Association and Significance of Allostatic Load with Outcomes of Patients with Chronic Myeloid Leukemia (CML)

Abstract

Introduction: Chronic psychosocial stress has been linked to cancer development and progression. Allostatic load (AL) has been proposed as a novel approach to measure the biological consequence of cumulative stress seeking to explain health disparities. As a multidimensional framework, AL delineates functioning across several physiologic networks including neuroendocrine, cardiovascular, metabolic, and inflammatory systems. Emerging evidence highlights the association between AL and cancer risk, yet little is known about its relevance in hematologic malignancies and its impact on treatment outcomes. Aim: To assess the influence of AL on the outcomes of CML patients (pts). Methods: We performed a retrospective analysis of a cohort of CML pts assessing sociodemographic, clinical, laboratory, and molecular data from 2003 to 2023. The AL was obtained from 23 biomarkers (peripheral pulse, systolic & diastolic blood pressure, hemoglobin, red & white blood cells, platelets, Na, K, Cl, CO2, Ca, urea, creatinine, glucose, total protein, albumin, AST, ALT, ALk, total bilirubin, body mass index, and estimated glomerular filtration rate). We calculated an AL index by summing the number of biomarkers that were out of normal range and categorizing the AL score as low (˂3) or high (≥3). The outcomes of interest were molecular response (MMR, MR 4, MR 4.5) and survival endpoints (freedom-free [FFS], event-free [EFS], transformation-free [TFS], and overall [OS]). Results: We included 132 CML pts; median age at diagnosis was 62 years (IQR, 46-72.5 years). Most pts were women (61.4%), more likely to identify as white (69.2%), then black (23.3%), and had multiple comorbidities (Median, Charlson Comorbidity Index 4, IQR 2-6). Reported healthy behaviors included regular exercise (76.8%), never smoking (64.8%), and not having history of substance abuse (85.4%). The mean AL index was 5.11 with 84.8% of pts allocated to high AL score (15.2% low). High AL was correlated with black race (OR= 3.527, CI 0.77-16.17), men (OR=1.73, CI 0.66-4.51), alcohol consumption (OR=0.55, CI 0.18-1.64), tobacco use (OR=0.48, CI 0.17-1.32), and substance abuse (OR=0.33, CI 0.093-1.17). AL was also associated with Social Determinants of Health, including living in metropolitan areas (OR=0.37, CI 0.10-1.318) or alone (OR=1.67, CI .46-6.23), and employment (OR=0.4, CI 0.1-1.3). Notably, pts with high AL presented a statistically significant lower probability of MMR (HR= 0.56, CI 0.31-0.98), and worse FFS (HR=2.76, CI 1.17-6.50). There was also a for pts with high AL not achieving MR4 (OR= 0.44, CI 0.17-1.15) or MR4.5 (OR=0.48, CI 0.18-1.28), having TKI failure (OR= 2.39, CI 0.90-6.34), transformation to accelerated or blast phase (OR=3.13, CI 0.39-25.06), and worse EFS (HR 1.15, CI 0.59-2.26) (illustrated in the figure). Conclusion: Pts with CML who have a high AL index showed an association with unfavorable treatment outcomes and deep molecular responses. AL, as a measurement of chronic stress, shows a potential ability to elucidate racial and socioeconomic disparities and predict molecular and clinical responses. Assessing AL through multiple time points could uncover help identify modifiable risk factors that could potential help improve outcomes.