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.