Introduction: Outcomes for children with de novo hematologic malignancies have improved significantly over the past 50 years. However, overall survival (OS) following relapsed or refractory (r/r) disease remains poor, with 5-year OS ranging from 20% to 66%. Clinical trials are crucial for developing novel therapeutic strategies to improve outcomes for this subset of patients.

Methods: The Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) consortium develops and conducts clinical trials for pediatric hematologic malignancies. TACL maintains an electronic Screening Log to capture data on the frequency of clinical trial enrollment among patients with r/r hematologic malignancies. Each TACL member site logs all occurrences of r/r disease requiring a therapeutic attempt in an electronic database on a monthly basis. We analyzed the TACL Screening Log to assess enrollment rates in therapeutic trials for r/r events from January 1, 2021, to December 31, 2023, to identify barriers to trial participation. We also queried ClinicalTrials.gov to compile a list of clinical trials enrolling pediatric patients with r/r hematologic malignancies for at least 6 months during this period to correlate the number of available trials with observed enrollment trends.

Results: A total of 895 unique patients from 33 pediatric academic institutions across the United States and Australia were screened for enrollment on therapeutic trials with 1115 total screens. The rate of enrollment on a clinical trial at time of r/r disease was 15% (132/895). Similar enrollment rates were observed for children (13%) and for adolescents and young adults (AYA) aged ≥15 years (11%). No differences in enrollment rates were noted based on sex, race or ethnicity. Patients with Down Syndrome (DS) demonstrated a much lower rate of trial enrollment (3% vs. 15% for those without DS).

Of the 1115 screening entries, enrollment was lower among patients with r/r Ph+ ALL (6%, 2/35), Hodgkin lymphoma (HL) (0%, 0/33) or non-Hodgkin lymphomas (NHL) (0%, 0/52) in comparison with B-lymphoblastic leukemia (B-ALL; 13%, 79/605), T-lymphoblastic leukemia (T-ALL; 11%, 7/65) and acute myeloid leukemia (AML;16%, 49/315). Among patients with leukemia, those with isolated extramedullary disease also had a particularly low rate of enrollment (2%, 2/112) compared to those with bone marrow involvement (14%, 116/806).

Enrollment increased with the number of prior treatment attempts but decreased with increasing number of prior bone marrow transplants. Reported barriers to enrollment included unavailability of suitable trial (47%), preference for non-trial therapies (25%), restrictive eligibility criteria (23%), and social or geographic factors (2%).

Our search of ClinicalTrials.gov identified 123 relevant clinical trials for r/r pediatric hematologic malignancies: 56 trials for r/r B-ALL/NHL, 32 for r/r T-ALL/NHL, 41 for r/r AML, 42 for r/r NHL and 19 for r/r HL. Of these, 39 (32%) were single institution trials while 36 (29%) were open at more than 20 institutions. 10 (24%) of the NHL trials were Molecular Analysis for Therapy Choice (MATCH) trials testing small molecule inhibitors for tumors (including lymphomas) with rare, genetic lesions. Various immunotherapies were investigated in 66 (54%) of the trials. 17 trials (14%) were primarily designed for adults, with lower age limit of 12 years.Conclusions: We found that 15% of children with r/r hematologic malignancies enrolled on a trial, consistent with previous studies but significantly lower than the estimated 42% enrollment rate for those with de novo disease. The historical disparity in trial participation between younger children and the AYA population appears to have narrowed within large pediatric medical centers, likely due to increased engagement efforts. Certain patient groups with r/r hematologic malignancies including those with DS, Ph+ ALL and isolated extramedullary involvement of leukemia show low rates of clinical trial enrollment due to lack of relevant trial options. No patients with r/r lymphoma enrolled on study despite a significant number of available trials, suggesting problems with access or restrictive eligibility criteria for this particular group. Identification of these enrollment barriers and gaps will facilitate efforts to improve clinical trial availability and participation, ultimately leading to new therapeutic developments and improved outcomes for this patient population with unmet need.

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2025
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