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C.E. Dandoy et al.
Introduction
Hematopoietic cell transplant (HCT) is accepted as the standard of care for children and adolescents with high risk or relapsed/refractory acute myeloid leukemia (AML).1-3 Total body irradiation (TBI) or busulfan (Bu) containing myeloablative conditioning regimens are commonly used to treat these patients.4,5 In 1992, a randomized trial in adults showed improved 2-year leukemia-free survival using conditioning with TBI-cyclophosphamide (Cy) com- pared to Bu-Cy using oral busulfan formulation, which was available at that time,6 however, there are limited data in children and adolescents. Intravenous Bu has subsequently been developed, which provides more consistent pharma- cokinetics and reliable dosing.7 Further, pharmacokinetic targeting of intravenous Bu dosing reduces treatment-relat- ed toxicity.8 In the modern era, in adults, intravenous Bu- conditioning has been shown to be associated with improved non-relapse mortality, and overall and disease- free survival in comparison to TBI-containing regimens.9,10 However, acute graft versus host disease (GvHD),11 acute liver injury,12 pulmonary injury (e.g., diffuse alveolar hemor- rhage), and bloodstream infections1,13,14 are reported to be higher with TBI-containing compared to non-TBI regimens. Late complications, including secondary malignancies, endocrine, metabolic, renal, ocular, and neurocognitive complications are also higher with TBI-containing com- pared to non-TBI myeloablative regimens.15-17 Although TBI-containing regimens are associated with significant toxicity in children,18 many physicians continue to use TBI- containing regimens for transplantation for de novo AML in children and adolescents. In the absence of a randomized trial comparing TBI-containing versus non-TBI regimens in children, we utilized data on HCT reported to an observa- tional registry, the Center for International Blood and Marrow Transplant Research (CIBMTR) to compare out- comes between the two treatment groups.
Methods
Patients
Data were reported prospectively to the CIBMTR, a voluntary working group of more than 450 transplant centers worldwide that contribute detailed data on allogeneic and autologous HCT. Participating centers report consecutive transplants and compli- ance is monitored by on-site audits. All patients are followed longitudinally until death or lost to follow-up. Eligible patients were aged ≤21 years undergoing first allogeneic transplantation with myeloablative conditioning for de novo AML in first or sec- ond complete remission between 2008 and 2016 and consented for research. Excluded were patients with an antecedent hema- tologic disorder or secondary AML, mismatched related donor transplant and non-calcineurin inhibitor GvHD prophylaxis reg- imens. Patients were broadly grouped into TBI-containing (TBI- Cy), TBI-Cy-fludarabine (Flu) and non-TBI (Bu-Cy and Bu-Flu) regimens. The study was approved by the Institutional Review Board of the National Marrow Donor Program.
Endpoint
Grades 2-3 acute GvHD, grade 3-4 acute GvHD, and chronic GvHD were defined using standard definitions.19,20 Relapse was defined as the recurrence of AML (morphologic, cytogenetic or molecular) and non-relapse mortality was defined as death in remission. Overall survival was defined where death from any
cause was considered an event. Leukemia-free survival was defined as being alive in continuous remission. Neutrophil recov- ery was defined as achieving a count of ≥0.5x109/L for 3 consecu- tive days. Platelet recovery was defined as achieving a count of ≥20x109/L without transfusions for 7 consecutive days. The day- 100 incidence of veno-occlusive disease, systemic bacterial, viral and fungal infection were compared between the two treatment groups. The 5-year incidence of post-transplant interstitial pneu- monitis, congestive heart failure, gonadal dysfunction, growth hormone deficiency and renal failure severe enough to warrant dialysis were compared between the two treatment groups.
Statistical methods
Patient-related, disease-related, and transplant-related out- comes were compared between treatment groups using Mann- Whitney tests (continuous variables) and Fisher’s exact/Chi- square test (categorical variables). A P-value of <0.05 was consid- ered statistically significant. Cox regression models were built for acute and chronic GvHD, non-relapse mortality, relapse, overall and leukemia-free survival.21 The main effect (TBI-containing vs. non-TBI regimens) was forced in all models, and other covariates were retained in the final model if they met a significance level of less than 0.05. Forward stepwise selection was used to identify significant covariates. The interaction between the main effect and significant covariates was examined. Assessment of the pro- portional-hazards assumption was done by examining the coeffi- cient of the logarithm of time from transplant to the last follow- up for each covariate. The coefficients for the covariates which violated the proportional hazards assumption were added as time-varying effects. The adjusted survival or cumulative inci- dence probabilities were calculated based on the final Cox mod- els.22,23 Center effects were tested for non-relapse mortality, relapse, overall and leukemia-free survival using the score test.24 All analyses were performed using SAS 9.4 (SAS Institute Inc, Cary, NC).
Results
Patient, disease and transplant characteristics
Six hundred and twenty-four patients transplanted at 124 transplant centers were eligible and their characteris- tics are shown in Table 1. TBI-containing regimens includ- ed TBI-Cy (38%, 76 of 199) and TBI-Cy-Flu (62%, 123 of 199). Non-TBI regimens included Bu-Cy (76%, 322 of 425) and Bu-Flu (24%, 103 of 425). Bu pharmacokinetics with dose adjustments were performed for 80% (338 of 425) of non-TBI transplantations. Patient and disease characteris- tics differed by treatment group. TBI-containing regimens were less likely to be used for children aged 3 years and younger, for transplants in first complete remission and more likely with umbilical cord blood (67%). In very young children (age ≤3 years, n=170), only 19% (33 of 170) received a TBI regimen. Bone marrow was the predomi- nant graft for non-TBI regimen transplants (48%). In vivo T- cell depletion with anti-thymocyte globulin was common with non-TBI regimens accounting for 52% of transplanta- tions compared to only 11% with TBI-containing regi- mens. The predominant GvHD prophylaxis with TBI-con- taining regimens was cyclosporine with mycophenolate and for non-TBI regimen, tacrolimus or cyclosporine with methotrexate. There were no differences between treat- ment groups regarding performance score, hematopoietic co-morbidity index, sites at diagnosis and cytogenetic risk. Most transplant centers used both TBI-containing and non-
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haematologica | 2021; 106(7)