Frequency, and Effect on Survival, of Ineligibility for Clinical Trials in Newly Diagnosed Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms
Authors: Percival Mary-Elizabeth M. , Othus Megan , Mirahsani Sarah , Gardner Kelda M. , Shaw Carole M. , Halpern Anna B. , Hendrie Paul C. , Becker Pamela S. , Sorror Mohamed L. , Walter Roland B. , Estey Elihu H. 
Published: November 2019

Introduction: Although National Comprehensive Cancer Network guidelines state "the best management of any patient with cancer is in a clinical trial," few adults with cancer participate in clinical trials. Consequently, ASCO and similar organizations have suggested modifications to eligibility criteria with the goal of increasing participation in clinical trials without a major increase in toxicity. Here we examine the effect of standard exclusion criteria on the ability to enroll patients with newly-diagnosed acute myeloid leukemia (AML) or high-grade myeloid neoplasms (≥10% blasts) on clinical trials. We compare survival outcomes of patients according to eligibility defined based on standard exclusion criteria.
Methods: We identified 442 consecutive patients diagnosed with AML or high-grade myeloid neoplasms at the University of Washington/Fred Hutchinson Cancer Research Center between January 1, 2014 and December 31, 2016 after approval by our Institutional Review Board. Pre-treatment characteristics were collected from our institutional database and medical records. Patients were considered "eligible" if they were ≥ 75 years of age, had performance status (PS) 0-2, GFR ≤ 60 ml/min, ALT ≤ twice the upper limit of normal, bilirubin ≤1.5mg/dl, no solid tumor diagnosed within two years preceding the diagnosis of AML/MDS, LVEF ≥ 49%, and no history of congestive heart failure or myocardial infarction. Patients were classified as "ineligible" if they failed to meet at least one of these criteria.
Results: 272 of our 442 patients (62%) received induction with intermediate or high intensity regimens, 23% received low intensity therapy, and 10% palliative care alone; treatment status was unknown in 6%. 207 patients (52% of those not electing palliative care) received treatment on a clinical trial. The same proportion were considered eligible, as defined above. Characteristics commonly associated with ineligibility were increased age (17%), decreased GFR (15%), and solid tumor within prior two years (14%). Univariate analysis demonstrated significant associations between ineligibility and male sex (p=0.013), secondary disease (p<0.001), higher treatment-related mortality score (p<0.001), and intensity of treatment (p<0.001). Multivariate analyses accounting for baseline covariates such as cytogenetics and age indicated the presence of one or more ineligibility factors was associated with significantly decreased overall survival [HR 1.75 (95% CI 1.32, 2.32)].
Discussion: Like observations in solid tumor patients (Lichtman et al, JCO 2017), we observed a high percentage (approximately half) of patients with newly diagnosed AML and high-grade myeloid neoplasms who had at least one characteristic that would make them ineligible to participate in typical clinical trials. Ineligibility was associated with decreased overall survival. Although this finding may have reflected the inability to enroll on clinical trials, it is at least equally plausible shorter survival would have been seen on trials compared to patients who were eligible and enrolled. The effects of exclusion criteria should be borne in mind when analyzing the results of clinical trials. Further clinical trials are needed for ineligible patients. One mechanism to ensure that ineligible patients would be studied would be the requirement by the FDA for a post-marketing study that would enroll patients not represented in the trials leading to approval, since these patients typically have few good options.

Disclosures
Percival: Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Othus:Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Gardner:AbbVie: Speakers Bureau. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Sorror:Advisory board participation and honorarium from JAZZ pharmaceuticals: Other: Mohamed Sorror, MD MSc Fred Hutchinson Cancer Research Center University of Washington . Walter:Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding.