Elsevier

Mayo Clinic Proceedings

Volume 86, Issue 12, December 2011, Pages 1188-1191
Mayo Clinic Proceedings

BRIEF REPORT
Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis

https://doi.org/10.4065/mcp.2011.0518Get rights and content

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.

Section snippets

RUXOLITINIB

Ruxolitinib (INCB018424) is an ATP mimetic JAK1 and JAK2 inhibitor.9 In healthy volunteers, the drug, given in single oral 25-mg doses, was rapidly absorbed with mean time to reach maximal drug concentration of less than 1 hour and mean half-life of 2 to 6 hours.11 The drug is metabolized by CYP3A4.12 Ruxolitinib was the first JAK inhibitor to be evaluated in patients with MF and has already undergone phase 1, 2, and 3 studies. The first phase 1/2 MF study using ruxolitinib was conducted at the

DISCUSSION

Our experience with ruxolitinib therapy for patients with MF suggests a remarkable and prompt activity in alleviating constitutional symptoms such as night sweats, pruritus, fatigue, and cachexia.9 The effect on splenomegaly was also notable. However, these benefits come with tradeoffs, including drug-induced anemia, thrombocytopenia, and, as we have described in the current report, potentially catastrophic adverse events during drug discontinuation. We speculate that the underlying mechanism

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    By inhibiting cytokine signaling, JAK inhibitors decrease inflammatory and hematopoietic reactions, leading to symptom reduction in myelofibrosis [2, 3, 4, 5]. After sudden cessation of JAK-inhibitor therapy, a withdrawal syndrome can occur, presenting with symptoms of a cytokine storm, such as acute respiratory distress syndrome (ARDS), septic-like shock and disseminated intravascular coagulation (DIC)-like syndrome [6, 7, 8]. Although rare, more cases are being reported due to the growing use of RUX [6, 7, 8].

  • Myeloproliferative Neoplasms

    2022, Encyclopedia of Cell Biology: Volume 1-6, Second Edition
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*

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.

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