Serious Adverse Events During Ruxolitinib Treatment Discontinuation in Patients With Myelofibrosis

Abstract

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.

Bone morbidity in chronic myeloproliferative neoplasms

“…Treatment with ruxolitinib reduces levels of inflammatory cytokines, including IL-6 and TNF-a that are commonly elevated in MF [61,62]. Due to the reduction in the level of inflammatory mediators during ruxolitinib treatment, the potential of reducing osteosclerosis and osteoporotic fractures exists [63].…”

How many JAK inhibitors in myelofibrosis?

“…Early reports suggested an apparent risk of a severe inflammatory syndrome with poor outcome after ruxolitinib withdrawal [29]. COMFORT-I trial patients recorded symptom scores on a daily basis and demonstrated that diseaserelated symptoms returned to baseline levels within 1 week of discontinuing ruxolitinib.…”

How We Treat Myeloproliferative Neoplasms

“…Early reports suggested an apparent risk of a severe inflammatory syndrome with a poor outcome after ruxolitinib withdrawal. 48 COMFORT-I trial patients recorded symptom scores on a daily basis and demonstrated that the disease-related symptoms had returned to baseline levels within 1 week of discontinuing ruxolitinib. After a 3-year followup period, no consistent pattern of AEs was observed that would suggest a severe inflammatory syndrome after ruxolitinib discontinuation in the COMFORT trials.…”