Successful Half-Dose Busulfan/Full-Dose Fludarabine Based Reduced Intensity Conditioning In High-Risk Pediatric And Adult Chronic Granulomatous Disease (CGD) Patients

Abstract

To examine the feasibility, safety and efficacy of hematopoietic stem cell transplantation (HSCT) in high-risk pediatric and adult patients with chronic granulomatous disease (CGD) using a low-toxicity conditioning regimen based on half-dosed (50-60%) Busulfan, full-dose Fludarabine and in-vivo T-cell depletion. 11 CGD patients (5, 7, 12, 13, 17, 18, 20, 23, 29, 35 and 39 ys; n=8 gp91-phox, n=2 p22-phox and n=1 p47 phox deficient) are described. All patients were therapy-refractory to conventional treatment suffering from infectious and/or inflammatory complications at HSCT, e.g. colitis, active infection (Aspergillus, Neisseria, Actinomyces, Staph. aureus) or had former lung aspergillosis. Stem cell donors consisted of 5 matched sibling, 4 MUD (10/10) and 2 MMUD (9/10) donors. Conditioning included 180 mg/qm Fludarabine (d -8 to -3), oral/iv. Busulfan (6.4-12 mg/kg; d -4 to -2; in pediatric patients with adjusted Busulfan kinetics) and Antithymocyte-Globulin Fresenius (4 × 10 mg/kg; d -4 to -1). In 4 patients (5, 7, 12 and 17 ys) receiving MUD or MMUD transplants, ATG-Fresenius was replaced by 0.5 mg/kg Alemtuzumab (Campath IH) (d -8 to -6). As stem cell source, bone marrow (2.3 to 6.0 × 10 6 CD34/kg) was used in the majority of cases (n=10), only one patient received unrelated PBSC (5 × 10 6 CD34/kg). GVHD-prophylaxis comprised Cyclosporine A (CSA) and Mycophenolate-Mofetil (MMF). MMF (1200 mg/qm) was administered until d +100 and tapered thereafter. Two patients received MTX instead of MMF. The early course after HSCT was uneventful. No acute GHVD was encountered. No infectious or inflammatory flare ups were observed. The hematological reconstitution with neutrophil (d +19 to +26) and platelet engraftment (d +21 to +22) was in time. Six to 63 (median 36) months after HSCT, 10 patients are alive and well (91%) with (95-100%) donor chimerism and stable hematopoiesis. NBT- and DHR-tests are normalized (95-98%). All active inflammatory and infectious foci are cured. One adult patient fathered a child after successful HSCT. One adult patient who had suffered from severe active therapy-refractory bilateral Aspergillosis at transplant and had received a MUD CMV negative PBSC died at day +150 due to pulmonary failure and endogenous CMV reactivation. This modified reduced intensity regimen is efficacious and well-tolerated in both pediatric and adult high-risk CGD-patients.