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Invited Commentary
August 2015

JAK/STAT Pathway Inhibitors and Neurologic Toxicity: Above All Else Do No Harm?

Author Affiliations
  • 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle
  • 2Division of Medical Oncology, University of Washington, Seattle
  • 3Division of Hematology, University of Washington, Seattle
 

Copyright 2015 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA Oncol. 2015;1(5):651-652. doi:10.1001/jamaoncol.2015.1591

Oncologists long ago recognized the fallacy of primum non nocere. The truth is that some harm may be deemed acceptable as long as the perceived benefits have the potential to outweigh the risks. Janus-associated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway inhibitors have demonstrated efficacy in the treatment of myelofibrosis, resulting in reduction of splenomegaly and constitutional symptoms, and improved survival.1-3 The COMFORT-I and COMFORT-II trials led to Food and Drug Administration approval for the JAK1/JAK2 inhibitor ruxolitinib for patients with myelofibrosis, and the RESPONSE trial, to approval for patients with polycythemia vera who are unresponsive or intolerant to hydroxyurea therapy. The principal adverse effects of ruxolitinib in the treatment of myelofibrosis include anemia, thrombocytopenia, ecchymosis, dizziness, and headache. A distinct neurological adverse effect, peripheral neuropathy, was reported in up to 44% of patients treated with the JAK1/JAK2 inhibitor momelotinib. In fact, neurologic toxic effects including dizziness, ataxia, aphasia, dysarthria, and amnesia led to termination of the clinical development of the JAK1/JAK2 inhibitor AZD1480.4

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