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agents may have only theoretical organ toxicity, the organ function parameters are infrequently adjusted or waived.
Clinical trial participation by patients with hematologic malignancies has received less attention. Statler et al. found patients retrospectively determined to be ineligible for Soutwest Oncology Group (SWOG) leukemia studies had similar outcomes as eligible patients treated on the same studies. However, many patients were found to be ineligible solely because of such administrative reasons as missing documentation or laboratory values drawn at the wrong time.5 A more recent single-center analysis exam- ining the effect of comorbidities and organ dysfunction found that a very high proportion of acute myeloid leukemia (AML) patients (88%) would have been exclud- ed from many clinical trials, but that outcomes did not differ significantly between eligible and ineligible patients.6 The authors therefore suggested that clinical trial eligibility criteria should be liberalized for AML patients.
In this single-center retrospective analysis, we exam- ined the proportion of patients at our center with newly- diagnosed AML or high-grade myeloid neoplasms who would have met standard clinical trial eligibility criteria. We also compared outcome in patients according to whether they met these criteria.
Methods
Patient population
Consecutive patients diagnosed with AML or high-grade myeloid neoplasms (10-19% blasts) at the University of Washington (UW)/Fred Hutchinson Cancer Research Center (FHCRC) between January 1, 2014 and December 31, 2016 were identified through our institutional database. The study was approved by the UW Institutional Review Board.
We identified 442 patients approximately equally divided between 2014, 2015, and 2016. Data on age, sex, performance status (PS), SWOG cytogenetic risk,7 treatment related mortality (TRM) score,8 induction treatment and intensity, and baseline values for glomerular filtration rate (GFR), creatinine, bilirubin, and alanine aminotransferase (ALT) were collected using the institional database. The TRM score uses pre-treatment patient and disease characteristics to estimate the probability of death within the first 28 days after induction. In a few patients, a sin- gle component for TRM calculation was missing so median val- ues from the database as a whole were used. Patients were clas- sified as having secondary disease if they had an antecedent hematologic disorder or previous exposure to chemotherapy. Induction treatment intensity was divided into three categories: high (containing cytarabine at 1g/m2/dose or more); intermedi- ate (including 7+3, CPX-351, or similar); and low (hypomethy- lating agents, low-dose cytarabine, or similar). We excluded patients from subsequent analysis who received either palliative care alone or unknown treatment in the community (n=70; 16% of the entire population). Additional information regarding prior malignancy (excluding prior AML, myelodysplastic syndrome, myeloproliferative neoplasms, and non-melanoma skin cancer), cardiac disease and/or low ejection fraction (EF) within 3 months of planned treatment, were collected from review of medical charts (performed by MEP). Response to induction chemotherapy was defined as complete remission (CR; absolute neutrophil count [ANC] >1,000/mL and platelet count <100,000/mL), CR with incomplete count recovery (CRi; ANC
Effect of eligibility criteria on outcomes in AML
<1,000/mL), or CR with incomplete platelet recovery (CRp; platelet count <100,000/mL). Measurable residual disease (MRD) was assessed using multiparameter flow cytometry.
Definition of eligibility for clinical trials
Patients were considered “eligible” for the purposes of our ret- rospective analysis had PS 0-2, GFR ≥60 ml/min, ALT ≤ twice the upper limit of normal (ULN), bilirubin ≤1.5 mg/dL, no solid tumor diagnosed within 2 years preceding the diagnosis of AML, left ventricular ejection fraction (EF) ≥50%, and no history of congestive heart failure (CHF) or myocardial infarction (MI). The criteria are similar to those in a previous analysis of solid tumor patients and mimic standard trial eligibility criteria.4 Patients were classified as “ineligible” if they failed to meet at least one of these eligibility criteria. Unknown values were not considered to make a patient ineligible. Though some trials exclude patients with older age, we did not use age as a criterion in light of the recent drug approvals in AML.9,10
Statistical analysis
Overall survival (OS) was measured from date of first evalua- tion to date of death, with patients last known to be alive cen- sored at the date of last contact. Fisher’s exact tests and Wilcoxon rank-sum tests were used to compare eligible and inel- igible patients. Fisher’s exact test was used to evaluate 28-day mortality; patients censored before day 28 were excluded from the analysis. Fisher’s exact test was used to evaluate response; response was not available on 29 patients. Cox regression mod- els and log-rank tests were used to evaluate associations with OS. All statistical analyses were performed using R.11
Results
Baseline characteristics
We identified 372 patients; 272 patients received inter- mediate or high intensity induction and 100 low intensity induction (Table 1). Of these, 207 patients (56%) received treatment on a clinical trial at UW/FHCRC.
Using the above-noted criteria (performance status, GFR, ALT, bilirubin, prior solid tumor within 2 years, EF, and history of CHF or MI), 220 patients (60%) would have been considered eligible. The reasons for ineligibili- ty are shown in Table 1. Typically, for a given eligibility criterion <10% of patients were ineligible. For example, only 2% of patients would have been ineligible based on the usual requirement for EF ≥50%, only 4% because of prior CHF, only 5% because of prior MI, only 5% because of elevated ALT, and only 5% because of abnormal biliru- bin. Only 3% of patients would have been ineligible because they had a solid tumor in the last 2 years, which is probably the most common solid-tumor free interval included in clinical trial eligibility criteria.
Relationship between ineligibility and survival
Univariate analyses showed strong associations between risk of death and ineligibility criteria including PS 3-4, GFR < 60 mL/min, and prior CHF or MI (Table 1). Associations between survival and abnormal ALT, abnor- mal bilirubin, or decreased EF were not noted, but there were relatively few patients in these categories. Patients with one or more ineligibility characteristics represented approximately 40% of the study population and had a 1.79-fold greater risk of death (95% Confidence Interval
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