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Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis

  • Author Footnotes
    * Dr Tefferi has served as Principal Investigator/coinvestigator for clinical trials that received institutional support (free drug and funds) from Incyte, Sanofi-Aventis, TargeGen, YM BioSciences, Cytopia, Bristol-Myers Squibb, Celgene, and Novartis. TargeGen, Cytopia, and YM BioSciences have also provided support for laboratory studies relevant to clinical trials. Dr Pardanani has served as Principal Investigator/coinvestigator for clinical trials that received institutional support (free drug and funds) from Incyte, Sanofi-Aventis, TargeGen, YM BioSciences, Cytopia, Bristol-Myers Squibb, Celgene, and Novartis. TargeGen and Cytopia have also provided support for laboratory studies relevant to clinical trials.
    Ayalew Tefferi
    Correspondence
    Individual reprints of this article are not available. Address correspondence to Ayalew Tefferi, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905
    Footnotes
    * Dr Tefferi has served as Principal Investigator/coinvestigator for clinical trials that received institutional support (free drug and funds) from Incyte, Sanofi-Aventis, TargeGen, YM BioSciences, Cytopia, Bristol-Myers Squibb, Celgene, and Novartis. TargeGen, Cytopia, and YM BioSciences have also provided support for laboratory studies relevant to clinical trials. Dr Pardanani has served as Principal Investigator/coinvestigator for clinical trials that received institutional support (free drug and funds) from Incyte, Sanofi-Aventis, TargeGen, YM BioSciences, Cytopia, Bristol-Myers Squibb, Celgene, and Novartis. TargeGen and Cytopia have also provided support for laboratory studies relevant to clinical trials.
    Affiliations
    Division of Hematology, Mayo Clinic, Rochester, MN
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  • Animesh Pardanani
    Affiliations
    Division of Hematology, Mayo Clinic, Rochester, MN
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  • Author Footnotes
    * Dr Tefferi has served as Principal Investigator/coinvestigator for clinical trials that received institutional support (free drug and funds) from Incyte, Sanofi-Aventis, TargeGen, YM BioSciences, Cytopia, Bristol-Myers Squibb, Celgene, and Novartis. TargeGen, Cytopia, and YM BioSciences have also provided support for laboratory studies relevant to clinical trials. Dr Pardanani has served as Principal Investigator/coinvestigator for clinical trials that received institutional support (free drug and funds) from Incyte, Sanofi-Aventis, TargeGen, YM BioSciences, Cytopia, Bristol-Myers Squibb, Celgene, and Novartis. TargeGen and Cytopia have also provided support for laboratory studies relevant to clinical trials.
      Ruxolitinib (INCB018424) is a JAK1 and JAK2 inhibitor recently evaluated for the treatment of myelofibrosis (MF) in early- and advanced-phase clinical trials. In 2 recent communications that focused on short-term and long-term ruxolitinib treatment outcome, respectively, the drug was shown to be effective in controlling constitutional symptoms and splenomegaly but was also associated with important adverse effects, including moderate to severe thrombocytopenia and anemia. The most recent of the 2 communications focused on 51 Mayo Clinic patients who participated in the original phase 1/2 ruxolitinib clinical trial and highlighted a high treatment discontinuation rate (92% after a median time of 9.2 months), primarily for loss of treatment benefit but also because of drug-associated adverse effects. The report also discussed the occurrence of sometimes severe withdrawal symptoms during ruxolitinib treatment discontinuation. This “ruxolitinib withdrawal syndrome” was characterized by acute relapse of disease symptoms, accelerated splenomegaly, worsening of cytopenias, and occasional hemodynamic decompensation, including a septic shocklike syndrome. In the current sponsor-independent analysis, we describe the details of these events in 5 severely affected cases (11%) among 47 Mayo Clinic patients with MF in whom ruxolitinib therapy had been discontinued. Our experience calls for full disclosure of the ruxolitinib withdrawal syndrome to patients with MF before initiating ruxolitinib therapy, and treatment discontinuation must be done under close physician supervision and preferably in a tapering schedule.

      Abbreviations:

      DLT (dose-limiting toxicity), ET (essential thrombocythemia), MF (myelofibrosis), MPN (myeloproliferative neoplasm), MTD (maximum tolerated dose), PMF (primary MF), PV (polycythemia vera)
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