Psychiatric and Substance Use Disorders Are Independent Predictors of Treatment Response and Outcomes in United States Veterans with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Combinations

BACKGROUND: Venetoclax (VEN) combinations have become the standard frontline therapy for patients with newly diagnosed acute myeloid leukemia (AML) who are deemed unable to tolerate intensive induction chemotherapy, either due to age or comorbidities. However, outcomes in the real-world setting have been inferior to those observed in clinical trials. Preexisting psychiatric diagnoses and substance use disorders (SUDs) have previously been associated with increased mortality in patients with cancer, but their prognostic influence in veterans with AML is unclear. The aim of this study was to measure the prevalence of psychiatric and SUDs in veterans with AML treated with VEN combinations, determining the impact of these conditions on treatment response and outcomes.

METHODS: This was a retrospective cohort study of veterans with newly diagnosed AML who received frontline therapy with VEN combinations within the national Veterans Affairs (VA) Healthcare System. To measure the prevalence of psychiatric and SUDs, we used the Centers for Medicare and Medicaid Services (CMS) Chronic Conditions Data Warehouse algorithm, which tracks health conditions by administrative claims data with International Classification of Diseases (ICD) diagnostic and procedural codes. Our endpoints were rates of complete remission or complete remission with incomplete marrow recovery (CR/CRi), early mortality (EM, or death within 60 days of treatment initiation), intensive care unit (ICU) admissions, and overall survival (OS). We evaluated the relationship between comorbid medical conditions and outcomes using Kaplan-Meier analysis and Cox proportional hazards regression models, first unadjusted, and then adjusted for all covariates. Patients who underwent allogeneic stem cell transplantation (HSCT) were excluded from statistical analyses.

RESULTS: We identified 452 veterans treated with VEN up to April 1, 2022 (Table 1). In combination with VEN, 60% (n=270) received azacitadine, 37% (n=168) received decitabine, and 3% (n=14) received low-dose cytarabine. Median age was 74.3 years (IQR: 71.2-78.5) with 52% ≥75 years. By European LeukemiaNet (ELN) 2017 risk classification, 61% (n=274) were classified as adverse risk. Forty-six percent (n=206) of veterans had a preexisting psychiatric diagnosis, and 19% (n=84) had SUDs; 11% (n=49) had both comorbidities. Psychiatric disorders were significantly more prevalent in younger veterans (68% in <65 years vs 50% in 65-74 years vs 39% in ≥75 years, p<0.003); same was true for SUDs (38% in <65 years vs 26% in 65-74 years vs 9% in ≥75 years, p<0.001). For the entire cohort, CR/CRi was achieved by 57% (n=257), and only 3% (n=12) received HSCT. Zero veterans with SUDs and 8 with psychiatric diagnoses were transplanted. At the end of study period, 69% (n=310) had died. Median OS was 216 days (95% CI: 195-254). The 60-day mortality rate was 20% (n=87), of which 8 veterans had primary refractory AML. ICU admissions after treatment initiation was significantly higher in veterans with SUDs compared to those without history of SUDs (5.0 versus 2.2 per 5 person-years, p<0.001). On multivariable analyses (Table 2), both psychiatric and SUDs were independently associated with decreased odds of CR/CRi. Veterans with psychiatric disturbances had a 1.97 times higher hazard of EM (95% CI: 1.16-3.39, p=0.01) and a 1.28 times higher hazard of death (95% CI: 1.00-1.64, p=0.05) compared to veterans without concurrent psychiatric disorders.

CONCLUSION: Psychiatric diagnoses and SUDs were not only prevalent among veterans with AML, but they also negatively impacted treatment response, EM, and OS—independently of age, sociodemographic variables, markers of disease risk, and VEN combination. Veterans with SUDs also had significantly higher ICU admissions after treatment initiation for AML. Compared to published clinical trials data, veterans experienced inferior outcomes. Veterans with psychiatric and SUDs may have difficulty adhering to regimens, reemergence of their mental instability and illness that is triggered by AML diagnosis and its treatment, or biologic mechanisms associated with these comorbidities. Better understanding of these factors contributing to health disparities and targeting these comorbidities with supportive care interventions alongside AML-specific therapy may improve outcomes and warrant further study.