Hydroxychloroquine for the prevention of acute graft-versus-host disease after unrelated donor transplantation

Abstract

Hydroxychloroquine (HCQ) is an immunosuppressive agent that interferes with antigen presentation and with activity against graft-versus-host disease (GVHD). In a phase II trial assessing the GVHD prophylactic effects of HCQ, 51 consecutive unrelated donor transplant recipients received HCQ in addition to cyclosporin A, methylprednisolone, and methotrexate. HCQ was initiated on pretransplantation day -21 at 800 mg/d and continued until day +100 after transplantation. HCQ was extremely well tolerated and was not associated with side effects. Pharmacokinetic analyses demonstrated large inter- and intrapatient variability. The addition of HCQ did not affect posttransplantation immune recovery. Grade II to IV acute GVHD was observed in 56% of patients, and grade III and IV GVHD was observed in 17%. Day +100 mortality was 22%. When compared with a matched cohort of patients reported to the International Bone Marrow Transplant Registry, patients receiving HCQ had comparable cumulative incidences of grade II to IV acute GVHD. However, lower incidences of grades III and IV GVHD and better GVHD-free survival were observed in HCQ-treated patients (P =.01). We conclude that prophylactic HCQ is well tolerated and associated with a low incidence of severe acute GVHD. An ongoing placebo-controlled randomized trial will further determine what role HCQ plays in preventing GVHD after allografting.

A Phase I Study of Erlotinib and Hydroxychloroquine in Advanced Non–Small-Cell Lung Cancer

“…The mean trough blood and plasma concentrations of HCQ in arm A patients were in good agreement with prior studies 25, 26 . Concurrent erlotinib resulted in a decrease in trough concentration of HCQ, consistent with enhanced first-pass HCQ metabolism from erlotinib-mediated CYP3A4 induction 27–29 .…”

Hydroxychloroquine: From Malaria to Autoimmunity

“…In addition to its immunomodulatory effects described above, HCQ was also shown to inhibit the T cell response to foreign minor and major histocompatibility antigens and therefore inhibit the development of graft versus host disease (GVHD) in mice [81]. A phase II trial in patients who received bone marrow transplantation, showed better GVHD free survival and lower incidence of high-grade GVHD in patients who were treated with HCQ in addition to the traditional immunosuppressive drugs [82]. However, a phase III trial failed to exhibit additional benefit in GVHD prevention when HCQ was added to monotherpay with cyclosporine A [83].…”

Assessing the potential role of photopheresis in hematopoietic stem cell transplant

“…There are several ways to prevent GvHD: depletion of donor T cells from the stem cell graft (ex vivo T-cell depletion); administration of T-cell antibodies to the patient (in vivo T-cell depletion); and use of immunosuppressive drugs, such as cyclosporine A (CsA), methotrexate (MTX), tacrolimus and mycophenolate mofetil (posttransplant immunosuppression). 23 New strategies of GvHD prophylaxis include the infusion of expanded mesenchymal stem cells and modulation of the APC/donor T-cell interaction using hydroxy-chloroquine, 27 anti-CD52 monoclonal antibodies, UVB prophylaxis and depletion of APCs by alloreactive donor natural killer (NK) cells in haploidentical HSCT. Other options are a modulation of epithelial damage and inflammation during pretransplantation conditioning by reducing the intensity of the conditioning regimens 28 and modulation of endotoxin and intestinal floral translocation.…”