[Show abstract][Hide abstract] 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.
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).
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 versus standard therapy (9%). Improvements in MPN-SAF symptom scores were consistent with improvements in EORTC QLQ-C30, PSIS, and PGIC scores.
Ruxolitinib provides clinically relevant improvements in QoL and ameliorates symptom burden in patients with PV who are hydroxyurea-resistant/intolerant. This article is protected by copyright. All rights reserved.
No preview · Article · Nov 2015 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: 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).
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).
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.
Full-text · Article · Nov 2015 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Polycythaemia vera (PV) is a chronic blood cancer; its clinical features are dominated by myeloproliferation (erythrocytosis, often leucocytosis and/or thrombocytosis) and a tendency for thrombosis and transformation to myelofibrosis or acute myeloid leukaemia. In the past 10 years the pathophysiology of this condition has been defined as JAK/STAT pathway activation, almost always due to mutations in JAK2 exons 12 or 14 (JAK2 V617F). In the same time period our understanding of the optimal management of PV has expanded, most recently culminating in the approval of JAK inhibitors for the treatment of PV patients who are resistant or intolerant to therapy with hydroxycarbamide. It has also been demonstrated that life expectancy for many patients with PV is not normal, nor is their quality of life. We critically explore these findings and discuss their impact. In addition, we highlight persisting gaps in our current management strategy; for example, what is the optimal first line cytoreductive therapy and, indeed, which patients need cytoreductive drugs.
No preview · Article · Oct 2015 · British Journal of Haematology
[Show abstract][Hide abstract] ABSTRACT: Introduction: Myelofibrosis (MF) is a clonal haematological disease associated with recurrent somatic gene mutations (JAK2V617F, MPL, CALR) and constitutive activation of the Janus kinase (JAK)/Signal Transducer and Activator of Transcription pathway. MF is often characterised by debilitating symptoms and JAK inhibitors (JAKIs) have revolutionised available therapeutic options. Ruxolitinib, a JAK1 and 2 inhibitor, is the only currently approved agent. Several other JAKIs are undergoing evaluation in the clinical trial setting and Pacritinib, a novel JAK2 and FLT3 inhibitor, is at an advanced stage of investigation with recent completion of a Phase III trial and another ongoing.Areas covered: Within this article we focus on pacritinib, summarising the development, preclinical and up-to-date results from the Phase I - III trials. We present the most recent data on efficacy and safety and indirectly compare this novel JAKI with ruxolitinib.Expert opinion: The kinome array data for pacritinib suggests that it has a range of targets differing to those for ruxolitinib. Pacritinib appears to be an effective agent for the control of MF-related symptoms and splenomegaly with potentially fewer haematological side-effects when compared with ruxolitinib and seems a particularly promising agent for anaemic and thrombocytopenic patients. It is also an attractive drug for potential combination studies due to its good tolerability.
No preview · Article · Oct 2015 · Expert Opinion on Pharmacotherapy
[Show abstract][Hide abstract] ABSTRACT: Background:
Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.
Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.
Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).
[Show abstract][Hide abstract] ABSTRACT: Over the last decade, unparalleled advances have been made within the field of 'Philadelphia chromosome'-negative myeloproliferative neoplasms (MPN) regarding both disease pathogenesis and therapeutic targeting. The discovery of deregulated JAK-STAT signalling in MPN led to the rapid development of JAK inhibitor agents, targeting both mutated and wild-type JAK, which have significantly altered the therapeutic paradigm for patients with MPN. Although the largest population treated with these agents incorporates those with myelofibrosis, increasing data supports potential usage in other MPNs such as essential thromocythaemia and polycythaemia vera. Many MPNs are associated with a hyperinflammatory state and deregulation of immune homeostasis. Over the last few years, research has focused on attempting to decipher the complex and context-dependent changes that contribute to this immune deregulation. Moreover, very recent studies have demonstrated significant JAK inhibitor-mediated effects within the T cell, natural killer cell and dendritic cell compartments following exposure to JAK inhibitors. In parallel, case reports of infections occurring following exposure to ruxolitinib, many of which are atypical, have focused research efforts on delineating JAK inhibitor-associated immunological consequences. Within this review article, we will describe what is currently known about MPN-associated immune deregulation and JAK inhibitor-mediated immunomodulation.
No preview · Article · Aug 2015 · Current Hematologic Malignancy Reports
[Show abstract][Hide abstract] ABSTRACT: The aim of this work is to produce recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles released from 1999 to 2015 (January) was used as a source of scientific evidence. Recommendations were produced using a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet (ELN) and European Blood and Marrow Transplantation Group (EBMT). Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention and management of relapse after transplant. Patients with intermediate-2- or high-risk disease and age less than 70 years should be considered candidates for allo-SCT. Patients with intermediate-1-risk disease and age less than 65 years should be considered candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood greater than 2%, or adverse cytogenetics. Pre-transplant splenectomy should be decided on a case by case basis. Patients with intermediate-2- or high-risk disease lacking an HLA matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors. Peripheral blood was considered the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants. The optimal intensity of the conditioning regimen still needs to be defined. Strategies such as discontinuation of immune-suppressive drugs, donor lymphocyte infusion or both were deemed appropriate to avoid clinical relapse. In conclusion, we provided consensus-based recommendations aimed to optimize allo-SCT in PMF. Unmet clinical needs were highlighted.Leukemia accepted article preview online, 21 August 2015. doi:10.1038/leu.2015.233.
No preview · Article · Aug 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: Myelofibrosis is a heterogeneous disorder, which, although sometimes asymptomatic in the early stages, is frequently associated with debilitating constitutional symptoms, poor quality of life and high degree of morbidity as the disease progresses. Ruxolitinib, a JAK1/2-inhibitor, has transformed the management of many patients by reducing disease-related symptoms and splenomegaly in intermediate-2 and high-risk patients. As demonstrated by the COMFORT studies, unprecedented clinical benefit can be gained by some patients on ruxolitinib; however, this is not without potential adverse effects, notably cytopenias, weight-gain and an increased risk of opportunistic infections. No other JAK inhibitors are currently approved for myelofibrosis. Moreover, long-term effects of JAK-inhibitor agents, such as ruxolitinib, remain unknown. Consequently, the use of ruxolitinib in the low-risk patient, in the absence of high symptom burden remains controversial and requires further randomized clinical trials. In such patients, an individualized approach should be adopted, balancing likely clinical benefit with the potential side-effect profile.
No preview · Article · Aug 2015 · Expert Review of Hematology
[Show abstract][Hide abstract] ABSTRACT: The approach to the diagnosis and management of essential thrombocythaemia (ET) is steadily changing, influenced by advances in molecular biology, data from clinical trials and retrospective analyses of patient cohorts. In the past decade options for clinical management largely remain unchanged, but who we treat, and with what target in mind, is evolving. A further area of change is recognition of symptoms that may be associated with ET, as well as other myeloproliferative neoplasms, and that potential options for their management are becoming available. Judicious and careful diagnosis is increasingly a fundamental key to successful management followed by cytoreductive therapy in a subset of patients. In this review we demonstrate our management strategies for ET using a case-based format.
No preview · Article · Aug 2015 · British Journal of Haematology
[Show abstract][Hide abstract] ABSTRACT: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials.
To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF.
Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles.
The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form).
The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P < .001). Symptom response rates at week 24 were 33 of 91 (36% [95% CI, 26%-46%]), 31 of 91 (34% [95% CI, 24%-44%]), and 6 of 85 (7% [95% CI, 2%-13%]) in the fedratinib 400-mg, 500-mg, and placebo groups, respectively (P < .001). Common adverse events with fedratinib treatment were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Encephalopathy was reported in 4 women who received fedratinib 500 mg/d. A diagnosis of Wernicke encephalopathy was supported by magnetic resonance imaging in 3 cases and suspected clinically in 1 case.
Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued.
clinicaltrials.gov identifier: NCT01437787.