Ibrutinib for the Treatment of Chronic Graft Versus Host Disease in Pediatric Patients

Abstract

Background Ibrutinib, a Bruton's Tyrosine Kinase inhibitor, is FDA approved for the treatment of chronic graft versus host disease (cGVHD) in adults. No data exist for the use of ibrutinib in pediatric patients. Methods We conducted a retrospective review on the use of ibrutinib for cGVHD at Cincinnati Children's Hospital Medical Center (CCHMC). All patients received an initial dose of 250 mg/m2 orally, once daily (max 420 mg), rounded to the nearest 70 mg for ease of administration. The ibrutinib dose was halved if patients were also on a strong concomitant CYP3A4 inhibitor. Responses were measured at 6 months after drug initiation using the 2014 NIH consensus panel response criteria. Plasma IL6 and CXCL9 before and after ibrutinib initiation were analyzed as surrogate markers of effectiveness. Results Twelve patients, median age 11 years (range 3-19), received ibrutinib between August 2017- October 2018 at CCHMC (Figure 1). Chronic GVHD grades were severe (n=8), moderate (n=1) and mild (n=3) at ibrutinib initiation. Ten patients had ≥2 organs involved, with skin being the predominant organ (n=9) followed by lung (n=6) and eyes (n=7). Two patients had steroid dependent cGVHD, while the rest were steroid-refractory. Eight patients were on a median steroid dose of 0.9 mg/kg/day at ibrutinib initiation. Median number of systemic cGVHD medications prior to ibrutinib was 2 (range 1-5). The median dose of ibrutinib was 140 mg (range 70-420 mg) daily, and median duration was 170.5 days (range 28-341 days). Four patients stopped ibrutinib on 28, 41, 54 and 82 days due to adverse events or death and could not be evaluated for 6-month response. Adverse events leading to discontinuation included recurrent fevers without a source (n=1), bleeding mouth sores (n=1), gastrointestinal distress with mouth sores (n= 1) and death due to pneumococcal sepsis(n=1) Of the 8 evaluable patients, 8 achieved a partial response at 6 months. Four of 6 patients with lung involvement had stable (n=2), improved (n=1) or recovered (n=1) lung function at 6 months. One patient had EBV reactivation, and 1 patient developed pneumococcal sepsis despite appropriate prophylactic therapy while on ibrutinib therapy. No fungal infections occurred while on ibrutinib. Additional adverse events reported included thrombocytopenia, neutropenia, muscle spasms and fatigue. Steroids were weaned in 8 patients to 50% of pre-ibrutinib dose (n=5), physiologic steroids (n=2) or discontinued (n=1) by 6 months. A decline in plasma IL-6 and CXCL9 levels was noted in all but one patient (Figure 2A and B). Interestingly, the patient with increasing cytokine levels was the patient discontinued from therapy early for recurrent fevers. Conclusion Ibrutinib administration at our proposed dosing regimen shows promising responses in cGVHD as salvage therapy. Larger studies are needed to establish dosing and efficacy in children