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.