Phase I Study of Alemtuzumab for Therapy of Steroid-Refractory Chronic Graft-versus-Host Disease

Abstract

Steroid-refractory chronic graft-versus-host disease (cGvHD) carries a poor prognosis with no agreed-upon algorithm for treatment. Since both B and T cells contribute to the pathophysiology of cGvHD, we conducted a Phase 1 study in subjects with steroid-refractory cGvHD using the anti-CD52 antibody alemtuzumab to transiently deplete most mononuclear subsets. 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) administered over 4 weeks. The maximum tolerated dose of alemtuzumab was Dose level 2. Thirteen patients were evaluable for toxicities, which were primarily infectious and hematologic. Rates of infectious complications in the first 12 weeks were 0% at Dose level 1 (n=3), 50% at Dose Level 2 (1 death, n=6), and 75% at Dose Level 3 (2 deaths, n=4). Of 10 patients evaluable for response, seven (70%) responded at 12 weeks, with a 30% complete response rate. Four subjects reduced steroid dose or discontinued an immunosuppressant at 12 weeks. The median decrease in steroid dose at 1 year was 61.6%. Infectious complications occurred predominantly in the first 3 months after therapy, but full B and T cell recovery took well over 12 months. Immunophenotypic profiling revealed early recovery by NK cells and relative sparing of CD4+ and CD8+ central memory T cell subsets. Our study indicates that therapy with alemtuzumab for steroid-refractory chronic GvHD is tolerable with close attention to dosing and may be active in subjects who have failed multiple therapies. The pattern of lymphocyte recovery after alemtuzumab will inform the biology and future therapy of cGvHD. The use of alemtuzumab in the context of therapy for cGvHD deserves study in larger Phase 2 trials.

A Prospective Study of Alemtuzumab as a Second-Line Agent for Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric and Young Adult Allogeneic Hematopoietic Stem Cell Transplantation

“…Alemtuzumab is commonly used as part of reduced-intensity conditioning regimens for allogeneic HCT [11] and can decrease the incidence of aGVHD [12,13]. Several adult case reports and case series have reported successful use of alemtuzumab for the treatment of SR-aGVHD [14–21] and SR-chronic GVHD [22]. We have previously reported our experience with alemtuzumab as a salvage therapy in SR-aGVHD, which resulted in an overall response rate of 73% [23], but there are no prospective studies of alemtuzumab use as a second-line agent in pediatric patients.…”

Hematopoietic Cell Transplantation, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

“…The safety and efficacy of alemtuzumab for the treatment of steroid-refractory cGVHD was evaluated in a phase I dose-escalation trial involving 13 patients. 197 Six subjects had moderate and 7 subjects had severe cGVHD per NIH consensus global scoring criteria; all subjects had involvement of skin and subcutaneous tissues. Alemtuzumab dosing was investigated in a 313 study design.…”

Alemtuzumab treatment for steroid-refractory acute graft-versus-host disease leads to severe immunosuppression but not to relapse of malignant disease

“…Alemtuzumab has long been used as part of the conditioning regimen to reduce alloreactivity. We and others have applied alemtuzumab treatment to diminish the cellular immune reactivity when needed in aGVHD [ 6 – 8 ] or cGVHD since it leads to almost complete depletion of lymphocytes in the blood and may alter the remaining lymphocyte subset composition thereafter [ 8 , 9 , 13 ]. Importantly, due to this intervention with alemtuzumab aGVHD could be reverted in approximately two thirds of the patients in the present study.…”