Safety and Efficacy of Ibrutinib Added to Rituximab-Based Primary Therapy of Chronic Graft-Versus-Host-Disease

Chronic graft-versus-host disease (cGVHD) and its treatment remains an important source of morbidity and mortality following allogeneic transplant. Historically, the foundation of cGVHD therapy has involved exposure to long courses of corticosteroids (CS), resulting in many adverse effects. We have previously demonstrated that inclusion of rituximab in the primary therapy of cGVHD can reduce corticosteroid exposure and shorten the need for systemic immunosuppression (IS) (Solomon et al. BMT 2019). Given the importance of B-cells in the development and maintenance of cGVHD, we hypothesized that dual B-cell targeting with a BTK inhibitor and rituximab would result in more rapid and sustained responses. To that end, we initiated a prospective single-arm phase II study to study the safety of ibrutinib (up to 12, 28-day cycles) added to rituximab and sirolimus in newly diagnosed cGVHD patients. The primary endpoint was the probability of being alive, free of active cGVHD and off IS at 12 months post treatment initiation (historical baseline 36% with rituximab-based therapy). Fifteen patients (median age 57) were enrolled. At the time of study entry, cGVHD NIH grade was mild, moderate, and severe in 3, 7 and 5 patients, respectively. Sites of cGVHD included mouth [10], skin [8], liver [3], Eye [2], GI [1], joints [1], lung [0]; median 2 sites (1-3). Of 14 efficacy-evaluable patients, 11 responded (≥PR, 78%) with 4 patients (29%) achieving the primary endpoint (off IS at 12 months). Of the 11 responders, 10 completed all 12 planned cycles of ibrutinib. CS were used sparingly with 12 patients receiving ≤28 days (5 with no CS use). After a median follow-up of 41 (33-50) months, 13 (87%) patients remain alive. Two patients experienced cancer relapse following study enrollment (3 and 11 months) and remain in remission following further therapy. Of the 11 patients alive without prior disease relapse, 7 are currently free of active cGVHD and off IS (64%, median time to IS discontinuation of 15 months). Of the 15 toxicity-evaluable patients, the most common adverse events included neutropenia (11, grade 3-4 [7]), lymphopenia (8), thrombocytopenia (7, grade 3-4 [3]), anemia (6, grade 3-4 [1]), GI (9, all grade 1-2), bleeding (5, grade 3-4 [2]), and AST/ALT elevation (3, grade 3-4 [1]). Adverse events of special interest included 2 grade 3 bleeding events (liver hematoma, severe epistaxis) and 9 infectious complications (occurring in 7 patients; grade 3-4 in 3 patients). Although the study was intended to enroll 35 patients, it was terminated early due to slow accrual. In summary, the addition of ibrutinib to rituximab is feasible with an acceptable safety profile. There were no grade 4-5 non-hematologic toxicities, felt to be at least possibly related to study drug, although grade 3 bleeding and infectious complications did occur. Grade 3-4 hematologic toxicities were frequent, requiring dose modifications in some patients. The regimen was efficacious (78% response) with low exposure to CS in most patients. Although the study did not complete enrollment due to slow accrual, the addition of ibrutinib to rituximab-based primary therapy of cGVHD does not appear to be superior to our historical experience with rituximab-based primary cGVHD treatment without ibrutinib.