Discussion
We describe acute and cGVHD incidence in a contemporary cohort of children with NMD undergoing allogenic HCT. There is abundant literature on the incidence and risk factors for GVHD in adult and pediatric HCT recipients with malignant disorders; however, similar reports are scarce for children with NMD. The larger published studies describing impact of GVHD on clinical outcomes included patients transplanted in the 1990s (5) or included patients transplanted over several decades. (10,11) Given changes in HCT practices, it was important to validate these results on a contemporary cohort of patients.
Regarding incidence of GVHD in pediatric patients with NMD, our findings are similar to findings from the Japanese transplant registry, which included all children with NMD transplanted between 1985 and 2016. (10) Umeda et al. reported cumulative incidences of aGVHD grade II-IV, aGVHD grade III-IV, and cGVHD of 24%, 9.1% and 17.8%, compared with 21.9%, 9.3% and 21.3% in our cohort. (10)
Our data shows that aGVHD grade III/IV, which developed in 9.3% of children with NMD, significantly affected the overall survival, while aGVHD grade I/II has no adverse impact on survival. Due to small numbers of deceased patients, we could not identify significant differences in cause of death between patients with and without aGVHD grade III/IV. The risk of infections was similar between the 2 groups and GVHD was considered the primary cause of death in 2 patients. Similar to previous reports, we could not document significantly reduced survival rates in children with cGVHD (5,10). Even when it does not affect survival, due to related morbidity and impact on quality of life, any acute or cGVHD represents an unwanted iatrogenic complication in children with NMD.
Due to genetic diversity of Florida’s population, finding a fully HLA-matched donor is difficult and 31% of our patients received stem cells from alternative donors such as mismatched cord blood, mismatched unrelated donors, and mismatched related donors. Our study indicates that only recipients of mismatched unrelated BM and PB had an increased risk of aGVHD grade III/IV, which was related to reduced survival. The incidence of aGVHD grade III/IV was lower in mismatched related donor recipients than in MRD, and was similar in mismatched UCB recipients to MRD.
Previous publications (Bertaina A et al., Zecca et al., Anurathapan et al.) reported absence of aGVHD grade III/IV in haploidentical transplant recipients, regardless which of the 3 depletion strategies was used (CD34 positive selection, αβ T-cell and CD19+ cell depletion, or in vivo T-cell depletion with post-transplant cyclophosphamide). (13-15)
In our previous analysis of data from the FPBCC, we observed inferior survival of children with NMD receiving HCT from mismatched unrelated donors, including mismatched cord blood, and we recommended that use of mismatched related donors be favored over mismatched unrelated BM, PB or UCB donors. (16) Findings from this study indicate that improved methods of GVHD prophylaxis are needed in children with NMD receiving mismatched unrelated BM or PB. Recent literature describes use of abatacept, alpha beta (αβ) T-cell and CD19-cell depletion, and post-transplant cyclophosphamide as promising methods for GVHD prophylaxis in children with NMD. (13,17-19) However, donor selection and the approach to GVHD prophylaxis when an HLA-matched donor is lacking, is the subject of research and until large randomized studies are available, the alternative donor selection and GVHD prophylaxis will likely remain center-specific. Only 1/5 FPBCC transplant centers performed ex-vivo T-cell depletion/CD34+ selection during the study period, and no centers performed αβ T-cell depletion, while all centers used post-transplant cyclophosphamide, which was used in the majority of haploidentical HCT recipients in this study. Post-transplant cyclophosphamide use results in excellent outcomes and significant reduction in grade III/IV GVHD; however, higher risk of graft failure in pediatric non-malignant conditions and hemoglobinopathies, and post-transplant late effects related to high dose chemotherapy warrant caution when using this method of GVHD prophylaxis in children with NMD. (20,21) Literature indicates that alpha beta CD3+/CD19+ cell depleted haploidentical HCT resulted in excellent survival, low GVHD rates, and good immune reconstitution, and this method is emerging as a promising strategy for GVHD prevention in children with NMD. (13) However, some investigators feel that significant myeloablation, required for T-cell depleted transplants, is a disadvantage of this approach.
Due to its retrospective, registry nature, our study lacked some relevant data, such as agents used for GVHD prophylaxis or method of T-cell depletion. Although we included 10-year pediatric transplant data, the numbers, particularly in some subgroups, are still low, emphasizing that transplants for pediatric NMD are rare events (only 20-25 of these transplants are done annually in Florida) and that consolidating data, not only across centers but across different NMD diagnostic groups, is necessary in order to understand outcomes and complications of those transplants.