Low-dose busulfan/full-dose 64258; udarabine-based reduced-intensity conditioning in 30 high-risk paediatric and adult chronic granulomatous disease patients

T. Güngör, M. Albert, U. Schanz, M. Slatter, A. Gennery, A. Waver, P. Teira, E. Haddad, I. Ahmad, S. Lachance, P.J. Shaw, P. Stepensky, I. Resnik, R. Seger, M. Hassan on behalf of the Working Party Inborn Errors

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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.

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Annual Meeting of the EBMT, 37th
    • EBMT 37th (2011)