Reduced‐toxicity conditioning regimen with busulfan, fludarabine, rATG, and 400 cGy TBI in pediatric patients undergoing hematopoietic stem cell transplant for high‐risk hematologic malignancies

Abstract

Background: Myeloablative conditioning regimens decrease the risk of relapse in pediatric patients undergoing allogeneic hematopoietic stem cell transplant (HCT) for hematologic malignancies, but cause significant toxicities Procedure: This prospective study evaluated the use of a reduced-toxicity, myeloablative regimen with dose-adjusted busulfan, fludarabine, antithymocyte globulin and 400 cGy of total body irradiation in 40 patients < 21 years of age undergoing HCT for high-risk leukemias. Busulfan pharmacokinetics were measured to target 4000 µmol*min/day in the first 30 patients; this was increased to 5000 µmol*min/day in the subsequent 10 in efforts to further decrease relapse risk Results: Overall survival at two-and five-years post-HCT was 67% and 51%, respectively. Relapse occurred in 11 patients (28%) at a median of seven months and was the leading cause of death. Transplant-related mortality was 8% and 13% at 100 days and one-year post-HCT, respectively. Trends toward improved survival were seen in patients transplanted for myeloid disease using bone marrow as stem cell source who achieved a busulfan AUC > 4000 µmol*min/day with two-year relapse-free survival approaching 80% Conclusions: This conditioning regimen is safe and effective in patients with highrisk leukemias, particularly myeloid disease. Larger studies are needed to compare its safety and efficacy to other myeloablative regimens in this population.

Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions

“…For the moment, fractionated TBI schedules giving doses of 12–14 Gy with lung shielding have been adopted as optimal schedules in ALL HSCT by many paediatric radiation oncology centres ( 27 , 28 ). Nonetheless, continuous reassessment of TBI optimization is needed as pre-HSCT factors improve and new combinations of chemotherapy with lower doses of TBI are researched ( 98 , 99 ).…”

Busulfan with 400 centigray of total body irradiation and higher dose fludarabine: An alternative regimen for hematopoietic stem cell transplantation in pediatric acute lymphoblastic leukemia

“…32,38 It was lower than rates reported by Rossoff et al as well as Modi et al who used a similar conditioning regimen for adults with AML. 25,33 Our low cGvHD rates despite a higher incidence of aGvHD may be explained by our method of giving ATG. 39,40 We follow a regimen similar to one recommended by Bacigalupo et al 40 In their 2001 paper, they suggest using ATG at 7.5 mg/kg, as this dose was not associated with increased infections and reduced cGvHD.…”

“…An abstract by Chaudhury et al., followed up by an in‐depth analysis by Rossoff et al. reported the outcomes using Bu–Flu–ATG and 400 cGy TBI regimen in a cohort of nine pediatric leukemia patients with ALL 24,25 . The group utilized Bu TDM similar to ours (4000 μmol*min/L/day), but a lower cumulative dose of Flu (150 mg/m 2 over 5 days).…”

“…25 High rate of relapse, cited as the most common reason for failure, was seen in 29% of subjects. 24,25 We surmise that a higher Flu dose in our cohort might have resulted in lower relapse rates.…”

“…The group utilized Bu TDM similar to ours (4000 μmol*min/L/day), but a lower cumulative dose of Flu (150 mg/m 2 over 5 days). The authors initially reported 1‐year OS and progression‐free survival (PFS) of 63% and 56%, respectively, 24 and a follow‐up 5‐year OS of 37% in their ALL cohort (one with positive MRD pre‐transplant) 25 . High rate of relapse, cited as the most common reason for failure, was seen in 29% of subjects 24,25 .…”