Industry-sponsored, oncology clinical trials are written with relatively standard eligibility criteria; over time the criteria of these studies have become restrictive, despite the fact that the National Comprehensive Cancer Network states “the best management of any patient with cancer is a clinical trial.” It is also difficult to enroll cancer patients in clinical trials for numerous reasons (location of academic center, preferences of patients and physicians, etc). The American Society of Clinical Oncology (ASCO) has encouraged researchers and physicians to broaden the eligibility criteria for clinical trials; this can increase the applicability of the trial results for patients who did not participate in trials.
One study published by Lichtman et al. reported that 50-85% of 10,000 patients with various types of cancer at Kaiser Permanente Northern California would not meet basic clinical trial eligibility; organ function parameters are seldomly adjusted or waived for eligibility criteria. Patients with hematologic malignancies have received limited attention in clinical trials. A study that examined comorbidities and organ dysfunction concluded that a large amount of acute myeloid leukemia (AML) patients (88%) would not have been eligible for the clinical trial. The authors of the study recommended the broadening of clinical trials eligibility criteria to include AML patients. The Percival Group, from the Clinical Research Division, examined the proportion of patients (with newly diagnosed AML or high-grade myeloid neoplasms) who would not have met clinical trial eligibility criteria. The patient outcomes in the study were compared based on whether they met eligibility criteria. The study was published in a recent issue of Haematologica.
The patients’ data were collected from the University of Washington/ Fred Hutchinson Cancer Research Center between Jan. 2014 – Dec. 2016. All medical data was collected using the institutional database. Patients were considered “eligible” for the analysis if they had the following: Performance Status (PS) 0-2, Glomerular-filtration rate (GFR) ≥ 60 ml/min, Alanine aminotransferase (ALT) twice the upper limit of normal (ULN), bilirubin ≤ 1.5 mg/dl, no solid tumor diagnosed within two years preceding the AML diagnosis, left ventricular ejection fraction (LVEF) ≥ 50%, and no history of congestive heart failure (CHF) or myocardial infarction (MI). Patients identified as ineligible for the study did not at least one of these criteria. The researchers identified a total of 372 eligible patients; 272 patients received intermediate or high intensity induction and 100 intensity induction.
Patients with one or more ineligibility criteria (40% of study’s population) had a 1.79-fold greater risk of death than patients who were considered eligible for participation in clinical trials (95% CI 1.37-2.33). Of the 144 ineligible patients, 73% failed to meet one eligibility criterion, 26% did not meet two eligibility criteria, and 5% did not meet 3 criteria. Figure 1 shows the survival probability or eligible and ineligible patients. In multivariable analysis, patients were 45% less likely to survive with the presence of one or more ineligible factors (HR: 1.45, 95% CI 1.08-1.93).
The Percival group’s results indicate that ineligibility is associated with decreased survival, while eligibility is associated with a population of patients with better outcomes following treatment. According to the Percival group, other factors such as social support, travel distance, and frailty level should be incorporated to grasp a better understanding of eligibility. Often patients are ineligible for trials because the sponsors understand that inclusion could lead to a less favorable outcome and thereby decrease the chances for regulatory approval. To accommodate patients and sponsors, regulatory approval of new drugs could be made conditional on subsequent conduct of trial in patients under-represented in the original studies.
This research was supported by supported in part by a Cancer Consortium Grant from the National Institutes of Health.
Fred Hutch/UW Cancer Consortium members Mary-Elizabeth Percival, Megan Othus, Anna Halpern, Pamela Becker, Mohamed Sorror, Roland Walter, and Elihu Estey contributed to this work.
Percival ME, Othus M, Mirahsani S, Gardner KM, Shaw C, Halpern AB, Becker PS, Hendrie PC, Sorror ML, Walter RB, Estey EH. 2020. Survival of patients with newly diagnosed high-grade myeloid neoplasms who do not meet standard trial eligibility. Haematologica. doi:10.3324/haematol.2020.254938