Treatment of Chronic Granulomatous Disease with Nonmyeloablative Conditioning and a T-Cell–Depleted Hematopoietic Allograft
Mitchell E. Horwitz, M.D., A. John Barrett, M.D., Margaret R. Brown, B.S., Charles S. Carter, M.T., Richard Childs, M.D., John I. Gallin, M.D., Steven M. Holland, M.D., Gilda F. Linton, M.T., Judi A. Miller, R.N., Susan F. Leitman, M.D., Elizabeth J. Read, M.D., and Harry L. Malech, M.D.
Background The treatment of chronic granulomatous disease withconventional allogeneic hematopoietic stem-cell transplantationcarries a high risk of serious complications and death. We investigatedthe feasibility of stem-cell transplantation without ablationof the recipient's bone marrow.
Methods Ten patients, five children and five adults, with chronicgranulomatous disease underwent peripheral-blood stem-cell transplantationfrom an HLA-identical sibling. We used a nonmyeloablative conditioningregimen consisting of cyclophosphamide, fludarabine, and antithymocyteglobulin. The allograft was depleted of T cells to reduce therisk of severe graft-versus-host disease. Donor lymphocyteswere administered at intervals of 30 days or more after thetransplantation to facilitate engraftment.
Results After a median follow-up of 17 months (range, 8 to 26),the proportion of donor neutrophils in the circulation in 8of the 10 patients was 33 to 100 percent, a level that can beexpected to provide normal host defense; in 6 the proportionwas 100 percent. In two patients, graft rejection occurred.Acute graft-versus-host disease (grade II, III, or IV) developedin three of the four adult patients with engraftment, one ofwhom subsequently had chronic graft-versus-host disease. Noneof the five children had grade II, III, or IV acute graft-versus-hostdisease. During the follow-up period, four serious infectionsoccurred among the patients who had engraftment. Three of the10 recipients died. Preexisting granulomatous lesions resolvedin the patients in whom transplantation was successful.
Conclusions Nonmyeloablative conditioning followed by a T-cell–depletedhematopoietic stem-cell allograft is a feasible option for patientswith chronic granulomatous disease, recurrent life-threateninginfections, and an HLA-identical family donor.
Source Information
From the Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (M.E.H., J.I.G., S.M.H., G.F.L., J.A.M., H.L.M.), the National Heart, Lung, and Blood Institute (A.J.B., R.C.), the Clinical Pathology Department (M.R.B.), and the Department of Transfusion Medicine (C.S.C., S.F.L., E.J.R.), National Institutes of Health, Bethesda, Md. Other authors were Ronald E. Gress, M.D., National Cancer Institute, and James Schermerhorn, P.A.-C., National Institute of Allergy and Infectious Diseases.
Address reprint requests to Dr. Horwitz at the Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10, Room 11N117, MC 1886, Bethesda, MD 20892, or at mhorwitz{at}nih.gov.
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