Adolescent and young adult (AYA) patients, defined as those between the ages of 15 and 29 years, and non-white patients are often under-represented in clinical trials of novel agents in hematologic malignancies, meaning that these patients might not benefit from the therapeutic advances gained through these trials. In two studies presented at the 2016 ASH Meeting on Hematologic Malignancies, researchers assessed efforts to increase clinical trial participation in these under-represented patient populations: the first in AYA patients with non-Hodgkin lymphoma (NHL)1 and the second in AYA patients with acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML).2
Adolescents and Young Adults With Non-Hodgkin Lymphoma
Over the past 25 years, the incidence of NHL in AYAs has increased, with diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, anaplastic large cell lymphoma, lymphocytic lymphoma, and primary mediastinal B-cell lymphoma as the most common subtypes in those 15 to 19 years old. AYA patients with NHL also have increased relapsed rates and mortality, compared with pediatric and adult NHL patients.
Melissa A. Crawley, MD, of the Department of Hematology and Oncology at the University of Tennessee Health Sciences Center/West Cancer Center in Memphis, Tennessee, and colleagues questioned whether being treated at adult centers could increase the availability of clinical trials for AYA patients with NHL and, subsequently, their outcomes.
Dr. Crawley and investigators conducted a keyword search of "NHL" in the ClinicalTrials.gov database to identify trials of novel agents in hematologic malignancies and collected data about the included age groups, sample size, investigational agents, and lymphoma subtypes. They also assessed whether the study sites were members of the Children's Oncology Group (COG) – a clinical trials group supported by the National Cancer Institute that is devoted exclusively to pediatric cancer research.
Trials were excluded from the analysis if the study regimen did not contain a novel pharmacologic agent or if a study focused solely on a transplant conditioning regimen.
A total of 404 trials were included in the analysis, 61 of which (15%) were studies of novel agents that were open to those younger than 18 years. The most commonly studied drug classes included:
- cellular therapy (chimeric antigen receptor-T cells, donor lymphocytes, and cytotoxic T lymphocytes; n=7)
- tyrosine kinase inhibitors (n=7)
- novel small molecules (n=7)
- monoclonal antibodies (n=5)
See TABLE 1 for clinical trial enrollment analysis.
Of the 343 trials that were limited to adult patients at least 18 years old, two-thirds (227) allowed the enrollment of patients with DLBCL, Burkitt lymphoma, anaplastic large cell lymphoma, lymphocytic lymphoma, follicular lymphoma, and primary mediastinal B-cell lymphoma – the most common lymphoma diagnoses in AYA patients.
"All agent classes were represented in trials open to patients who were at least 18 years old," Dr. Crawley and authors noted. "However, three agent classes were excluded from clinical trials in the under-18 subset: BiTE immunotherapy, PI3K inhibitors, and pleiomorphic pathway modifiers."
Notably, more than half of these trials (n=178; 51%) had at least one study site that was a member of COG. "While this suggests that AYAs treated at COG member sites may have access to trials studying novel agents, the extent to which AYAs are being enrolled in these trials requires further study," the authors concluded.
Under-Representation of Minorities in Acute Lymphocytic and Acute Myeloid Leukemias
Compared with white and Asian children with ALL and AML, patients in underserved populations (including African-American and Hispanic children, Hispanic females, and AYA patients 15 to 39 years old) have worse survival outcomes. In the second study, Nupur Mittal, MD, and colleagues compared clinical trial enrollment rates among these populations before and after implementation of a focused initiative to enhance trial enrollment among these patients and, potentially, address disparities in survival.
"It is accepted that the dramatic historic decrease in mortality from ALL and AML in children and more recently AYA patients is directly related to improved participation in NCI-sponsored COG clinical trials," Dr. Mittal, from the Department of Pediatrics in the Division of Pediatric Hematology Oncology at Rush University Medical Center in Chicago, Illinois, and authors wrote. "It is also known that [patients in these minority populations] are underrepresented in COG clinical trials and may benefit from targeted attention."
The 2008 program was a collaboration between two COG institutions (the University of Illinois at Chicago and Rush University) and one non-member hospital (John H. Stroger Hospital of Cook County); this UIC/Rush/Stroger COG Clinical Trials program created a unified COG program, using one lead international review board and one research team.
The authors compared COG enrollment data from the pre-merger period (2002-2008) and the post-merger period (2008-2014), and collected information about clinical trial participants' race/ethnicity, age at diagnosis, gender, insurance status, and leukemia type.
In the post-merger period, the rates of Hispanic, African-American, and AYA patients enrolled in therapeutic clinical trials all increased (TABLE 2). Enrollment rates were very low for patients with AML before the merger, and these patients experienced the greatest growth in enrollment after the clinical trials program was implemented.
In addition to increasing the number of patients involved with clinical trials, the UIC/Rush/Stroger COG Clinical Trials program also increased the number of providers across all institutions who were engaged in COG enrollment. In the pre-merger period, seven providers (6 pediatric oncologists and 1 medical oncologist) were involved in COG enrollment; in the post-merger period, that number increased to 18 total providers (9 pediatric oncologists, 6 medical oncologists, and 3 pediatric nurse practitioners).
"A significant increase in COG leukemia trial enrollment, especially for under-represented minorities and AYAs, was a direct result of the creation of the novel program," the authors concluded. "Improving access to these clinical trials is essential to addressing current disparities in leukemia survival. … The UIC/Rush/Stroger COG Program serves as a model for improved collaboration between competing institutions and specialists within institutions to increase access to current clinical trials for minority and AYA patients with leukemia."
- Crawley MA, Stein M, Patel K, Martin MG. Clinical trial availability in adolescent and young adult patients with non-Hodgkin lymphoma. Abstract #89225. Presented at the ASH Meeting on Hematologic Malignancies, September 16-17, 2016; Chicago, IL.
- Mittal N, Martinez M, Davidson J, et al. Improving access for adolescents and young adults (AYAs) and underrepresented minorities with leukemia to children's oncology group (COG) clinical trials: A novel collaborative approach to address disparities in leukemia. Abstract #89542. Presented at the ASH Meeting on Hematologic Malignancies, September 16-17, 2016; Chicago, IL.
|TABLE 1. Clinical Trial Enrollment and COG Availability Per Agent Class|
|Agent Class||Allows enrollment of patients <18 years old||Limited to patients â‰¥18 years old||COG availability|
|Cytotoxic T lymphocytes||9||3||10|
|CAR T cell||12||22||19|
|Immunotherapy (CLTA4, PD1, PDL1, vaccine)||1||42||28|
|Tyrosine kinase inhibitors||7||46||27|
|Pleomorphic pathway modifier||0||4||1|
|COG = Children's Oncology Group; HDAC = histone deacetylases; CAR = chimeric antigen receptor; mTOR = mammalian target of rapamycin; IMiD = immunomodulatory drug; BiTE = bi-specific T-cell engagers|
|TABLE 2. Pre-Merger Versus Post-Merger Outcomes|
|Pre-Merger Period(2002-2008)||Post-Merger Period(2008-2014)||Percent Increase|
|Factors studied||ALL||AML||Total leukemia||ALL||AML||Total leukemia||ALL||AML||Total leukemia|
|Clinical trial enrollments||51||1||52||67||41||108||31||4,000||108|
|Therapeutic trial enrollments||19||0||19||29||13||42||52||13 vs. 0||121|
|Hispanic patients enrolled||9||0||9||40||4||44||773||4 vs. 0||370|
American patients enrolled
|AYA patients enrolled*||6||0||6||32||11||43||400||11 vs. 0||610|
|*AYA = 15-39 years old; ALL = acute lymphocytic leukemia; AML = acute myeloid leukemia; AYA = adolescents and young adults|