Transplantation from Matched Unrelated Donors (MUD) for Thalassemia and Other Congenital Red Cell Disorders.
Authors: Leung Kathryn S. , Kuehnle Ingrid , Gottschalk Stephen , Bollard Catherine M. , Lee Dean A. , Heslop Helen E. , Brenner Malcolm K. , Krance Robert A. 
Published: April 2020

Abstract
Since 1981, over 1600 patients with thalassemia have undergone allogeneic transplantation from matched related donors (MRD) with encouraging long term results. Unfortunately, the majority of patients do not have MRD and half of these patients die before age 35 from side effects of iron overload.
Because advances in HLA typing and improvement in supportive care have resulted in comparable outcomes for children with leukemia transplanted from matched unrelated donor (MUD) we have been studying MUD transplantation in patients with hemoglobinopathies or with inherited severe anemia requiring chronic transfusion therapy. We used intravenous (IV) busulfan 12.8 mg/kg-16 mg/kg, cyclophosphamide 200 mg/kg, fludarabine 120 mg/m2, and Campath 1H. Tacrolimus was given as additional graft versus host disease (GvHD) prophylaxis. Here we report our experience with 8 patients: 2 ß-thalassemia major, 3 compound heterozygous Eß-thalassemia, 2 congenital sideroblastic anemia, and 1 Diamond-Blackfan anemia (DBA). The median age at transplantation was 4.5 years (2 yrs-11 yrs). Three patients were male and 5 were female. Seven patients were on chronic transfusion and chelation therapies. The median length of chronic transfusion therapy was 3.5 years (2yrs-5yrs) and of chelation therapy was 2 years (1yr-3yrs). The patient with DBA experienced intolerable side effects from chronic steroid therapy which became ineffective 1 year prior to transplant resulting in increasing transfusion frequency. One patient with thalassemia had been treated for acute lymphocytic leukemia (ALL) and was off chemotherapy for almost 4 years. Prior to transplant, all patients underwent liver biopsy which showed periportal fibrosis (stage 2–3) in 5 patients. Hepatic iron load ranged from 11,000 mcg/gm to 32,500 mcg/gm. Hence, the patients were class 1 or 2 according to the Pesaro risk classification. All patients engrafted. With a median follow-up of 12 months (1.5 months–16 months), donor chimerism remains at 100% in 6 patients and is between 86% and 100% in 2 patients. All patients are transfusion independent with median day of red blood cell (RBC) engraftment of 16 days (11 days–68 days). One patient required brief erythropoietin therapy for persistent non-transfusion dependent anemia. Acute GvHD occurred in 4 patients with 3 patients having GvHD grades 1–2. The patient who was previously treated for ALL had grade 4 GvHD to the skin, intestine, and liver. Post transplant liver biopsy for persistent elevated transaminases in 3 patients showed 1 CMV hepatitis, 1 mild to moderate GvHD, and 1 with idiopathic granulomatous inflammation. Other viral infections include 1 each of CMV bronchiolitis, BK virus hemorrhagic cystitis, and Parainfluenza type 1 bronchiolitis. All viral infections resolved with treatment. The patient previously treated for ALL died from GvHD and disseminated fungal infection. The overall disease free survival is 87% at 16 months. These initial promising results indicate that MUD stem cell transplant should be considered for patients with thalassemia and other inherited severe anemia who lack a matched sibling donor.