The Impact of Comorbidities and Organ Dysfunction Commonly Used for Clinical Trial Eligibility Criteria on Outcome in Acute Myeloid Leukemia (AML) Patients Receiving Induction Chemotherapy
Authors: Statler Abby , Hobbs Brian P. , Radivoyevitch Tomas , Siebenaller Caitlin , Mukherjee Sudipto , Advani Anjali S. , Gerds Aaron T. , Nazha Aziz , Patel Bhumika J. , Carraway Hetty E. , Sekeres Mikkael A. 
Published: February 2020

Background: Clinical trial recruitment is hindered by patient (pt), provider, and organizational barriers. The prohibitory impact of specific comorbidity/organ function criteria, however, has not been studied in the AML pt population. While intended to protect pts, trial eligibility criteria, when excessive, exclude pts irrespective of expected toxicities (Statler et al. Leukemia 2017). Yet, research demonstrates adverse events and outcomes are similar among eligible and ineligible AML pts (Statler et al. Blood 2018). We characterized the multi-morbidity prolife of AML pts prior to induction chemotherapy and compared outcomes among those with and without baseline comorbidities/organ dysfunction that have been used in clinical trial eligibility criteria.
Methods: Adult (≥18 years) AML pts who received chemotherapy at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic/renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Univariate associations between dose modifications and pt characteristics were tested using logistic regression. Cox proportional hazards and logistic regression were used to identify significant prognostic factors for overall survival (OS) and complete remission (CR) status per International Working Group criteria. Kaplan-Meier method was used to estimate median OS.
Results: Of 1,082 AML pts analyzed, the median age was 60.6 years (IQR: 50.2, 69.1), 53.1% (n=574) were male, 86.8% (n=939) were white, and 45.7% (n=494) had Medicare insurance. A majority (n=680, [62.9%]) had de novo AML, and 55.3% (n=598) had intermediate-risk disease. Pts were treated with: intensive cytarabine-based (n=901 [83.3%]), or non-intensive (low-dose cytarabine or hypomethylating agents (n=181 [16.7%]). Of those with comorbidities, the most common were vascular (n=540 [49.9%]), endocrine (n=272 [25.1%]), and neurological (n=220, [20.3%]) (Tables 1 and 2).
With a median follow-up of 12.9 (IQR: 4.67-43.13) months, the median OS for the cohort was 15.1 months (range 0.03-189.25). In multivariate analyses controlling for treatment, age, sex, insurance, number of comorbidities, AML etiology, and ELN risk, the only comorbidity associated with OS was liver disease (HR=1.90, P=.004). However, baseline AST (3xULN vs. normal: HR=1.02, P=.94; &gt;3-5x ULN vs. normal: HR=1.42, P=.30.), ALT (3xULN vs. normal: HR=0.76, p=0.45, &gt;3-5xULN vs. normal: HR=1.58, P=.23) and bilirubin (1.5xULN vs. normal: HR=1.34, P=.08) were not associated with a worse OS. Minor renal dysfunction was also not associated with OS, when measured by creatinine (1.5xULN vs. normal: HR=1.06, P=.52) or creatinine clearance by Cockcroft-Gault (CrCl 84-60 ml/min: HR=0.95, P=.62). Baseline LVEF abnormalities, though, were associated with increased mortality, and as severity increased the effect size increased in a dose-response fashion (50-40%: HR=1.38, P=.04; &lt;40%: HR=1.66, P=.009). The pattern for baseline prolonged QTc was similar; increasing values of QTc was associated with increased mortality (&gt;480ms: HR=1.36, P=.04; ≥501: HR=1.72, 95%, P=.001).
With the exception of liver comorbidities (OR=0.26, P=.03), our analysis failed to identify significant evidence of association between response and comorbidities/organ dysfunction. Comorbidities and liver function abnormalities were also not associated with dose modifications during AML treatment, while pts with clinically significant renal (CrCl ≤ 30 ml/min) and/or cardiac (LVEF ≤50%) abnormalities at baseline did have a higher odds of a dose reduction in univariate analysis.
Conclusions: The majority of AML pts within this cohort (n=953 [88.1%]) presented with at least 1 comorbidity and/or 1 clinically insignificant liver or renal abnormality that could have excluded them from clinical trials. Yet, survival, response, and dose modification outcomes did not significantly differ between pts with and without comorbid conditions or minor liver/renal abnormalities. These results suggest future AML trials may liberalize comorbidity and organ function eligibility criteria, which will likely improve recruitment rates and provide equitable access to investigational products.

Disclosures
Hobbs: SimulStat Inc.: Consultancy; Amgen: Research Funding. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Gerds:Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Roche: Research Funding; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Celgene Corporation: Consultancy, Research Funding. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.