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.