Long Term Outcomes of Unrelated Donor Bone Marrow Transplantation in Children with Severe Aplastic Anemia: An Update of the Milwaukee Experience.
Authors: Talano Julie-An , Camitta Bruce , Keever-Taylor Carolyn , Anderson Lynnette , Wallach Caitlin , Casper James , Margolis David 
Published: October 2019

Abstract
We demonstrated that partially T-cell depleted unrelated donor HSCT for Severe Aplastic Anemia (SAA) is a reasonable treatment option for children and young adults who fail immune suppression therapy. (Margolis et al., 1996, Br J Haematol.)We now report, long term follow up data for 40 patients transplanted for SAA between the years 1986 to 2002. The patient group consisted of 22 males and 18 females, ranging in age from 0.5–24.3 (median 8.5) yrs. Retrospective molecular HLA typing shows that donors were matched for nine patients, and mismatched for 31. Patients were conditioned with cytosine arabinoside, cyclophosphamide, and total body irradiation, as previously described. Some patients additionally received ATG to promote engraftment. The marrow product underwent partial T-cell depletion using an antibody and complement process as described. in the original report. GVHD prevention was with cyclosporine. Three patients did not engraft. All three with non-engraftment died within 60 days of BMT from infectious and hemorrhagic complications. Since employing ATG as part of the conditioning regimen, all patients have engrafted. Of the 37 patients who engrafted the median time to an ANC>500 was 16 (range 8–25) days. Eight patients developed Grade II AGvHD, 1 grade III and 2 grade IV. Of 29 evaluable patients, 12 developed limited chronic GVHD, and 3 developed extensive CGvHD. Twenty-one patients are currently surviving with a follow-up of 4 to 19 yrs. (median 12.7 yrs.). Overall survival is 52% at 12 yrs. Of the 19 patients that died, causes of death included infection n=7, (PCP n=1, CMV n=2, Aspergillus n=1, Adenovirus n=2, PTLD n=1); GVHD n=2; Graft failure n=3; Multiorgan system failure n=2; ARDS n=1; Hemorrhage n=2; VOD n=1; Secondary malignancy n=1 (Hodgkin’s disease n=1). Of the 21 surviving patients, all patients have a Karnofsky score ≥ 90%. The late effects in our survivors include two secondary malignancies (osteosarcoma and vaginal carcinoma in situ); cataracts n=11; growth retardation n=11; gonadal dysfunction n=6; hypothyroidism n=5; cognitive problems n=4; musculoskeletal problems (AVN, osteoporosis) n=7; hyperlipidemia n=3; and renal disease n=2. One patient had a subsequent pregnancy that resulted in a preterm delivery at 26 weeks and a neonatal death. Our experience, now with long follow-up, shows that an intensive conditioning regimen to prevent graft rejection, coupled with partial T-cell depletion of an unrelated donor bone marrow graft to decrease the risk of GVHD, provides for durable survival with an acceptable incidence of acute and chronic GVHD. The relatively low incidence of GVHD is notable in view of the number of patients with donors who had identified HLA disparity. However, there are long-term risks associated with this regimen including secondary malignancies, delayed growth and development, metabolic problems, and musculoskeletal problems. We are encouraged by the recently reported short-term results using regimens for this disease which avoid or limit the use of TBI. Recognizing that many patients have donors with HLA disparity, which increases the risks of graft rejection and GVHD, we believe that combining partial T cell depletion with advanced immunomagnetic methods of graft manipulation and a fludarabine based regimen may allow us to balance the risks of graft rejection, GVHD, and late-effects that are unique to patients with SAA.