Inflammatory biomarkers, geriatric assessment, and treatment outcomes in acute myeloid leukemia.

OBJECTIVES: To investigate changes in inflammatory biomarkers during induction therapy for older adults with acute myeloid leukemia (AML) and their associations with geriatric assessment (GA) measures and outcomes. METHODS: This was a single institution ancillary study to a prospective observational study (N = 20 consecutive adults aged ≥60 with newly diagnosed AML who received induction chemotherapy). Biomarkers (Interleukin-6 [IL-6], IL-6 soluble receptor [IL-6 sR], tumor necrosis factor alpha [TNFα], TNFα soluble receptor 1 [TNFα sR1], interleukin-3 [IL-3], C-reactive protein [CRP]) were collected at start of induction, weekly for three weeks, and post-induction and were compared over time using paired t-tests. GA was administered at baseline and post-induction, and correlated with biomarker levels using Spearman correlations. Survival was estimated using Kaplan-Meier and compared by categorized biomarker level using Wilcoxon tests. RESULTS: Biomarker levels were stable during induction, except for CRP and IL-6 sR. Declines in objectively measured physical function [Short Physical Performance Battery (SPPB); r = 0.71, p < 0.01] and increases in self-reported limitation in instrumental activities of daily living (r = 0.81, p < 0.01) were correlated with increased TNFα sR1. Declines in SPPB were correlated with increased CRP (r = -0.73, p < 0.01). Improvement in depression was correlated with increased IL-6 sR (r = -0.59 p = 0.02). Survival was shorter in those with baseline TNFα or CRP levels above the median (6.1 vs. 40.2 months and 5.5 vs. 27.6 months respectively, p = 0.04 for both). CONCLUSION: Among older adults with AML, the relationships between TNFα sR1, CRP, and IL-6 sR with change in physical and emotional health during treatment warrants further investigation.

Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular magnetic resonance.

BACKGROUND: In a murine anthracycline-related cardiotoxicity model, increases in cardiovascular magnetic resonance myocardial contrast-enhanced T1-weighted signal intensity are associated with myocellular injury and decreases with left ventricular ejection fraction. We sought to determine whether T1- and T2-weighted measures of signal intensity associate with decreases in left ventricular ejection fraction in human subjects receiving potentially cardiotoxic chemotherapy. METHODS AND RESULTS: In 65 individuals with breast cancer (n=51) or a hematologic malignancy (n=14), we measured left ventricular volumes, ejection fraction, and contrast-enhanced T1-weighted and T2-weighted signal intensity before and 3 months after initiating potentially cardiotoxic chemotherapy using blinded, unpaired analysis of cardiovascular magnetic resonance images. Participants were aged 51 ± 12 years, of whom 55% received an anthracycline, 38% received a monoclonal antibody, and 6% received an antimicrotubule agent. Overall, left ventricular ejection fraction decreased from 57 ± 6% to 54 ± 7% (P<0.001) because of an increase in end-systolic volume (P<0.05). T1-weighted signal intensities also increased from 14.1 ± 5.1 to 15.9 ± 6.8 (P<0.05), with baseline values trending higher among individuals who received chemotherapy before study enrollment (P=0.06). Changes in T1-weighted signal intensity did not differ within the 17 LV myocardial segments (P=0.97). Myocardial edema quantified from T2-weighted images did not change significantly after 3 months (P=0.70). CONCLUSIONS: Concordant with previous animal studies, cardiovascular magnetic resonance measures of contrast-enhanced T1-weighted signal intensity occur commensurate with small but significant left ventricular ejection fraction declines 3 months after the receipt of potentially cardiotoxic chemotherapy. These data indicate that changes in T1-weighted signal intensity may serve as an early marker of subclinical injury related to the administration of potentially cardiotoxic chemotherapy in human subjects.

Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia.

We investigated the predictive value of geriatric assessment (GA) on overall survival (OS) for older adults with acute myelogenous leukemia (AML). Consecutive patients ≥ 60 years with newly diagnosed AML and planned intensive chemotherapy were enrolled at a single institution. Pretreatment GA included evaluation of cognition, depression, distress, physical function (PF) (self-reported and objectively measured), and comorbidity. Objective PF was assessed using the Short Physical Performance Battery (SPPB, timed 4-m walk, chair stands, standing balance) and grip strength. Cox proportional hazards models were fit for each GA measure as a predictor of OS. Among 74 patients, the mean age was 70 years, and 78.4% had an Eastern Cooperative Oncology Group (ECOG) score ≤ 1. OS was significantly shorter for participants who screened positive for impairment in cognition and objectively measured PF. Adjusting for age, gender, ECOG score, cytogenetic risk group, myelodysplastic syndrome, and hemoglobin, impaired cognition (Modified Mini-Mental State Exam < 77) and impaired objective PF (SPPB < 9) were associated with worse OS. GA methods, with a focus on cognitive and PF, improve risk stratification and may inform interventions to improve outcomes for older AML patients.

The feasibility of inpatient geriatric assessment for older adults receiving induction chemotherapy for acute myelogenous leukemia.

OBJECTIVES: To test the feasibility and utility of a bedside geriatric assessment (GA) to detect impairment in multiple geriatric domains in older adults initiating chemotherapy for acute myelogenous leukemia (AML). DESIGN: Prospective observational cohort study. SETTING: Single academic institution. PARTICIPANTS: Individuals aged 60 and older with newly diagnosed AML and planned chemotherapy. MEASUREMENTS: Bedside GA was performed during inpatient exmination for AML. GA measures included the modified Mini-Mental State Examination; Center for Epidemiologic Studies Depression Scale; Distress Thermometer, Pepper Assessment Tool for Disability (includes self- reported activities of daily living (ADLs), instrumental ADLs, and mobility questions); Short Physical Performance Battery (includes timed 4-m walk, chair stands, standing balance); grip strength, and Hematopoietic Cell Transplantation Comorbidity Index. RESULTS: Of 54 participants (mean age 70.8 ± 6.4) eligible for this analysis, 92.6% completed the entire GA battery (mean time 44.0 ± 14 minutes). The following impairments were detected: cognitive impairment, 31.5%; depression, 38.9%; distress, 53.7%; impairment in ADLs, 48.2%; impaired physical performance, 53.7%; and comorbidity, 46.3%. Most were impaired in one (92.6%) or more (63%) functional domains. For the 38 participants rated as having good performance status according to standard oncologic assessment (Eastern Cooperative Oncology Performance Scale score ≤1), impairments in individual GA measures ranged from 23.7% to 50%. Significant variability in cognitive, emotional, and physical status was detected even after stratification according to tumor biology (cytogenetic risk group classification). CONCLUSION: Inpatient GA was feasible and added new information to standard oncology assessment, which may be important for stratifying therapeutic risk in older adults with AML.