Current Portfolio:
AALL1721 : CD19-CAR T cell therapy with tisagenlecleucel for
relapsed and refractory B cell ALL dramatically improved survival rates
from negligible with chemotherapy alone to 50-60% but many patients
still do not experience benefit from this treatment.1,
39, 40 AALL1721, a CT-ALL collaboration tests the hypothesis that
earlier treatment with tisagenlecleucel in high risk patients (i.e.,
MRD(+) at the end of consolidation) will produce higher rates of durable
remission compared to other treatment strategies. The trial has enrolled
100 out of a planned 140 patients and is expected to complete accrual in
2023.
ASCT2031: Allogeneic HCT is the best option for cure for many
high-risk malignancies, but acute and chronic GVHD cause substantial
short and long-term morbidity and mortality. Preliminary data from phase
2 studies in both children and adults showed that transplants from
haploidentical donors using GVHD prophylaxis that included either T-cell
receptor (TCR)αβ+ T cell/CD19+ B cell depletion or post-HCT
cyclophosphamide with tacrolimus and mycophenolate prophylaxis
(PTCy/Tac/MMF) reduced severe acute and chronic GVHD without increasing
relapse or TRM.41, 42 ASCT2031 is a phase 3 randomized
trial that hypothesizes that recipients of a haploidentical donor HCT
using either TCRαβ+ T cell/CD19+ B cell depletion or PTCy/Tac/MMF
prophylaxis will have less severe GVHD without more relapses than
recipients of HLA-matched unrelated donor (MUD) HCT using standard
tacrolimus and methotrexate prophylaxis. Eligible patients must have
either acute leukemia or myelodysplastic syndrome (MDS) and access to
both donor sources for randomization. Because certain racial and ethnic
groups have a probability of <20% to identify a
MUD,43 patients without access to both donor sources
can be non-randomly assigned to a haploidentical arm. A study sub-aim
will explore differences in outcomes by racial and ethnic group among
patients who otherwise receive identical treatment. This trial opened in
November 2022 and is expected to complete accrual in 4 years.
AAML1831 tests if a TKI more specific for FLT3, gilteritinib,
improves outcomes in patients with AML with FLT3 abnormalities.
High-risk patients with FLT3 alterations (based on a risk algorithm) are
directed to allogeneic HCT from the best available donor followed by
maintenance gilteritinib. The joint CT and AML task force designed the
transplant portion of AAML1831 to reduce heterogeneity in transplant
practice and simplify analyses. This trial is accruing about 230
patients per year.
Future Directions :
Cytomegalovirus (CMV) infection is common post-HCT, requires toxic
treatment with antiviral drugs, and can be
life-threatening.44 Letermovir is an antiviral
medication approved by the U.S. Food and Drug Administration (FDA) for
CMV prophylaxis in adult HCT recipients, but its efficacy in pediatric
HCT is unknown.45 ACCL1932 will randomize pediatric
allogeneic HCT recipients (2:1) to either 14 weeks of prophylaxis with
letermovir or surveillance. The primary endpoint is the development of
clinically significant CMV infection. The study will open in 2023.
ASCT2121 is an open label phase 2 study to test the efficacy low dose
interleukin-2 (LD IL-2) as treatment for steroid refractory chronic GVHD
(cGVHD) which develops in approximately 50% of HCT recipients and is
the leading cause of late morbidity and mortality. Multiple single
center adult and pediatric clinical trials with steroid-refractory cGVHD
demonstrated efficacy for LD IL-2 with response rates as high as 80% in
children and without any significant
complications.46-48 COG and Cancer Therapy Evaluation
Program (CTEP) approved a multicenter study to validate the efficacy of
LD IL-2 using the same dose and schedule as previously published. The
study will open after FDA approval and provided that drug supply can be
obtained following the sale of IL-2 to a new supplier.
The AML/CT task force is a standing collaboration charged with
developing new strategies to prevent relapse after HCT for AML. A small
trial testing the combination of uproleselan, an E-selectin antagonist
that sensitizes AML to chemotherapy, with intensive pre-HCT conditioning
is currently underway through the PTCTC (NCT05569512) and may lead to a
definitive COG trial, if warranted. Additionally, the task force is
considering several possible post-HCT maintenance trial designs.
Improving the safety of allogeneic HCT remains a key priority, and GVHD
remains the major driver for morbidity and TRM. Most cases of GVHD
require treatment with systemic steroids that can cause numerous side
effects, and children are uniquely susceptible to steroid-related
impacts on growth and development.49 A multicenter
study through the Mount Sinai Acute Graft versus Host Disease
International Consortium (MAGIC) uses GVHD biomarkers to identify low
risk GVHD patients at onset and then uses serial clinical and biomarker
response monitoring to guide rapid steroid tapers. The goal of this
study is to decrease toxicity and improve quality of life by reducing
the cumulative exposure to systemic steroids (NCT05090384). MAGIC also
studied steroid free treatment of GVHD using the JAK1 inhibitor
itacitinib in adolescent and adult patients with biomarker-confirmed
low-risk GVHD. Itacitinib monotherapy was as effective as systemic
steroid treatment in a matched control group (response rate 89% vs
86%, p=0.67) and resulted in significantly fewer severe infections
(27% vs 42%, p=0.04).50 Similar trials in younger
pediatric cohorts could be facilitated through the COG CT committee.
Chronic and refractory viral infections remain a significant contributor
to TRM following allogeneic HCT. Single or oligocenter trials of
virus-specific T cells (VSTs) to treat these infections using expanded
cells from seropositive donors, banks of VSTs from healthy donors, and
genetically modified VSTs from either the donor or the patient have
shown good response rates with limited toxicity.51Building on ANHL1522, a future direction of the CT committee is to
conduct definitive studies testing VSTs for infection control.
Engineered cellular therapy for B cell malignancies with CAR T cell
therapy has changed the landscape of treatment of relapsed and
refractory pediatric ALL. Future trials under development include a
CT-ALL collaboration to test anti-CD19 CAR T-cells as primary therapy
for ALL at first relapse. New immune effectors such as tumor specific
engineered T-cells and engineered NK cells against a variety of
oncologic targets including solid tumors are also actively being
developed for future study within COG.
Cellular therapies for cancer and infection control face several
challenges. First, these therapies are high risk and require complex
orchestration of manufacturing and distribution (Figure 2). Second,
compliance with Foundation for the Accreditation of Cellular Therapy
(FACT) standards for immune effector cell therapies require substantial
medical and administrative effort. Third, while the development of novel
cellular therapies often occurs at individual sites, eligible patients
are rare and studies to assess efficacy for patients with the greatest
need due to poor prognosis with current treatment options (e.g.,
relapsed brain cancer, sarcomas) are not feasible for single centers.
COG has an outstanding record of collaboration between diseases and
disciplines to develop novel chemotherapy-based treatment trials, and
this same level of engagement is needed to achieve the sample sizes
needed for trials testing cellular therapies. COG AALL1721 demonstrated
the ability to recruit patients, collect lymphocytes, ship to a central
location for manufacturing, and return the cellular therapy product for
infusion at the treating institution. Future trials testing innovative
cellular therapies will benefit from pairing the expertise of the
Developmental Therapeutics Committee in early phase clinical trials with
the expertise of the CT committee in cell collection techniques and
monitoring the unique toxicities associated with these therapies while
testing efficacy.