DISCUSSION
Five transfusion-dependent DBA patients successfully underwent targeted BU-based conditioning 3 HLA-matched or 2 one-locus HLA-mismatched unrelated donor BMT; in the latter 2 cases, transplantation was at >10 and >20 years of age. The longest transfusion-dependent case, which showed the highest ferritinemia had one graft failure but was rescued by CB transplantation after our established low-dose TBI regimen. The targeted BU-based intermediate intensity regimen was optimal for alternate donor BMT in DBA patients.
For successful HCT, the diverse clinical expression and high penetrance of DBA hamper the search for suitable family donors. Organ dysfunction associated with anomaly and/or iron overload increases the risk of regimen related toxicities (RRTs). Repeated transfusion augments the risk of rejection. RIC is preferable to reduce RRT and late complications in IBMFS. In a recent report from Brazil,8 the 5-year overall survival rates after HLA-matched sibling donor, HLA-matched unrelated donor, and HLA-mismatched donor HCT were 80%, 73%, and 29%, respectively. In the EBMT database, the 3-year event-free survival rate of patients who received unrelated donor HCT was >80%.9In Japan,3 8 of 9 DBA patients underwent successful RIC-unrelated donor BMT, but all 9 patients received RIC regimen with both irradiation and alkylators. Appreciable intensity is required for complete donor chimerism to reduce the risk of graft failure and myeloid malignancy. TBI should be avoided in conditioning regimens for non-malignant disease, especially for cancer predisposition syndromes. BU or treosulfan (Treo) and FLU-based myeloablative conditioning (MAC) has been recommended for HCT for DBA patients.10 Treo and alemtuzumab-RIC has been reported in a limited number of cases;4-7 however, neither is licensed in Japan. Our targeted BU-based regimen was effectively used for children and adults. The dosage can be further personalized for wider ranges of circulating BU levels in infants.11 Alemtuzumab is more effective than rATG in preventing GVHD in patients with non-malignant disorders.12 Replacement of rATG with alemtuzumab may improve engraftment and decrease chronic GVHD without resulting in delayed immune reconstitution.13 Because chronic GVHD increases the risk of post-transplant neoplasms in DBA patients,14 rATG would be replaced by alemtuzumab. More recently, a critical precaution of Treo dose individualization has been reported in infants and children undergoing allo-HCT for non-malignant conditions.15 Precise targeted conditioning is needed for pediatric patients even in the setting of BU or Treo.
Colorectal cancer, osteogenic sarcoma and cardiac Purkinje cell tumor have been reported in DBA patients, most frequently at a median of 9 years after MAC-HCT.16-19 The combination of alkylators and TBI raises the risk of osteogenic sarcoma in pediatric patients after MAC-HCT;20 however, there is no information on the effect of a single alkylator in RIC-HCT. The cancer risk and clonal hematopoiesis may be more accelerated with age in IBMFS. Cancer vigilance is needed to optimize the time and conditioning of DBA patients as well as the age at HCT.
Acknowledgements: We thank to all of the staff who participated in the treatment of patients in Kyushu University (Fukuoka, Japan) and Kobe Children’s Hospital (Hyogo, Japan), and the staff members of Hirosaki University (Aomori, Japan) for the genetic analysis of the patient. This work was supported by the Health and Labor Sciences Research grants under Grant Number 19FC1005.
Conflict of Interest Statement: The authors declare no conflict of interest in association with the present study.