Objective: To examine the effi cacy and safety of hematopoietic stem cell transplantation (HSCT) after low-dose (50-65 %) Busulfan, full-dose Fludarabine conditioning and in-vivo T-cell depletion in high-risk pediatric and adult chronic granulomatous disease (CGD) patients. Patients and methods: 30 CGD patients (4-39; median 11 ys) with X-linked (n=19) and autosomal recessive (n=11) disease are described. The majority of patients were refractory to treatment suffering from infectious and/or infl ammatory complications, e.g. granulomatous colitis (n=13), active infection (e.g. Aspergillus) (n=15) or oxygene-dependent restrictive lung disease (n=2). Stem cell donors were 14 matched sibling/related donors and 11 MUD (10/10) and 5 MMUD (9/10) donors. Conditioning comprised 180 mg/sqm Fludarabine (d -8 to -3) and oral/iv. Busulfan (6.4-12 mg/kg; d -4 to -2). Pediatric patients received a therapeutic drug monitoring aiming at a cumulative AUC of Busulfan between 45 to 65 mg/L x h. For in-vivo T-cell depletion ATG-Fresenius (40 mg/kg) or Thymoglobuline-Genzyme (7.5 mg/kg) were administered. Pediatric CGD (4-17 ys) patients with MUD/MMUD transplants received Alemtuzumab (0.5 mg/kg; d -8 to -6) instead of ATG. Bone marrow (2.3-6.0 x 10 6 CD34/kg) was the prefered stem cell source, three patients received PBSC (5-11 x 10 6 CD34/kg). GVHD-prophylaxis comprised mainly CSA and MMF and in a few cases MTX. Results: The follow-up period is 2-97 (median 10) months. Acute GVHD I-II was encountered in 11 patients. No serious infectious or infl ammatory fl are-ups were observed. Neutrophil (d +19-26) and platelet engraftment (d +21-25) was in time. Three limited chronic GVHD (limited to skin) were observed. The disease-free survival is 93 % (28/30). The overall survival is 97 % (29/30). Two patients with a low cumulative AUC for Busulfan under 45 mg/L x h had autologuous reconstitution. Both were retransplanted. Two patients had transient pure red cell aplasias. Twenty-eight patients are alive and well with stable (95-100%) donor myeloid chimerism. NBT-/DHR-tests are normalized. All active infl ammatory and infectious foci are cured. One adult patient fathered a child after HSCT. Despite full myeloid engraftment, one adult patient died due to pulmonary failure (d+187). Conclusion: This RIC regimen is effi cacious and well-tolerated in both pediatric and adult high-risk CGD-patients. Targeting Busulfan is regarded to be of major importance to prevent autologous reconstitution.
Full conference title:
Annual Meeting of the EBMT, 37th
- EBMT 37th (2011)