Non-Myeloablative Conditioning Targeting Host Immunosuppression Is Successful in Matched Sibling Donor Stem Cell Transplantation for Hemoglobinopathies in Children

• Published in: Blood 2014-12, Vol.124 (21), p.3873-3873
• Main Authors: King, Allison A, Bunin, Nancy, Sahdev, Indira, Brochstein, Joel A, Abraham, Allistair, Dioguardi, Jacqueline, Kamani, Naynesh R., Anderson, Eric Jon, Willert, Jennifer, Chan, Ka Wah, Grimley, Michael, Douglas, Dorothea N., Adams, Roberta H., Chaudhury, Sonali, Yu, Lolie C., Gilman, Andrew, Andreansky, Martin, Cuvelier, Geoff D.E., Gillio, Alfred P., Kasow, Kimberly A., Haut, Paul R., Hale, Gregory A., Dalal, Jignesh, Jain, Akshat, Hanson, Eric, Murray, Lisa, Shenoy, Shalini
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.3873.3873

▪ Background: Myeloablative hematopoietic cell transplantation (HCT) provides a cure for children with hemoglobinopathies, but transplant related early and late morbidity remains a challenge. Toxicities associated with myeloablative chemotherapy include early complications such as mucositis, hemorrhagic cystitis, seizures, and hepatic injury. Late effects such as infertility and compromised linear growth impair long-term quality of life, often decreasing enthusiasm for the procedure. Reduced intensity preparative regimens are especially attractive in children with non-malignant disorders to mitigate these toxicities but have been associated with increased risk of graft rejection. The primary objective of this study was to determine the toxicity and efficacy of a non-myeloablative preparative regimen using alemtuzumab, fludarabine, and melphalan followed by HCT from HLA matched related donors (MRD) in children with hemoglobinopathies. Methods: Following institutional review board approval, and parent and/or patient consent, participants were enrolled at 18 centers. Children < 21 years of age with severe sickle cell disease (SCD) manifestations, or transfusion dependent (> 8 red blood cell transfusions per year) thalassemia with a MRD and a performance status > 40 were eligible for inclusion. The preparative regimen included alemtuzumab (total dose 48 mg) IV (between days –22 and –19), fludarabine (30 mg/m2/day) (days –8 to –4) and melphalan (140 mg/m2) on day -3. Graft versus host disease (GVHD) prophylaxis included a calcineurin inhibitor (tapered after day 100, and methotrexate (7.5 mg/m2 on days 1, 3 and 6) or mycophenolate mofetil. Five patients also received methylprednisone (1 mg/kg/day) between days 1 and 28; this practice was discontinued in 2007. Results: A total of 52 children (43 with SCD and 9 with thalassemia), median age 11 years (range, 10m - 20y) underwent HCT between March 2003 and July 2014. Of these, 46 received bone marrow, 5 received marrow and cord blood (CB), and 1 received CB alone. Median follow up was 35.5 months (range, 3 – 136). Forty-nine children were alive at last follow up (Figure 1); 48 were symptom-free; one CB recipient had disease recurrence following graft rejection and successfully underwent a 2nd HCT. No hepatic veno-occlusive disease was noted. Three deaths 6, 11 and 21 months post HCT were from GVHD related causes [bronchiolitis obliterans (n=1); infection with GVHD (n=2)]. The cumulative incidence of graft failure a