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C.E. Dandoy et al.
higher with non-TBI regimens, negating an advantage for overall or leukemia-free survival. The net contribution of non-relapse mortality or relapse for either treatment group was not sufficient to lead towards an overall or leukemia-free survival advantage. Our findings are in keeping with another pediatric study from Japan that also failed to show differences in overall and leukemia-free survival between TBI-containing and non-TBI Bu regi- mens.1 We hypothesize there are several factors that influenced relapse risks including acute grade 2-4 GvHD. TBI regimens were largely used with cord blood trans- plants and TBI-Cy-Flu was the predominant regimen. Others have reported lower relapse with TBI-Cy-Flu reg- imen compared to other TBI- and non-TBI containing reg- imens for cord blood transplant.25 The higher incidence of bacterial, viral and fungal infections with the TBI-contain- ing regimens within the first 3 months after transplanta- tion likely contributed to early transplant-related mortal- ity. Whether this is an effect of the conditioning regimen or the type of donor is challenging to differentiate as TBI regimens were predominantly used for cord blood trans- plants. In the subset, limited to transplants between 2012 and 2016, the incidence of bacterial and viral infections was also higher with TBI-regimens and consistent with the main analysis. However, the incidence of invasive fungal infection decreased to 2% with TBI regimens and 1% with non-TBI regimens for transplants between 2012 and 2016 (P=0.89) although this had negligible effect on non-relapse mortality (HR 1.18, P=0.72). A higher 5-year overall survival recorded with TBI-Cy-Flu compared to non-TBI regimens may be acceptable for some consider- ing cord blood transplant even though growth hormone and gonadal deficiency is higher with TBI-Cy-Flu regi- men.25 For transplantations with HLA-matched sibling or adult unrelated donors intravenous Bu-Cy or Bu-Flu is preferred.26,27 A recent study from the European Society for Blood and Marrow Transplant (EBMT) observed lower relapse and higher leukemia-free survival for AML in first complete remission with Bu-Cy-melphalan com- pared to Bu-Cy and TBI-Cy.28 Our study did not include the Bu-Cy-melphalan regimen.
Hematopoietic recovery was lower with TBI-containing regimens. We hypothesize the lower recovery rates are in part explained by the predominant use of umbilical cord blood graft with TBI-containing regimens and in part, by use of intravenous Bu for all patients and pharmacokinetic data available for 80% of patients in the non-TBI group. Higher neutrophil but not platelet recovery with intravenous Bu containing regimens compared to TBI-containing regimens has been reported in adults with acute leukemia.10
Consistent with other reports, TBI-containing regimens were associated with higher incidence of thyroid and growth hormone deficiency compared to non-TBI regi- mens.21,22 Although not studied in the current analysis, oth- ers have recorded higher risk of cataracts, neuropsycholog- ical and cognitive abnormalities with TBI-containing regi- mens.22-24 The 5-year incidence of cardiac failure and renal failure were modest (<10%) but did not differ between treatment groups. Although not the focus of the current study, two recent publications studied the association between myeloablative conditioning regimens and second neoplasm. Those reports did not record a higher risk with TBI-containing compared to non-TBI regimens.27,29
There are limitations to studying the effect of trans- plant conditioning regimen in a retrospective cohort. First, we do not know the factors that influenced choice of conditioning regimen other than in the youngest age group (≤3 years), approximately 70% of those who received TBI regimen were in second complete remission. Although we performed a carefully controlled analyses there may be unknown or unmeasured factors that may have influenced the outcomes recorded. Second, over the course of the study, effective molecular flow cytometric measures of detectable disease in patients in complete remission at transplantation may have helped refine prog- nosis after transplantation30 although it can be argued that the effect of minimal residual disease (MRD) would be consistent across both treatment groups. Among 166 patients for whom MRD status was available, 6 of 33 (18%) patients who received TBI and 17 of 133 (13%) patients who received non-TBI regimens were MRD neg- ative at transplantation. Third, we know most patients who received Bu had pharmacokinetic dose adjustments, but we do not have data on dose adjustments to examine whether an increase or decrease to the prescribed Bu dose was associated with outcomes. Our study spanned a 9- year period, a strength considering our sample size, but leukemia-free and overall survival may be influenced by transplant period. A careful analysis failed to find an effect of transplant period on outcomes other than a lower incidence of invasive fungal infection with TBI reg- imens.
Our findings are relevant regarding a discussion on the choice of TBI-containing or non-TBI regimen when consid- ering allogeneic transplantation for children and adolescents with de novo AML. In the absence of a survival advantage with either regimen group, the non-TBI regimens, Bu-Cy or Flu-Bu, are preferred although when considering umbilical cord blood transplantation TBI-Cy-Flu may be preferred.25
Disclosures
No conflicts of interest to disclose.
Contributions
CED, SMD, KWA, AEK, JL and ME designed the study; SB- S prepared the study file, KWA and YH analyzed the data; CED, SMD, KWA, YH and ME interpreted the results; CED drafted the manuscript; SMD, KWA, YH, AEK, JL, SB-S, HA-A, NB, JC, SG, NG, RH, NRL, JL, MM, TO, TP, AS, PS, LW and ME critically reviewed and edited the manuscript; all authors approved the final version.
Funding
The CIBMTR is supported primarily by Public Health Service Grant/Cooperative Agreement 5U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); grants N00014- 15-1-0848 and N00014-16-1-2020 from the Office of Naval Research. The views expressed in this article do not reflect the offi- cial policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.
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haematologica | 2021; 106(7)