Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: A randomized clinical trial

Animesh Pardanani, Claire Harrison, Jorge E. Cortes, Francisco Cervantes, Ruben A. Mesa, Donald Milligan, Tamás Masszi, Elena Mishchenko, Eric Jourdan, Alessandro M. Vannucchi, Mark W. Drummond, Mindaugas Jurgutis, Kazimierz Kuliczkowski, Emanuil Gheorghita, Francesco Passamonti, Frank Neumann, Abhay Patki, Guozhi Gao, Ayalew Tefferi

Research output: Contribution to journalArticle

Abstract

Importance: 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. Objective: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. Design, Setting, and Participants: 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 primaryMF, 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 400mg or 500mg, or placebo, for at least 6 consecutive 4-week cycles. Main Outcomes and Measures: The primary end pointwas 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). Results: 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. Conclusions and Relevance: 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.

Original languageEnglish (US)
Pages (from-to)643-651
Number of pages9
JournalJAMA Oncology
Volume1
Issue number5
DOIs
StatePublished - Aug 2015
Externally publishedYes

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Primary Myelofibrosis
Randomized Controlled Trials
Safety
Placebos
Essential Thrombocythemia
Polycythemia Vera
Splenomegaly
Brain Diseases
Anemia
Spleen
Magnetic Resonance Imaging
Wernicke Encephalopathy
TG101348
Symptom Assessment
Poisons
Transaminases
Creatinine
Therapeutics
Tomography
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis : A randomized clinical trial. / Pardanani, Animesh; Harrison, Claire; Cortes, Jorge E.; Cervantes, Francisco; Mesa, Ruben A.; Milligan, Donald; Masszi, Tamás; Mishchenko, Elena; Jourdan, Eric; Vannucchi, Alessandro M.; Drummond, Mark W.; Jurgutis, Mindaugas; Kuliczkowski, Kazimierz; Gheorghita, Emanuil; Passamonti, Francesco; Neumann, Frank; Patki, Abhay; Gao, Guozhi; Tefferi, Ayalew.

In: JAMA Oncology, Vol. 1, No. 5, 08.2015, p. 643-651.

Research output: Contribution to journalArticle

Pardanani, A, Harrison, C, Cortes, JE, Cervantes, F, Mesa, RA, Milligan, D, Masszi, T, Mishchenko, E, Jourdan, E, Vannucchi, AM, Drummond, MW, Jurgutis, M, Kuliczkowski, K, Gheorghita, E, Passamonti, F, Neumann, F, Patki, A, Gao, G & Tefferi, A 2015, 'Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: A randomized clinical trial', JAMA Oncology, vol. 1, no. 5, pp. 643-651. https://doi.org/10.1001/jamaoncol.2015.1590
Pardanani, Animesh ; Harrison, Claire ; Cortes, Jorge E. ; Cervantes, Francisco ; Mesa, Ruben A. ; Milligan, Donald ; Masszi, Tamás ; Mishchenko, Elena ; Jourdan, Eric ; Vannucchi, Alessandro M. ; Drummond, Mark W. ; Jurgutis, Mindaugas ; Kuliczkowski, Kazimierz ; Gheorghita, Emanuil ; Passamonti, Francesco ; Neumann, Frank ; Patki, Abhay ; Gao, Guozhi ; Tefferi, Ayalew. / Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis : A randomized clinical trial. In: JAMA Oncology. 2015 ; Vol. 1, No. 5. pp. 643-651.
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abstract = "Importance: 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. Objective: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. Design, Setting, and Participants: 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 primaryMF, 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 400mg or 500mg, or placebo, for at least 6 consecutive 4-week cycles. Main Outcomes and Measures: The primary end pointwas 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). Results: 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. Conclusions and Relevance: 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.",
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TY - JOUR

T1 - Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis

T2 - A randomized clinical trial

AU - Pardanani, Animesh

AU - Harrison, Claire

AU - Cortes, Jorge E.

AU - Cervantes, Francisco

AU - Mesa, Ruben A.

AU - Milligan, Donald

AU - Masszi, Tamás

AU - Mishchenko, Elena

AU - Jourdan, Eric

AU - Vannucchi, Alessandro M.

AU - Drummond, Mark W.

AU - Jurgutis, Mindaugas

AU - Kuliczkowski, Kazimierz

AU - Gheorghita, Emanuil

AU - Passamonti, Francesco

AU - Neumann, Frank

AU - Patki, Abhay

AU - Gao, Guozhi

AU - Tefferi, Ayalew

PY - 2015/8

Y1 - 2015/8

N2 - Importance: 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. Objective: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. Design, Setting, and Participants: 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 primaryMF, 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 400mg or 500mg, or placebo, for at least 6 consecutive 4-week cycles. Main Outcomes and Measures: The primary end pointwas 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). Results: 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. Conclusions and Relevance: 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.

AB - Importance: 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. Objective: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. Design, Setting, and Participants: 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 primaryMF, 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 400mg or 500mg, or placebo, for at least 6 consecutive 4-week cycles. Main Outcomes and Measures: The primary end pointwas 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). Results: 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. Conclusions and Relevance: 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.

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