Rates of Infection in Myelofibrosis Patients Treated with Ruxolitinib
Authors: Zarzour Ahmad , Tabarroki Ali , Taftaf Rokana , Visconte Valeria , Ai Jing , Hamilton Betty K. , Papadantonakis Nikolaos , Lichtin Alan E. , Horwitz Leonard J. , Advani Anjali S. , Sekeres Mikkael A. , Tiu Ramon V. 
Published: October 2019

Abstract
Ruxolitinib is the only JAK 1/2 inhibitor approved by the FDA for the treatment of myelofibrosis (MF). It has been established that ruxolitinib helps improve disease-related constitutional symptoms and splenomegaly. However, studies have shown that ruxolitinib affects several cytokines (IL1, IL6, and TNF-α) and other immune processes (dendritic cells function and T-cell response) and has been linked to increased incidence of opportunistic and non-opportunistic infections. Here we report our experience at the Cleveland Clinic. A total of 50 patients (pts) with MF treated with ruxolitinib were included. The median age of the cohort was 68 years (range: 41-89), 28 of them were males and 22 were females. According to the Dynamic International Prognostic Scoring System (DIPSS), 5 pts had high risk, 23 had intermediate-2 risk, 21 had intermediate-1 risk and 1 had low risk disease. Of these pts, 18 developed infections during their treatment course. Of these infections, 12 were CTCAEv4.0 grade 1-2 and 6 were grade 3-4. Median age of the group was 66 years-old ranging between 50 and 83. Males=9 and females =9. The group was risk-stratified with DIPSS into high risk (N=3), intermediate-2 risk (N=7) and intermediate-1 risk (N=8).The infection started several months after initiation of JAK inhibitor treatment ranging between 2 weeks to 22 months (median of 8 months). Of note, 10 pts had episodes of infections prior to starting ruxolitinib (pneumonia N=5, cellulitis N=3, oral herpes N=2, UTI N=2, genital herpes N=1, Clostiridium difficile diarrhea N=1, viral diarrhea N=1, neutropenic fever N=1, spontaneous bacterial peritonitis N=1 and psoas muscle abscess N=1) . None of the patients had an active infection at the time of starting ruxolitinib. The median total dose given to the pts who developed grade1-2 infection was 20 mg daily, and for those who had grade 3-4 infection it was 15 mg daily. A variety of infections have been reported including pneumonia (N=4), cellulitis\folliculitis (N=4), Clostridium Difficile diarrhea (N=2), URI (N=1), neutropenic fever (N=1), MSSA bacteremia (N=1), herpes zoster activation (N=2), spontaneous bacterial peritonitis (N=1), perineal abscess (N=1) and one pt had a gluteal abscess after a bone marrow biopsy. Most of these infections resolved using oral or topical antibiotics (N=12). However, 6 pts required hospital admissions, and 5 of them required intravenous antibiotics. One of them required admission to the intensive care unit and two others required surgical interventions. Duration of treatment ranged between 1 to 8 weeks (median 2 weeks). Ruxolitinib had to be discontinued due to the severity of the infection in 2 pts, while the others either had a dose reduction or no dose alteration. Two pts required prophylactic antibiotics; one had recurrent SBP despite antimicrobial prophylaxis, while another pt required acyclovir prophylaxis while receiving glucocorticoids with ruxolitinib with no reactivation of Zoster infection. Predisposing factors for infections included a procedure (BMBx N=1), the concurrent use of other immunosuppressive drugs (steroids N=3, other agents N=3) and the prior use of systemic antibiotics in the pts who had C Diff infections (N=2). Only 2 pts had subsequent infections, one had oral herpes and the other had candida esophagitis which required hospitalization and treatment with IV antifungal drugs while on high dose steroids (dexamethasone 4 mg PO twice daily) for immune thrombocytopenia at the time of infection. Though 5 pts had already died at the time of the chart review, none of them died of infectious complications. In summary, infections can occur in patients treated with ruxolitinib but are generally mild. Most infections resolve after an adequate course of oral antimicrobial therapy suggesting that prophylactic antimicrobial agents may not be necessary or cost-effective in the vast majority of MF pts treated with ruxolitinib.

Disclosures
No relevant conflicts of interest to declare.