are potential therapeutic targets for NPM1c + AML. Nucleophosmin (NPM1) gene mutation induces a specific gene expression program leading to acute myeloid leukaemia. Here, the authors show that mutant NPM1 activates a HOXB locus-associated long non-coding RNA which is essential for its associated oncogenic transcriptional program and leukaemia development.

This trial showed clinically significant responses in spleen size and quality of life among patients with myelofibrosis receiving ruxolitinib, a JAK1 and JAK2 inhibitor. The agent has some myelotoxicity, but this study showed a survival advantage with ruxolitinib. Myelofibrosis, a myeloproliferative neoplasm, is manifested by abnormal blood counts (anemia, thrombocytosis or thrombocytopenia, and leukocytosis or leukopenia), splenomegaly, and debilitating symptoms (e.g., fatigue, weakness, abdominal pain, cachexia, weight loss, pruritus, night sweats, and bone pain), which are thought to be caused by the combined effects of massive splenomegaly and elevated levels of proinflammatory cytokines. 1 Survival ranges from approximately 2 to 11 years, depending on defined prognostic factors. 2 Traditional therapeutic options, including splenectomy, have limited benefit. 3 Although allogeneic stem-cell transplantation may cure myelofibrosis, few patients are eligible for this treatment. Although the gain-of-function mutation in the gene encoding Janus kinase . . .

Myeloproliferative neoplasms (essential thrombocythemia, ET; polycythemia vera, PV; myelofibrosis, MF) are monoclonal malignancies associated with genomic instability, dysregulated signaling pathways, and subsequent overproduction of inflammatory markers. Acknowledged for their debilitating symptom profiles, recent investigations have aimed to determine the identity of these markers, the upstream sources stimulating their development, their prevalence within the MPN population, and the role they play in symptom development. Creation of dedicated Patient Reported Outcome (PRO) tools, in combination with expanded access to cytokine analysis technology, has resulted in a surge of investigations evaluating the potential associations between symptoms and inflammation. Emerging data demonstrates clear relationships between individual MPN symptoms (fatigue, abdominal complaints, microvascular symptoms, and constitutional symptoms) and cytokines, particularly IL-1, IL-6, IL-8, and TNF-α. Information is also compiling on the role symptoms paradoxically play in the development of cytokines, as in the case of fatigue-driven sedentary lifestyles. In this paper, we explore the symptoms inherent to the MPN disorders and the potential role inflammation plays in their development.