Management of myelofibrosis after ruxolitinib failure.
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ABSTRACT:
SUBMITTER: Bose P
PROVIDER: S-EPMC8565616 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC7237516 | biostudies-literature
Project description:Ruxolitinib, a Janus kinase (JAK)-1 and JAK-2 inhibitor, is the first-in-class drug to be licensed in the United States for the treatment of high- and intermediate-risk myelofibrosis (MF). Several other JAK inhibitors are in development with some currently undergoing phase-3 clinical trial testing. None of the currently available JAK inhibitors are specific to mutant JAK2; their mechanism of action involves attenuation of JAK-STAT signaling with downregulation of proinflammatory cytokines, rather than selective suppression of the disease clone. Accordingly, while ruxolitinib and other JAK inhibitors are effective in controlling splenomegaly and alleviating constitutional symptoms, their benefit in terms of reversing bone marrow fibrosis or inducing complete or partial remissions appears to be limited. The experience to date with ruxolitinib shows that despite its salutary effects on quality of life, over half of the patients discontinue treatment within 2-3 years. In the current perspective, we examine the incidence and causes of ruxolitinib 'treatment failure' in MF patients based on our personal experience as well as a review of the published literature. We also discuss the challenges in defining and classifying ruxolitinib failure, and within the context of several clinical scenarios, we provide recommendations for the post-ruxolitinib management of MF patients.
| S-EPMC4315890 | biostudies-literature
Project description:BackgroundRuxolitinib is established as treatment for symptomatic myeloproliferative neoplasm (MPN)-associated myelofibrosis. The strict inclusion and exclusion criteria and dose modification rules that applied to the COMFORTI and II studies that led to the licensing of ruxolitinib are not always applicable to routine clinical practice. Thus physicians now face decisions regarding ruxolitinib use that were not addressed in these pivotal trials.MethodsWe performed an online survey of hematologists practicing in Europe, Israel, the United Kingdom and the United States. Demographic details regarding the physicians and their practice as relates to MPNs were collected. Management decisions pertaining to the use of ruxolitinib were obtained regarding 10 clinical scenarios relating to anemia, thrombocytopenia, frailty, infection and lack or loss of response to ruxolitnib in MF patients.Results140 physicians responded to the survey. There were marked differences regarding their decisions for ruxolitinib administration in MF patients with or developing anemia or thrombocytopenia. Similarly there was little consensus regarding management of patients refractory or losing a response to ruxolitinib. There were differences between "MPN-focused" and "non-MPN-focused" physicians in certain areas.ConclusionPhysician practices regarding management of MF patients experiencing ruxolitinib-related toxicities or in whom response to the drug is lost was variable. This was true of "MPN-focused" and "non-MPN-focused" physicians in certain cases. Physician education and experience in using ruxolitinib may improve patient management.
| S-EPMC8190959 | biostudies-literature
Project description:IntroductionThe discovery of the activating JAK2 V617F mutation in patients with myelofibrosis (MF) led to the development of JAK2 inhibitors. The first such inhibitor to enter clinical trials was ruxolitinib . This review summarizes preclinical and clinical data of ruxolitinib in MF.Areas coveredA literature search through Medline employing the terms 'ruxolitinib,' 'INCB018424' and 'myelofibrosis' was undertaken. The results from Phase I/II studies in patients with MF showed that ruxolitinib led to durable improvements in splenomegaly, and symptoms associated with MF. Two Phase III trials have compared ruxolitinib against placebo and best available therapy, and in both studies ruxolitinib demonstrated superior rates of spleen control and symptom improvement, and additional analysis demonstrated a survival benefit with ruxolitinib treatment. The main toxicities seen with ruxolitinib are cytopenias, which are managed with dose adjustments. Recent reports documented sporadic cases of immunosuppression-related infections. Ruxolitinib is the first drug ever approved for the therapy of patients with MF.Expert opinionUnderstanding the factors that predict the rate and duration of response to ruxolitinib would improve our ability to manage patients treated with this medication. Clinical trials combining ruxolitinib with novel compounds that are also active in MF will further improve therapy for this disease.
| S-EPMC4824286 | biostudies-literature
Project description:Fedratinib is an oral, selective Janus kinase 2 (JAK2) inhibitor. The phase II JAKARTA2 study assessed fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) who were resistant or intolerant to prior ruxolitinib per investigator assessment. Patients received fedratinib 400 mg/day in 28-day cycles. The JAKARTA2 outcomes were initially reported using a last-observation-carried forward (LOCF) analysis in a "Per Protocol" population. This updated analysis of JAKARTA2 employs intention-to-treat analysis principles without LOCF for all treated patients (ITT Population; N = 97), and for a patient subgroup who met more stringent definitions of prior ruxolitinib failure (Stringent Criteria Cohort; n = 79). Median duration of prior ruxolitinib exposure was 10.7 months. The primary endpoint was spleen volume response rate (SVRR; ≥35% spleen volume decrease from baseline to end of cycle 6 [EOC6]). The SVRR was 31% in the ITT Population and 30% in the Stringent Criteria Cohort. Median duration of spleen volume response was not reached. Symptom response rate (≥50% reduction from baseline to EOC6 in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) was 27%. Grade 3-4 anemia and thrombocytopenia rates were 38% and 22%, respectively. Patients with advanced MF substantially pretreated with ruxolitinib attained robust spleen responses and reduced symptom burden with fedratinib.
| S-EPMC7317815 | biostudies-literature
Project description:Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are referred to as the classic Philadelphia chromosome (BCR-ABL1)-negative myeloproliferative neoplasms. Although each has distinct pathologic features, all 3 display alterations in Janus kinase (JAK) signal transduction activator of transcription signaling. Myelofibrosis is the most serious of the 3, associated with shortened survival (median survival, 5-7 years); bone marrow failure with anemia; progressive splenomegaly; and chronic, burdensome symptoms, including fatigue, night sweats, itching, abdominal discomfort, loss of appetite/early satiety, unintentional weight loss, and bone, chest, and abdominal pain. Treatments for MF have been mainly palliative, with the exception of allogeneic stem cell transplantation, which, although potentially curative, is feasible only in a small subpopulation of patients. In November 2011, ruxolitinib, an inhibitor of JAK1 and JAK2, was approved by the US Food and Drug Administration for the treatment of intermediate- or high-risk MF, including primary MF, post-PV MF, and post-ET MF. In clinical trials, ruxolitinib was shown to reduce spleen volume and improve MF-related symptoms and quality-of-life measures. Evidence also suggests that ruxolitinib therapy has a survival advantage over placebo and best available therapy. Thrombocytopenia and anemia were the most common adverse events with treatment. Ongoing trials are assessing the efficacy and safety of ruxolitinib therapy in patients with PV and ET.
| S-EPMC5025038 | biostudies-other
Project description:Myelofibrosis (MF), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. Clinical hallmarks include splenomegaly, anemia, and debilitating symptoms. In 2 randomized phase III studies, the Janus kinase (JAK) 1/JAK2 inhibitor ruxolitinib significantly improved splenomegaly and disease-related symptoms compared with placebo (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment [COMFORT-I]) or best available therapy (COMFORT-II) in patients with intermediate-2 or high-risk MF. Although ruxolitinib therapy was associated with dose-dependent anemia and thrombocytopenia, these adverse events rarely led to treatment discontinuation. This update of the clinical effects of ruxolitinib in patients with MF was based on original articles and meeting abstracts published after the primary publication of the COMFORT trials in March 2012. Long-term follow-up data from the COMFORT trials and clinical experience with ruxolitinib in unselected patient populations suggest that improvement of splenomegaly and symptoms is durable. Patients benefit from ruxolitinib therapy across subgroups defined by age, MF type, risk category, performance status, JAK2 V617F mutation status, extent of splenomegaly, or presence of cytopenias. In COMFORT-I, platelet counts stabilized with dose adjustments, and hemoglobin levels gradually recovered to slightly below baseline after the first 8 to 12 weeks of therapy. After initial increases, the need for red blood cell transfusions decreased to a level similar to that found in the placebo group. The 2-year follow-up data from the COMFORT trials suggest that patients with intermediate-2 or high-risk MF receiving ruxolitinib therapy may have improved survival compared with those receiving no (placebo) or traditional therapy.
| S-EPMC5556922 | biostudies-other
Project description:BackgroundIn this retrospective cohort of patients with primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis, 57 patients with MF who received ruxolitinib for MF-related symptoms or symptomatic splenomegaly were evaluated.MethodsThe median age of the patients in this cohort was approximately 58 years. Of these, there were 33 patients (57.9%) in INT-1, 23 patients (40.4%) in INT-2, and 1 patient (1.8%) at high risk. Overall, spleen size reduction of at least 35% (spleen response) was achieved in 56.6% and 63.3% of all cohort and INT-1 risk at any time, respectively.ResultsSymptom response and clinical improvement were observed in 21.7% and 60.7% of patients, respectively. Anemia and thrombocytopenia were prevalent, but manageable. About 73.7% of patients continued treatment during a median follow-up of 22 months. Two-year OS probability was approximately 84.5% (95% CI, 63.1‒94.0%) and 62.3% (95% CI, 37.5‒79.6%) for the intermediate-1 and -2 risk groups, respectively.ConclusionReal-life experience in a community-based hospital confirms the efficacy and safety profile of ruxolitinib in intermediate-risk myelofibrosis. Treatment discontinuation rates were lower than those in clinical trials.
| S-EPMC8721444 | biostudies-literature
Project description:Considerable clinical experience regarding the long-term efficacy and safety of ruxolitinib has been gathered since the drug was approved in the USA for patients with intermediate or high-risk myelofibrosis (MF) in November 2011. Findings from the pivotal phase 3 COMFORT studies showed that ruxolitinib-associated reductions in MF-related splenomegaly and symptom burden occur rapidly and in the majority of patients. Two- and 3-year follow-up data further suggest that the benefits of ruxolitinib are durable and associated with a survival advantage compared with conventional therapies. However, careful management of treatment-related thrombocytopenia and anemia with dose modifications and supportive care is critical to allow chronic therapy. Based on preliminary evidence, ruxolitinib also allows spleen size and symptom reduction before allogeneic stem cell transplantation without negative effect on engraftment or outcomes. In recent studies, ruxolitinib provided effective management of hematologic parameters and symptoms in patients with polycythemia vera refractory to or intolerant of hydroxyurea.
| S-EPMC4223534 | biostudies-literature
Project description:Despite significant improvements in the signs and symptoms of myelofibrosis (MF), and possible prolongation of patients' survival, some have disease that is refractory to ruxolitinib and many lose their response over time. Furthermore, patients with ≥3 mutations are less likely to respond to ruxolitinib. Here we describe outcomes after ruxolitinib discontinuation in MF patients enrolled in a phase 1/2 study at our center. After a median follow-up of 79 months, 86 patients had discontinued ruxolitinib (30 of whom died while on therapy). The median follow-up after ruxolitinib discontinuation for the remaining 56 patients was 32 months, with median survival after discontinuation of 14 months. Platelets <260 × 109/L at the start of therapy or <100 × 109/L at the time of discontinuation were associated with shorter survival after discontinuation. Of 62 patients with molecular data at baseline and follow-up, 22 (35%) acquired a new mutation while receiving ruxolitinib (14 [61%] in ASXL1). Patients showing clonal evolution had significantly shorter survival after discontinuation (6 vs 16 months). Transfusion dependency was the only clinical variable associated with clonal evolution. These findings underscore the need for novel therapies and suggest that clonal evolution or decreasing platelet counts while on ruxolitinib therapy may be markers of poor prognosis.
| S-EPMC5580275 | biostudies-literature