A Phase I Study of Alemtuzumab Dosing for Steroid-Refractory Chronic Graft-Versus-Host Disease

Abstract 744 Introduction: There are no definitive therapies for chronic graft-versus-host disease refractory to steroid therapy. Alemtuzumab transiently depletes B and T cells and can decrease the incidence of acute and chronic GvHD when part of pre-transplant conditioning. In steroid-refractory acute GvHD, alemtuzumab has induced complete response rates of 20–35%, but optimal dosing in acute or chronic GvHD treatment has not been established. We report a phase 1, dose-escalation study assessing alemtuzumab as therapy for steroid-refractory chronic GvHD (cGvHD). Methods: Patients with cGvHD refractory to prednisone at > 0.5mg/kg/day were eligible. The primary objective was to determine maximum tolerated dose (MTD) and toxicity. The secondary objective was to determine efficacy. Subjects received alemtuzumab on Days 1, 3, 5, 8, 15 and 22. Three regimens were investigated in a 3+3 dose escalation design: 3 mg × 6 (Dose level 1); 3 mg × 1, then 10 mg × 5 (Dose level 2); and 3 mg × 1, 10 mg × 1, then 30mg × 4 (Dose level 3). Dose-limiting toxicities were Grade 4 or 5 toxicities occurring within 12 weeks of initiating therapy. During the study period, doses of other immunosuppressants were held constant; antiHSV, antiPJP and antifungal prophylaxis was required. CMV reactivation was treated pre-emptively. GvHD severity was assessed by NIH consensus criteria at initiation and 12 weeks. Results: Safety: 13 subjects were enrolled: 3 at Dose level 1, 6 at Dose level 2 and 4 at Dose level 3. All were evaluable for toxicity. 6 subjects had moderate and 7 subjects had severe cGvHD at initiation. The median number of organs involved was 4 (range 1–7). A median of 5 systemic immunosuppressants other than steroids (range 2–7) had been previously used. Dose level 2 was the MTD. Subjects experiencing > Grade 3 infections in the first 12 weeks were 0 at Dose level 1, 3 at Dose level 2 (1 death), and 3 at Dose level 3 (2 deaths). (Table) Bacterial pathogens included E.coli, pseudomonas and corynebacterium. Viral pathogens included parainfluenza, influenza A, BK virus and adenovirus. The CMV reactivation rate was 30.8%; there were no parenchymal CMV infections. Between 12 and 24 weeks, significant infections were seen in 1 of 10 subjects. Subjects experiencing > Grade 3 neutropenia +/− thrombocytopenia, were 0 in Dose level 1, 1 in Dose level 2 and 2 in Dose level 3 in the first 12 weeks. Monocyte and lymphocyte numbers fell immediately upon treatment at all dose levels. Monocyte numbers returned to starting levels in 9 of 13 subjects at time of last censoring; lymphocytes numbers returned to starting levels in 5 of 13 subjects. Time to restoration of lymphocyte numbers ranged from 6 to >27 months. Efficacy: Ten of 13 subjects were evaluable for response at Week 12. The overall response rate was 70%. The complete response rate was 30%, all observed at the MTD. (Table) Responses were seen predominantly in skin and joint/fascia/muscle. 4 of 10 subjects reduced steroid dose or discontinued an immunosuppressant at 12 weeks. At 24 weeks, only 2 of 10 subjects had increased steroids or initiated new GvHD therapies. At 1 year, 4 of 8 subjects evaluable were on Conclusions: Our dose-escalation study establishes an MTD for alemtuzumab of 3 mg × 1, then 10 mg × 5 doses over a 4 week period. We observed significant rates of infectious complications, but they occurred early in the course of therapy, despite prolonged lymphopenia, and in a dose-dependent manner. Our response rate of 70% suggests efficacy for alemtuzumab in the treatment of steroid-refractory chronic GvHD in patients who have failed multiple therapies. The use of alemtuzumab in this context deserves study in larger phase II trials. Disclosures: Off Label Use: Alemtuzumab used in off-label indication for treatment of chronic graft-versus-host disease in the setting of a Phase 1 clinical trial.