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.