Unrelated Donor Umbilical Cord Blood Transplant Following Intrauterine Transfusions for Treatment of Alpha Thalassemia Major.
Authors: Rivers Angela E. , Richard Douglas , Harris Neil , Chui David H.K. , Slayton William B. , Baacke Keri , Staba Susan Lynn 
Published: October 2019

Abstract
Homozygous α0-thalassemia (deletion of all 4 α-globin genes) results in Hb Bart’s (γ4 tetramers). The high oxygen affinity of Hgb Bart’s leads to severe hypoxia inutero with resulting profound edema (hydrops) and congestive heart failure. Almost universally fetal death occurs prior to diagnosis, therefore not allowing the opportunity for treatment. Advancement of maternal-fetal medicine and neonatal ultrasound has led to the possibility of in utero diagnosis and treatment with inrauterine transfusions. Also, cases of premature infants surviving and undergoing chronic transfusion therapy have been reported. Hematopoietic stem cell transplant (HSCT) has become increasingly used in the cure of beta thalassemia, and provides the potential to cure a0thalassemia as well. To date, 3 reported cases of a0thalassemia have been successfully treated with HSCT. Two children underwent matched sibling bone marrow transplant at 20 and 21 months of age and one underwent a 5/6 HLA matched sibling umbilical cord blood transplant (UCBT). One child had received intrauterine transfusions. We report a case of an infant with a0thalassemia successfully treated with intrauterine transfusion therapy followed by unrelated donor UCBT. The child’s mother, of Cambodian descent, presented to the obstetrician at 23 weeks with concerns of decreased fetal movement. Fetal ultrasound revealed a thickened placenta and hydrops fetalis. Based on the family’s nationality and history of previous fetal loss, the suspicion of a0thalassemia was raised. Umbilical cord blood sampling revealed a hypochromic, microcytic anemia with target cells. The hemoglobin electrophoresis demonstrated Hgb Barts and Portland. Subsequent genotyping confirmed deletion of all 4 α-globin genes. Options presented to the family included termination of pregnancy as well as the option of intrauterine transfusion followed by either chronic transfusion therapy with iron chelation or the possibility of HSCT. The patient received three intrauterine transfusions prior to delivery at 32 weeks gestation. A poor physical profile, non-reassuring heart rate and breech position led to the premature delivery. Apgars were 1 at one minute, 6 at five minutes, and 9 at ten minutes. The baby was admitted to the NICU and required mechanical ventilation for two days. The hospital course was relatively uneventful and included red blood cell transfusion. After discharge, he was maintained with intermittent transfusions until 6 months of age. Following informed consent, he was conditioned for transplant with busulfan, cytoan and rabbit ATG. Since the infant lacked an HLA matched sibling, he received a 5/6 HLA matched unrelated donor umbilical cord blood unit delivering 11.8 × 107 nucleated cells/kg. Neutrophil engraftment (ANC>500) was achieved on day + 15. FK506 and methotrexate 5mg/m2 on days 1, 3 and 6 was utilized for GVHD prophylaxis. His course was complicated by moderate venoocclusive disease, small subdural hemorrhage, and CMV and adenovirus viremia. He has not had any evidence of graft versus host disease. Initial chimerism (RFLP) showed approximately 63% donor derived cells, and subsequent testing showed increasing chimerism and 100% T-cell engraftment. He clinically is doing very well post transplant. This case demonstrates that intrauterine transfusion followed by unrelated donor UCBT is feasible for the treatment of a0thalassemia.