REVIEW Umbilical cord blood transplantation for non-malignant diseases VK Prasad and J Kurtzberg The Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, NC, USA Many factors, including lower risk of GVHD, rapid availability of 4/6���6/6 matched cord blood (CB) units and incremental gains in the outcomes, have led to an increasing use of CB transplantation (CBT) to treat many patients who lack fully matched adult BM donors. A large electronically searchable worldwide inventory of publicly banked CB units allows for quicker donor identification and selection. In this review, we examine the current status and cumulative experience of related and unrelated donor CBT for the treatment of non- malignant diseases, including hemoglobinopathies, BM failure syndromes, primary immunodeficiency diseases (PIDs) and inherited metabolic disorders (IMDs), and conclude that CBT offers a promising and effective therapy for these diseases. Future strategies to facilitate earlier diagnosis and to decrease transplant-related risks should further improve the short- and long-term outcomes. Every effort should be made to perform transplantation early in the course of disease before extensive damage to various tissues and organs ensues. Bone Marrow Transplantation (2009) 44, 643���651 doi:10.1038/bmt.2009.290 published online 5 October 2009 Keywords: inherited metabolic diseases aplastic anemia immunodeficiency sickle cell anemia thalassemia umbili- cal cord blood transplantation Introduction Non-malignant diseases from a wide diagnostic spectrum, including hemoglobinopathies (for example, thalassemia and sickle cell disease), BM failure syndromes (for example, congenital or acquired aplastic anemia and Fanconi anemia), primary immunodeficiency diseases (PIDs for example, SCID, chronic granulomatous disease and Wiskott���Aldrich syndrome (WAS)), inherited metabolic disorders (IMDs for example, leukodystrophies and mucopolysaccharidoses) and others, can be successfully treated by allogeneic hematopoietic SCT (HSCT). In each of these diseases, donor-derived cells have the ability to correct the underlying defect, either by direct repopulation of the hematopoietic and immune systems or by indirect delivery of the missing enzymes or other critical building blocks across the cellular membranes. The lower risk of GVHD and rapid availability of 4/6���6/6 matched cord blood (CB) units has led to a greater acceptance of CB transplantation (CBT).1���10 The majority of CBT, since the first one from a matched sibling in 198811 and from an unrelated donor in 1993,12 have been performed for malignant diseases. However, for patients with non- malignant diseases, CBT offers unique advantages includ- ing broader donor access and rapid procurement. In addition, many studies have shown that hematopoietic progenitor cells derived from related or unrelated umbilical CB units are at least as effective as those derived from the BM or growth factor-mobilized peripheral blood.1,2,4,6,13 Biologically, transplantation in patients with non-malig- nant diseases facilitates the study of the effect of graft characteristics on transplant outcomes in an environment in which graft vs malignancy effect is not a competing risk factor. Currently, HLA typing by intermediate resolution for class I (A and B) loci and high resolution for HLA class II (DRB1) is considered optimal and CB units matching at X4/6 loci are considered adequate. CB units with pre-cryopreservation cell counts of X2.5 3 107 nucleated cells (NCs)/kg are considered adequate for better matching grafts, but doses above 5 107/kg yield superior results and can be achieved in most pediatric patients.1,2,4,10,14 Cord blood transplantation (CBT) for patients with hemoglobinopathies Hemoglobinopathies, such as thalassemia, sickle cell disease (SCD) and other complex defects, can cause major morbidity, poor quality of life and early death from the combined effects of anemia, hemolysis, iron overload and ineffective erythropoiesis. Early transplantation from a suitable donor prevents and reverses many of these problems. Because of different natural histories, the specific questions regarding the time of transplantation, criteria for patient selection and supportive care guidelines differ for patients with thalassemia and SCD. However, the overall concept and design of transplantation is similar. The curative potential of HSCT in hemoglobinopathies has been clearly shown. However, difficulties in defining the criteria for patient selection, limitations in donor Received 2 September 2009 accepted 2 September 2009 published online 5 October 2009 Correspondence: Dr VK Prasad, Division of Pediatric Blood and Marrow Transplantation, Box 3350, Duke University Medical Center, Durham, NC 27710, USA. E-mail: vinod.prasad@duke.edu Bone Marrow Transplantation (2009) 44, 643���651 & 2009 Macmillan Publishers Limited All rights reserved 0268-3369/09 $32.00 www.nature.com/bmt

patients, have described the experience of unrelated CBT (UCBT) for the treatment of patients with hemoglobino- pathies. The youngest patient was a 2-month-old boy who received a high cell dose, 4/6 HLA-matched unrelated CB units after BU/CY/ATG conditioning.32 He promptly engrafted with donor cells, is currently alive and well with 100% donor chimerism, almost 11 years after transplant. He developed autoimmune hemolytic anemia in the early post transplant course, which was treated with a short course of azathioprine and steroids and resolved completely by 2 years after transplant. Until 2007, a total of 16 patients with thalassemia and 7 patients with SCD had been reported to have undergone UCBT,32���39 The results from the first published series of unrelated donor CBT was very encouraging. In this Taiwanese report of five children (median age 3.7 years, range 2.3���11.4 years all Pesaro class 1) with thalassemia major treated with unrelated donor CBT (median cell dose 8.8 107/kg) from 1-Ag (n �� 3) or 2- Ag (n �� 2) mismatched (high-resolution typing) units after BU (14 mg/kg), CY (200 mg/kg) and ATG cytoreduction and CyA/methylprednisolone prophylaxis, all patients engrafted with full donor chimerism and became transfu- sion independent by 5 weeks after transplantation.40 Four patients developed transient corticosteroid-responsive grade I���III aGVHD but there was no cGVHD. All patients were alive and well, with full donor hematopoietic chimerism and transfusion independence at a median follow-up of 303 days after transplant (range 120���360 days). In another report, the same group reported on five older children (median age 11.1 years, range 10���13.1 years) with thalassemia who received double CBT from unrelated mismatched donors after the same cytoreduction.36 One patient developed secondary graft failure and the other four developed transient corticosteroid-responsive grade I���III acute GVHD and later limited skin GVHD. At 18.5 months (range 11���32 months), three were alive, well and transfusion independent and one was alive but transfusion dependent. Results from other small and single case reports are similar to the above findings. A 2007 review of four previously published case reports summarized the experi- ence of unrelated donor CBT in seven children with SCD all of whom had a history of stroke. HLA matching was 4/6 in five and 5/6 in two cases. Myeloablative cytoreduction was used in four (BU �� CY �� ATG in three and BU �� CY �� ATG �� Flu in one) and reduced-intensity con- ditioning in three patients. Unrelated donor CBT was curative in three of seven patients (two in myeloablative and one in reduced-intensity conditioning group) whereas three patients are alive with SCD after primary graft failure. In an abstract at the annual meeting of the American Society of Blood and Marrow Transplantation in February 2009, Jaing et al.41 presented promising results with unrelated donor CBT in 30 children (median age 5 years, range 1���14 years) with b-thalassemia major (Pesaro 1���21, Pesaro 2���8) transplanted between 2003 and 2008 after myeloablative conditioning with BU �� CY �� ATG. Single CB unit was used for 21 and double for 9 patients, providing a high median cell dose of 10.9 107/kg. The CB units were 4/6 (n �� 24), 5/6 (n �� 11) or 6/6 (n �� 4) matched. The OS survivals at 1 and 3 years were 87��6% and 82��8%, whereas DFS at 1 and 3 years was 85��7% and 78��9%, respectively. The risk of grade II���IV aGVHD and extensive cGVHD were 61��11% and 4��4%, respectively. These results in patients who have been followed for a median of 16 months (range 0.3���58 months) are very encouraging with DFS rates similar to those after matched related transplants. Despite recent advances, there is significant TRM and morbidity associated with myeloablative transplants for hemoglobinopathies. Various approaches, including im- proved cellular criteria for donor CB unit selection, pre- implantation genetic diagnosis and embryo selection as well as decreasing the toxicity of the transplant regimen, need to be undertaken in an effort to improve the risk���benefit ratio and to reach the ultimate goal of making transplants available to larger numbers of eligible patients. In an abstract at the American Society of Blood and Marrow Transplantation meeting, Bhatia et al.42 presented the results of reduced-intensity conditioning using BU (3.2��� 4 mg/kg/day 4 days), Flu (30 mg/m2/day 6 days) and alemtuzumab (2 mg/m2 1 day, 6 mg/m2 2 days and 20 mg/m2 2 days) in 14 patients with symptomatic SCD. The graft sources were matched sibling BM (n �� 6), matched sibling CB (N �� 2) and unrelated donor CB (n �� 6). Using a different RIC combination (alemtuzumab, Flu and melphalan) and a variety of graft sources (sibling BM n �� 5, sibling PBSC n �� 5, unrelated BM n �� 3 and unrelated CB N �� 3) in 16 children with non-malignant diseases, Shenoy et al.43 achieved successful durable engraftment in 14 patients without significant GVHD. Engraftment with CB donors required a higher dose of melphalan (140 mg/m2) as compared with engraftment with other stem cell sources. On the basis of these and other data, the Clinical Trials Network recently initiated a multicenter prospective study (CTN0601) of unrelated BM or CBT for the treatment of children with SCD. Cord blood transplantation (CBT) for patients with primary immunodeficiency disorders (PIDs) HSCT is curative in most children with a variety of PIDs if a suitable donor is available in a timely manner. However, a majority of patients will not have a suitable matched sibling BM donor because of the limitations posed by a combination of Mendelian inheritance of HLA and the genetic nature of these diseases. Alternative donor trans- plants using T-cell-depleted grafts from haploidentical parents have been used successfully in many patients with SCID however, many patients will fail to reconstitute B- cell function.44 Furthermore, anecdotal reports of late graft failure, more than a decade after transplant, are emerging as longer follow-up is available. CB offers an attractive option because of ready availability and less stringent HLA matching requirements. The low risk of GVHD after CBT is additionally useful as many patients with PID, such as Wiskott���Aldrich syndrome (WAS), Omen syndrome and sometimes SCID, have inherent dermatological problems. In addition, CB units with good cell dose are more easily available for PID patients because of their young age and low body weight. Cord blood transplant for non-malignant diseases VK Prasad and J Kurtzberg 645 Bone Marrow Transplantation