Clinical Assessment of Cumulative Stress Via Allostatic Load in Chronic Myeloid Leukemia Patients: Implications for Treatment Outcomes

Introduction: Allostasis refers to the physiological process that enables adaptation to varying conditions and demands, including cumulative stress, through the production of mediators such as adrenaline and cortisol. Allostatic load (AL) is a tool designed to quantify the biological impact of chronic stress over time. AL utilizes a scoring system integrating various clinical features and biomarkers across cardiovascular, neuroendocrine, immune, and metabolic systems. Allostatic overload has been associated with worse treatment outcomes and prognosis in several diseases, including cancer. Data on the influence of AL in patients with chronic myeloid leukemia (CML) is scarce.

With the advent of tyrosine kinase inhibitor (TKI)-based therapies, the life expectancy of CML patients has improved to levels comparable to the general population. However, many patients require multiple lines of treatment (LoT), and failure of initial TKI therapy can introduce additional cumulative stress. This study aims to investigate the AL burden in CML patients and its association with LoT.

Methods: We conducted a retrospective analysis of a cohort of CML patients treated at a referral cancer center in Georgia between 2003 and 2023. The AL score was calculated at the time of the first visit. encompassing 22 biomarkers across four domains: 1) Cardiovascular, systolic, and diastolic blood pressure, and heart rate, 2) Metabolic, Na, K, Cl, CO2, Ca, urea, creatinine, glucose, total protein, albumin, AST, ALT, ALP, Alk, eGFR, body mass index (BMI), 3) Immune, red and white blood cells, platelets, and hemoglobin. Patients were sorted into low (<5) and high (≥ 5) AL group using the median AL score as the cutoff (Median 5, IQR 4-7). Odds ratios (OR) to assess the association between AL and treatment outcomes were calculated. P values below 0.05 were considered statistically significant.

Results: Our cohort included 237 CML patients. Most patients were male (n=141, 59.9%), identified as Caucasian (n=165, 69.5%), and the mean age at the diagnosis was 58.5 years (range, 27-93). Most patients were diagnosed in chronic phase (n=202, 89.9%). Median time from CML diagnosis to first AL assessment was 33 months (IQR, 5-90) and from diagnosis to data-cut-off was 120 months (IQR 71,5-178). In the cohort, 45.6% of patients (n=108) were at first LoT, while 25% (n=83) required three or more LoT, and 19.4% (n=46) were at second LoT. Sixteen patients (6.8%) died during follow-up; these included 7 CML-related deaths (3%). Median time from AL measurement to last follow-up or death was 30 months (IQR 6-66.5). Among the 22 biomarkers included in the AL index, most of the out-of-range values were identified in the immune system (Hb, RBC, and WBC), followed by the cardiovascular (SBP and DBP) and metabolic domains (Cl, Glucose and BMI).

Older CML patients had high AL at the diagnosis (p=0.02). In addition, individuals at the second LoT had lower AL than patients undergoing the third or subsequent LoT (p=0.01). A slightly higher rate of patients receiving the first LoT presented high AL (48.6% vs 42.9%). There was a greater number of patients with high AL who died during the course of CML treatment than of patients with low AL (11.7% vs. 2.4%, p=0.01). The statistical significance remained for CML-specific death (p=0.03).

CML patients receiving their second or subsequent LoT with high AL tended to have lower odds to reach the major molecular response (MMR; OR: 0.49; CI: 0.24-1.01; p=0.05). AL was also a predictor of overall (OR: 10.7; CI: 1.29-89.21; p=0.01) and CML-specific (OR: 1.1; CI:1.0-1.1 ; p=0.04) death for patients treated with the front line therapy but not patients undergoing the subsequent LoT (p>0.05).

Conclusion: Our findings highlight the significant burden that chronic stress/AL impose on CML patients, particularly those undergoing multiple LoT. The association between allostatic overload and increased mortality risk underscores the importance of incorporating AL assessments into the management of CML.