Transplant Specific Trials (Table 1):
ASCT0431 : This randomized trial of sirolimus-based GVHD prophylaxis after HCT for acute lymphoblastic leukemia (ALL) closed after an interim analysis of the first 145 patients determined the primary endpoint, improved survival, would not be met.4 However, correlative studies have proved a rich resource that informed subsequent studies.5, 6 First, GVHD was protective against relapse (hazard ratio (HR), 0.4; p=0.04), demonstrating the correlation of GVHD with the graft-vs-leukemia (GVL) effect in pediatric ALL. Second, the threshold for MRD by multichannel flow cytometry-based MRD (MFC-MRD) pre-HCT for increased risk of relapse was established at ≥0.1% (HR, 3.3; p=0.01). Third, precise MRD testing using next-generation sequencing (NGS) pre-HCT based on immunoglobulin heavy chain (IgH)-variable, diversity, and joining (V[D]J) or T-cell receptor clonal rearrangements (NGS-MRD) was the best predictor for relapse. Patients who were NGS-MRD(-) pre-HCT had significantly lower 2-year relapse rates compared to patients who were NGS-MRD(+) (0% vs 53%, p<0.001). Furthermore, patients who were NGS-MRD(-) pre-HCT were less likely to relapse than patients who were MFC-MRD(-); (0% vs 16%, p=0.02) and more likely to survive (96% vs 77%, p=0.004).4, 7 The exceptionally low rate of relapse in patients NGS-MRD(-) pre-HCT led to a trial testing a novel, potentially less toxic preparative regimen for patients with pediatric ALL in deep remission. Total body irradiation (TBI)-based preparative regimens for pediatric ALL reduce relapse compared to chemotherapy-based preparative regimens but at the cost of more short- and long-term toxicity.8, 9 PTCTC trial NCT03509961 is testing whether a novel radiation-free regimen is as effective as TBI-based regimens for NGS-MRD(-) ALL patients.
ASCT1221: Allogeneic HCT is the only current curative option for patients with JMML but needs improvement given high rates of both relapse and treatment complications. Challenges with HCT for JMML include young age at diagnosis (<2 years), high disease burden that does not respond well to chemotherapy, and morbidities such as massive hepatosplenomegaly and pulmonary infiltrates.10 A busulfan-cyclophosphamide-melphalan (Bu-Cy-Mel) preparative regimen is the standard of care but transplant related mortality (TRM) rates approach 20%.11, 12ASCT1221 tested if a less toxic preparative regimen, busulfan-fludarabine (Bu-Flu), would provide disease control with less mortality. Fifteen patients were randomized to either Bu-Cy-Mel (n=6) or Bu-Flu (n=9). There were fewer cases of veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) on the Bu-Flu arm (2/9, 22%) compared to the Bu-Cy-Mel arm (3/6, 50%), but the study was closed early based on large differences in 18 month event-free survival (EFS) favoring Bu-Cy-Mel (83% vs 22%), although this did not reach statistical significance.13
BMT CTN 0501: This joint collaboration between COG and the BMT CTN tested the hypothesis that 1-year survival would be better for pediatric patients transplanted with two partially human leukocyte antigen (HLA)-matched umbilical cord blood units UCB units compared to one UCB unit based on studies showing better survival in adults transplanted two UCB units14-16. Eligible patients (≤21 years, had a high-risk hematologic malignancy, and two adequately matched (≥4/6 HLA-match for A, B, and DR) UCB units, where at least one unit had a cell dose of ≥2.5 X 107 nucleated cells/kg recipient body weight) were randomly assigned to transplant with either two UCB (n=111) or one UCB (n=113) unit. All patients received the same TBI-based preparative regimen and GVHD prophylaxis strategy. One year overall survival (OS) from the time of randomization was not different between the two vs one UCB unit arms (65% vs 73%, p=0.17). There were also no statistically different rates of disease-free survival (DFS), relapse, TRM, neutrophil recovery and rates of grade II-IV acute GVHD. Patients transplanted with one UCB recovered platelet counts earlier (58 vs 84 days, p=0.04) and experienced less grade III-IV acute GVHD (13% vs 23%, p=0.02).17 Single UCB unit is the standard of care for cord blood HCT in children given the shorter hematologic recovery time, lower risk of severe acute GVHD, and cost-savings.