Discussion
Our primary study interest was in determining the treatment approach to
monomorphic PTLD across Canadian pediatric centers. For the majority
(89%) of children in our study, RIS was a component of initial
management. There is widespread support for this strategy. The European
Reference Network on Pediatric Transplantation surveyed 13 centers and
the most common initial PTLD treatment was reduction of
immunosuppression.21 The majority of children also
received rituximab with chemotherapy. LMB-96 and low-dose
cyclophosphamide with prednisone were the favored chemotherapy regimens.
Almost all children receiving alternate regimens had rare, non-B cell,
disease. Choquet and Trappe et al demonstrated rituximab’s safety and
efficacy in adults with B-cell lineage PTLD and Maecker-kolhoff et al
confirmed the same for children.23,28,30 Two pediatric
PTLD trials, reported by Gross et al., successfully treated children
with EBV +ve PTLD, post-SOT, using low-dose cyclophosphamide and
prednisone (CP), with addition of rituximab (CPR) for those with CD20
positivity. Two-year EFS rates were 67% for the CP combination and 71%
for the CPR combination, however, the authors did not consistently
describe histopathological subtypes treated, and included children with
non-monomorphic disease, making generalizability of their findings to
all children with monomorphic PTLD difficult.18,19
In children with B-cell monomorphic PTLD, the challenge lies in
determining which patients a clinician should anticipate having a good
response to low-dose cyclophosphamide with prednisone and which require
more intensive chemotherapy such as LMB-96. While LMB-96 is associated
with excellent survival in, otherwise, healthy children with mature
B-cell lymphoma, its toxicity profile may be concerning post-SOT.25-26,31 PTLD risk stratification, to guide allocation
of therapy, is evolving. Giraldi et al. recently published a standard vs
high-risk classification system, derived from age-adjusted International
Prognostic Indices, with tailored treatment: RIS/rituximab vs multiagent
chemotherapy.25-26,29 We did not explore rationale
used by Canadian physicians to decide treatment approach but advanced
stage disease (stage III/IV), which Giraldi et al. consider ‘high-risk’,
and the large number of Burkitt lymphoma cases, could explain prevalence
of LMB-96 usage.26 No survival benefit was observed
according to chemotherapy regimen used (CPR vs LMB96), which may be
explained by the small patient number in our cohort.
For monomorphic PTLD patients, with co-morbidities and risk of graft
failure, chemotherapy is not always
deliverable.18-23,25-26 Prockop et al. therapeutically
treated 13 SOT recipients, with EBV +ve PTLD, with EBV-CTLs; 7 (54%)
were paediatric patients < 18 years of
age.24 Complete or partial remission was achieved in 7
(54%) patients.24 An industry-sponsored EBV-CTL study
is currently recruiting children with PTLD.32 Although
CTLs were not administered to patients in our cohort, it is conceivable
that future management will shift to favor novel therapies, alongside
aforementioned risk-stratification tools to identify children expected
to derive significant benefit from polychemotherapy.24-26,32-34
As a retrospective study, recall bias may have impacted data collected.
Further, larger Canadian pediatric centers participated but smaller
centers did not, this could limit generalizability of our findings.
Acknowledging limitations, our findings suggest a, relatively,
consistent approach to monomorphic PTLD management. This should
encourage future collaboration and development of Canada-wide treatment
protocols to improve outcomes for children with this challenging
disorder.