Treatment patterns and outcomes of octogenarian patients with acute myeloid leukemia
Authors: Vijaya R. Bhatt, Valerie Shostrom, James O. Armitage, Krishna Gundabolu
Journal: American Journal of Hematology (2019)

The incidence rate of acute myeloid leukemia (AML) increases with age, and is substantially high for octogenarians.1 Octogenarians frequently have high-risk AML, multiple comorbidities, and poor functional status.1, 2 Clinical trials often exclude these patients; observational studies focusing on this unique group are sparse. In this context, we have performed a National Cancer Data Base (NCDB) analysis to determine treatment practices and outcomes specifically of unselected cohort of octogenarian patients. The institutional review board at the University of Nebraska Medical Center determined that an approval is not necessary for the database study using de-identified data. The NCDB captures 70% of all new diagnoses of cancer from 1500 accredited hospitals in the United States. Trained registrars use nationally standardized data item and coding definitions, and standardized data transmission format specifications to capture and submit data. The quality of the database is rigorously monitored. International Classification of Diseases for Oncology version 3 codes 9840-9861, 9865, 9867-9874, and 9891-9931 were utilized to capture patients aged 80-89 years, who were diagnosed with AML during the calendar years, 2003-2014. The NCDB provided records of 112 308 patients with newly diagnosed AML; 17 099 patients (15.2%) were octogenarians. We excluded patients with acute promyelocytic leukemia (n = 339), those who received part of first course treatment or decision not to treat outside of the reporting facility (n = 2107), and those with missing data (2554). We divided AML subtypes into core-binding factor AML, therapy-related AML or AML with myelodysplasia-related changes and other intermediate/high-risk AML. While the first three AML subtypes are specifically captured, the NCDB does not differentiate between other high- vs intermediate-risk AML subtypes. Insurance was classified as Medicare, Private, and all others (none, Medicaid, and other government) because of small number of patients in the last category. Income and education data are area-based metrics derived from zip code data and do not represent patient-level data. Further details are described in our prior publication.3 Chi-square test was used to determine the relationship between 1-month mortality and the categorical potential predictors. The variables with P < .20 were used in a multiple logistic regression model to predict 1-month mortality, and backward selection was used to determine the final model. For each variable, univariate survival analyses were performed, and Kaplan-Meier curves were generated. Within each variable, the Kaplan-Meier curves for each strata were compared using the log rank test. The variables with P < .20 were included in a multivariate Cox proportional hazard model, and the model was reduced using backward elimination where 0.05 was the criteria for a term to remain in the model. Random intercept models were fit taking into consideration clustering by facility type. PC SAS version 9.4 was used for all summaries and analyses. The baseline characteristics of the study population (n = 12 099) are presented in Table 1. The majority (98%) received care in a facility situated in an urban location. A total of 5009 patients (41%) received chemotherapy within a median of 7 days of diagnosis (range 0-671 days). Patients received multiagent (25.3%, n = 1267), single agent (70.2%, n = 3517), or unspecified chemotherapy regimen (4.5%, n = 225). Reasons for not receiving chemotherapy were cited as the presence of contraindication (16.4%, n = 1163), patient's or family's refusal (14.3%, n = 1013), death prior to therapy (3.2%, n = 225), recommended but not administered for unspecified reason (0.7%, n = 50) and other unspecified reasons (65.4%, n = 4639). Only eight patients (0.07%) received hematopoietic cell transplant. One-month mortality was 41% (95% confidence interval [CI] 40.3%-42.1%), and median overall survival (OS) was 1.5 months (95% CI 1.4-1.5 months). Patients who did vs did not receive chemotherapy had a better median OS (3.2 vs 0.9 months) (Table S1 and Figure S1). Although determining the effect of chemotherapy was not a focus of this study, the median OS (4.0 vs 3.1 months) was slightly higher among patients treated with multiagent vs single-agent chemotherapy. A multiple logistic regression model and random intercept model (Table S2) identified higher comorbidity burden, treatment at a nonacademic facility and certain AML subtypes as factors associated with higher risk of 1-month mortality. The risk of 1-month mortality was higher among core binding factor AML, as compared to therapy-related AML or AML with myelodysplasia-related changes but lower compared to other intermediate/high-risk AML. A multivariate Cox proportional hazard model demonstrated a lower probability of OS among female, white, lower income status, higher comorbidity burden, and other intermediate/high-risk AML. Treatment at an academic facility, and longer distance traveled to receive care were associated with higher OS. The effect of female sex on OS disappeared on random intercept model. Our large national database study highlights that 15% of all new AML cases are diagnosed in octogenarian patients, less than half of whom receive chemotherapy for initial treatment. The 1-month mortality is 41%, and the median OS is 1.5 months. This is in sharp contrast to an expected life expectancy of several years for Americans who are alive at the age of 80 years. Only a few prior studies have a primary focus of examining outcomes of octogenarians (Table S3). A larger Swedish AML registry study with 1511 octogenarians demonstrated a modest use of intensive chemotherapy (18% and 5%) and hypomethylating agent (17% and 11% in the years 2012-2016) among patients aged 80-84 years, and 85-89 years, respectively. The use of intensive chemotherapy resulted in complete remission in 47% and 38% of patients in the two age groups.2 In an analysis of 138 patients treated with intensive chemotherapy in cooperative group trials, the presence of normal vs adverse karyotype, and within patients with normal karyotype, the presence of NPM1 mutation but not FLT3 mutation correlated with improved 1-year OS.4 Prior studies either did not assess predictors of OS or had relatively small number of patients to have adequate statistical power.2, 4 Our study included a large number of patients and demonstrated the impact of factors such as comorbidity burden, AML histology, race, income status, and treatment facility on OS, largely consistent with the results of our prior study in AML among adults aged ≥18 years.3 In the current study, longer distance traveled to receive care was associated with improved OS, possibly because of association with distance traveled and better performance status or receipt of care in academic centers. Whites were slightly more likely to have worse OS for unclear reasons. Core binding factor AML, compared to therapy-related AML or AML with myelodysplasia-related changes, had higher 1-month mortality but similar OS. Core binding AML had better outcomes than other intermediate/high-risk AML. The reason for these findings is unclear but the study did not have data on performance status. Prior studies in this age group have also demonstrated conflicting results on the prognostic value of karyotype.4, 5 Also, the Swedish AML registry1 demonstrated similar 1-month mortality rates between de novo and secondary AML cohorts with the same age. Although not the focus of this study, patients who received multi-agent vs single-agent chemotherapy had marginally improved OS likely because of therapy itself or differences in health status at baseline. Patients who have better performance status1 and less comorbidities6 are more likely to receive intensive chemotherapy; better health status, at least in part, may explain higher OS.1 Given the limitations of the study to differentiate between the impact of chemotherapy vs the differences in performance status at baseline, and lack of knowledge regarding specific chemotherapy used, these results are exploratory in nature. The use of intensive chemotherapy was of no benefit in the Roswell Park study.5 In the Swedish AML registry studies, complete remission rates with intensive chemotherapy declined with increasing age.1, 2 Intensive chemotherapy was beneficial for older adults up to the age of 79 years, however, the low-intensity control arm received suboptimal therapy such as low-dose cytarabine and hydroxyurea. For the entire cohort of patients aged 80-89 years, OS was approximately 10% at a year.1 The potential limitations of our study include lack of information on performance status, and specific chemotherapy utilized, as well as the use of zip-code data to estimate the income and educational status. In summary, the poor utilization of chemotherapy, high 1-month mortality and poor long-term OS of octogenarians with AML in this large database study demonstrate an unmet need of this patient population and calls for action to develop multidisciplinary geriatric leukemia programs, chemotherapy and supportive care pathways, and clinical trials specifically targeted toward such high-risk population. The National Cancer Data Base (NCDB) is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The data used in the study are derived from a deidentified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology used or the conclusions drawn from these data by the investigators. The project described was supported by the National Institute Of General Medical Sciences, 1U54GM115458-01 and the Fred & Pamela Buffett Cancer Center Support Grant from the National Cancer Institute (P30 CA036727). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Vijaya R. Bhatt reports serving as a consultant for Pfizer, CSL Behring, Agios, Partner Therapeutics, Abbvie, and Incyte, and has received research funding from Incyte, Tolero, and National Marrow Donor Program. James O. Armitage reports serving as a consultant for Conatus—IDMC, Samus Therapeutics, and Ascentage, and is on Board of Director's for Tesaro bio, Inc. There are no conflicts of interest for any other authors. All authors reviewed and critically revised the manuscript, and approved the final version of the manuscript. Concept development: Bhatt Study design: Bhatt, Shostrom Data analysis: Bhatt, Shostrom Interpretation of the results: Bhatt, Shostrom, Armitage, Gundabolu Drafting the initial manuscript: Bhatt, Shostrom Supplementary table I Overall-survival based on treatment Supplementary Table II. Random intercept model for one-month mortality and overall survival Supplementary Table III. Key studies in Octogenarians with acute myeloid leukemia Supplementary Figure 1. Kaplan-Meier for overall survival of the entire study cohort Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.