Impact of Conditioning Regimen in Allogeneic Hematopoetic Stem Cell Tansplant for Children with AML beyond the First Complete Remission: Total Body Irradiation Versus Busulfan- a Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study
Authors: Sisler India , Domm Jennifer , Ryan Robin , Levine John E. , Pulsipher Michael , Haut Paul R. , Schultz Kirk R. , Koyama Tatsuki , Koehler Elizabeth , Frangoul Haydar 
Published: April 2020

Abstract
Busulfan (Bu) based preparative regimen is the most commonly used regimen for children with AML in 1st complete remission (CR). However conditioning regimens for children with AML beyond the first clinical remission (≥ 2nd CR) often include total body irradiation (TBI), which may result in significant long term sequelae. There are limited data concerning outcome in children with AML beyond 1st CR and no data comparing conditioning regimens in this population. One hundred fifty-one patients ≤ 21 years with AML in ≥ CR2 were included in this study. These patients were treated at 47 pediatric transplant centers between 2000 and 2007 with complete data forms reported to the PBMTC database. The median follow up was 2.6 years (range 0.25–8.02). One hundred thirty-four (92%) were in CR2 with a median age 9.2 years (range 0.8–21.6). Ninety (60%) received TBI based regimens and 61 (40%) received Bu based regimens. A majority of those patients received TBI or Bu in combination with cyclophosphamide. Twenty-six (17%) received related donor transplants and 125 (83%) received stem cells from unrelated sources. Thirty nine percent of patients received cord blood transplants. AML was considered high risk in 4 (3%) patients, intermediate risk in 98 (82%) and low risk in 17 (14%). The median time between CR1 and relapse was 12 months (range 1–60) and from achieving 2nd CR to transplant was 1.5 months (range 0.23–10.4). There were no significant differences between patients receiving TBI and Bu conditioning regimens with respect to age, sex, disease risk, pretransplant performance score, duration of CR1, time from CR2 to transplant and stem cell or donor source. There were significantly more patients with history of extramedullary disease in the TBI group (36% vs. 18%, p=0.02). Transplant related mortality (TRM) was not significantly different between the TBI and Bu groups (22% vs. 16%, p=0.29). Infection was the most common cause of death accounting for 39 % of the overall TRM. The probability of relapse at 2 years was 26% and 27% in the TBI and Bu groups, respectively, and it was not significantly different (p=0.93). The probability of progression free survival (PFS) and overall survival (OS) at 2 years was 55% and 56 % respectively. There was no difference in PFS (p=0.29) or OS (p=0.11) between the 2 groups. A multivariable analysis was performed including patients age, donor relation (related versus unrelated), presence of extramedullary disease, donor sex, duration of CR1, time from CR2 to transplant, presence of HLA mismatch and use of TBI. Longer duration of CR1 was associated with improved OS (HR=0.93, 0.90 – 0.97, p&lt;0.001) and PFS (HR=0.94, 0.91 – 0.97, p&lt;0.001). Longer time from CR2 to transplant decreased OS (HR=1.28, 1.07 – 1.53, p=0.007) and PFS (HR=1.21, 1.02 – 1.44, p=0.033). Receiving a transplant from HLA mismatched donor decreased OS (HR=2.04, 1.07 – 3.86, p=0.030) and PFS (HR=2.04, 1.10 – 3.77, p=0.024). The use of TBI was not associated with improved PFS (HR=1.18, 0.66–2.11, p=0.58) or OS (HR=1.42, 0.77–2.65, p=0.27). Shorter duration of first complete remission, longer time from second remission to transplant and receiving HLA mismatched allogeneic transplant adversely affected PFS and OS. Our study provided no evidence of an advantage to using TBI in children with AML beyond first complete remission.