JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis

Harrison, Claire; Kiladjian, Jean‐Jacques; Al-Ali, Haifa Kathrin; Gisslinger, Heinz; Waltzman, Roger J.; Stalbovskaya, Viktoriya; McQuitty, Mari; Hunter, Deborah; Levy, Richard S.; Knoops, Laurent; Cervantes, Francisco; Vannucchi, Alessandro M.; Barbui, Tiziano; Barosi, Giovanni

doi:10.1056/nejmoa1110556

Cited by 1,595 publications

(1,589 citation statements)

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“…In patients with MF, there is evidence of meaningful improvement in symptoms with ruxolitinib versus placebo, as evaluated by the MPN‐SAF (Mesa et al , 2013), and versus best available therapy (47% receiving HC) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire−Core 30 (EORTC QLQ‐C30) (Harrison et al , 2012). Similar findings were observed in the randomized, open‐label, multicentre, phase 3 RESPONSE trial, which evaluated ruxolitinib versus best available therapy (59% receiving HC) in patients with PV who were intolerant of or resistant to HC (Vannucchi et al , 2015).…”

Section: Discussionmentioning

confidence: 99%

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double‐blind, double‐dummy, symptom study (RELIEF)

et al. 2016

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SummaryThe randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

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Section: Discussionmentioning

confidence: 99%

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double‐blind, double‐dummy, symptom study (RELIEF)

et al. 2016

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“…Ruxolitinib is a JAK1/JAK2 inhibitor. Two randomized studies comparing ruxolitinib with either placebo or best supportive care have now been published and both showed the efficacy of the drug in reducing spleen size and alleviating constitutional symptoms [138,139]. In the ruxolitinib clinical trial that compared the drug with "best available therapy" [139], the spleen response was 28.5% with ruxolitinib vs. 0% without it; ruxolitinib therapy was associated with thrombocytopenia (44.5% vs. 9.6%), anemia (40.4% vs. 12.3%) and diarrhea (24.0% vs. 11.0%).…”

Section: Th Anniversary Issuementioning

confidence: 99%

“…Two randomized studies comparing ruxolitinib with either placebo or best supportive care have now been published and both showed the efficacy of the drug in reducing spleen size and alleviating constitutional symptoms [138,139]. In the ruxolitinib clinical trial that compared the drug with "best available therapy" [139], the spleen response was 28.5% with ruxolitinib vs. 0% without it; ruxolitinib therapy was associated with thrombocytopenia (44.5% vs. 9.6%), anemia (40.4% vs. 12.3%) and diarrhea (24.0% vs. 11.0%). The long-term outcome of ruxolitinib therapy in MF was recently reported and disclosed a very high treatment discontinuation rate (92% after a median time of 9.2 months) and the occurrence of severe withdrawal symptoms during ruxolitinib treatment discontinuation ("ruxolitinib withdrawal syndrome") characterized by acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias and occasional hemodynamic decompensation, including a septic shock-like syndrome [140].…”

Section: Th Anniversary Issuementioning

confidence: 99%

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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“…The JAK1‐2 inhibitor ruxolitinib is a potent anti‐inflammatory agent and has shown promising results in the treatment of patients with MF3, 4, 5 and PV6 in regard to reducing splenomegaly, constitutional symptoms, and inflammation‐mediated comorbidities. However, in the large majority of patients, ruxolitinib does not markedly reduce the JAK2 V617F allele burden (%V617F) 5, 6, 7…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

et al. 2018

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Interferon‐α2 reduces elevated blood cell counts and splenomegaly in patients with myeloproliferative neoplasms (MPN) and may restore polyclonal hematopoiesis. Its use is limited by inflammation‐mediated toxicity, leading to treatment discontinuation in 10‐30% of patients. Ruxolitinib, a potent anti‐inflammatory agent, has demonstrated benefit in myelofibrosis (MF) and polycythemia vera (PV) patients. Combination therapy (CT) with these two agents may be more efficacious than monotherapy with either, potentially improving tolerability of interferon‐α2 as well. We report the preliminary results from a phase II study of CT with pegylated interferon‐α2 and ruxolitinib in 50 MPN patients (PV, n = 32; low‐/intermediate‐1‐risk MF, n = 18), the majority (n = 47) being resistant and/or intolerant to interferon‐α2 monotherapy. Objectives included remission (2013 revised criteria encompassing histologic, hematologic, and clinical responses), complete hematologic response (CHR), molecular response, and toxicity. Follow‐up was 12 months. Partial remission (PR) and sustained CHR were achieved in 9% and 44% of PV patients, respectively. In MF patients, complete or partial remission was achieved in 39%, and sustained CHR in 58%. The median JAK2V617F allele burden declined significantly in both groups. Hematologic toxicity was the most common adverse event and was managed by dose reduction. Thirty‐seven serious adverse events were recorded in 23 patients; the discontinuation rate was 20%. We conclude that CT with interferon‐α2 and ruxolitinib is efficacious in patients with low‐/intermediate‐1‐risk MF and, to a lesser extent, in patients with PV. These preliminary results encourage phase III studies as well as a study with CT in newly diagnosed MPN patients.

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JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis

Cited by 1,595 publications

References 23 publications

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double‐blind, double‐dummy, symptom study (RELIEF)

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double‐blind, double‐dummy, symptom study (RELIEF)

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

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