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.