Ruxolitinib discontinuation syndrome: incidence, risk factors and management in 251 patients with myelofibrosis

Soon after ruxolitinib (RUX) discontinuation, a rebound cytokine storm may cause potentially severe adverse events. A “RUX discontinuation syndrome” was observed in 13.5% out of 251 RUX-treated patients with myelofibrosis. In the few severe cases, RUX rechallenge can rapidly be beneficial.
Ruxolitinib discontinuation syndrome: incidence, risk factors and management in 251 patients with myelofibrosis

Ruxolitinib is the first JAK1/JAK2 inhibitor (JAKi) approved for the treatment of splenomegaly and symptoms related to myelofibrosis (MF). In the early phase I/II study of RUX in MF, most patients experienced relapse of symptoms and splenomegaly after discontinuation, and life-threatening adverse events (AEs) occurred in 11% of patients. Further cases of severe AEs attributed to RUX discontinuation have been subsequently described, despite a careful stepwise reduction of RUX. These events, attributed to an acute rebound of cytokine storm, were defined as RUX discontinuation syndrome (RDS) and typically present within 3 weeks from RUX discontinuation.

With this study, we aimed to investigate modalities of RUX discontinuation, incidence, timing, and severity of RDS and outcome and risk factors associated with RDS in a real-world context.

In 2016 we established a clinical network to collect information about RUX therapy in MF, now including 21 hematology centers and 700 RUX-treated MF patients, coordinated by our Hematology Institute in Bologna.

Our Research Manager Daniela Bartoletti and I at the Hematology Institute “L. and A. Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria of Bologna, Italy.

We conducted a specific survey to obtain data on timing and modalities of RUX discontinuation, and subsequent outcome. RDS included all symptoms that presented within 21 days from RUX discontinuation and that we attributed to RUX discontinuation. Based on previous definition, we graded RDS as follows :

Classification of RDS according to Shanavas M, Biol Blood Marrow Transplant. 2016 March ; 22(3): 432–440. HCT: hematopoietic allogeneic transplantation.

After a median time on RUX of 36.1 months, 251 patients discontinued RUX and were evaluable for RDS. Daily dose at RUX stop and causes of discontinuation are detailed below.

Detailed daily doses at RUX stop and causes of RUX discontinuation.

RUX was abruptly discontinued in 162 patients while RUX dose was first gradually decreased in 89 patients. RUX tapering pattern was very variable among Centers.

We observed an RDS in 34 (13.5%) patients after a median of 7 days from RUX stop. RDS was mild in 61.8% and moderate in 29.4% of the 34 patients.

Types and management of mild and moderate RDS. HCT: hematopoietic allogeneic transplantation; HU: hydroxyurea.

Three cases of RDS were severe, but no RDS was fatal.

Outcome of the three patients who experienced a severe ruxolitinib discontinuation syndrome (RDS). PPV-MF: Post-Polycythemia Vera Myelofibrosis. PMF: Primary Myelofibrosis. TSS: Total Symptoms Score. ICU: Intensive Care Unit. ARDS: Acute Respiratory Distress Syndrome. CMV: Cytomegalovirus.

We also found that thrombocytopenia and large splenomegaly at RUX stop predicted a higher RDS risk. Therefore, RDS may occur also in patients deemed to be refractory to the drug.

Risk factors at RUX stop associated with subsequent discontinuation syndrome.

Our results confirm the need for a careful surveillance of MF patients at the time of RUX discontinuation. A quick switch to alternative treatments, if indicated, should be planned especially for patients with large splenomegaly. In the absence of available alternatives, the occurrence of RDS may indicate residual disease control activity and identify a population that may still benefit from JAK2i.

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