Impact of uncontrolled hyperglycemia during induction chemotherapy on response and survival outcomes in patients with adult B-cell acute lymphoblastic leukemia (B-ALL) on HCVAD-based regimens

Abstract

Abstract Hyperglycemia is a well-recognized complication of induction chemotherapy in patients with B cell acute lymphoblastic leukemia (B-ALL). Due to the use of high dose dexamethasone, induction chemotherapy frequently leads to worsening of hyperglycemia, particularly in patients with pre-existing metabolic dysfunction. Uncontrolled hyperglycemia is increasingly recognized as an adverse prognostic factor in various malignancies. In pediatric B-ALL population, hyperglycemia requiring insulin administration during induction chemotherapy was found to be associated with increased morbidity and mortality. Despite this clinical observation, the prognostic significance of hyperglycemia in adult B-ALL remains poorly characterized. We conducted a retrospective, single-center study of adult patients with newly diagnosed B-ALL who received treatment at MD Anderson Cancer Center between January 2017 and January 2022. The primary objective was to evaluate the association between uncontrolled hyperglycemia during induction chemotherapy and treatment outcomes, including rate of complete remission (CR), measurable residual disease (MRD) negativity by flow cytometry at CR, relapse incidence, event-free survival (EFS) and overall survival (OS). Secondary objectives aimed to identify factors associated with adverse outcomes in patients with hyperglycemia. Data including baseline demographics, comorbidities, steroid dosing, glucose measurements, and induction response as assessed by bone marrow evaluation were collected. Multivariable logistic regression models were used to assess independent predictors of adverse outcomes in B-ALL patients with uncontrolled hyperglycemia during the induction cycle. A total of 246 patients were included in the analysis. Median age at B-ALL diagnosis was 48 years, and 54% of the patients were male. B-ALL diagnoses included 142 (57.7%) Philadelphia (Ph)-negative, 52 (21.1%) Ph-positive, and 52 (21.1%) Ph-like B-ALL. Patients were stratified by the presence or absence of uncontrolled hyperglycemia during induction therapy, defined as a fasting serum glucose level >180 mg/dL for at least two consecutive days. Uncontrolled hyperglycemia was observed in 93 patients (38%). Baseline characteristics were similar between the two groups, except for a higher prevalence of pre-existing diabetes mellitus in the hyperglycemia cohort (29% vs 4%, p < 0.001) and an elevated median body mass index (BMI) at baseline (33 vs 29 kg/m², p = 0.002). The median follow-up time from diagnosis was 36 months. Complete remission (CR) rates were 91% in the hyperglycemia group compared to 97% in the non-hyperglycemic group (p = 0.14). MRD negativity rates by flow-cytometry were 45% versus 49% at the time of CR, respectively (p = 0.56). The median event-free survival (EFS) was 47.5 months in the hyperglycemia group, whereas it was not reached in the non-hyperglycemia group (p = 0.029); the 3-year EFS rates were 46.24% and 58.82%, respectively. Similarly, the median overall survival (OS) was 61.2 months in the hyperglycemia group, while the median OS was 65.7 months in the non-hyperglycemia group (p = 0.021); the 3-year OS rates were 52.69% and 65.40%, respectively. Subsequently, a multivariable logistic regression was performed including hyperglycemia in addition to other clinical and demographic factors. Uncontrolled hyperglycemia, higher BMI, and prior history of diabetes were associated with worse EFS (OR=1.291; 95% CI 1.008 - 1.821, p= 0.043). Uncontrolled hyperglycemia, higher BMI, Philadelphia like B-ALL, and age >60 were independent predictors for worse OS (OR=1.671; 95% CI 1.158 - 3.013, p=0.049). Other covariates, including gender, race, ethnicity, cumulative dexamethasone dose, WBC at presentation, endocrinology consultation status, and time to insulin use, did not reach statistical significance. In conclusion, uncontrolled hyperglycemia during induction chemotherapy is independently associated with significantly shorter EFS and OS in adult patients with B-ALL. Despite unclear mechanism of action, hyperglycemia can increase infection risk, promote pro-inflammatory and pro-leukemic signaling, and result in chemotherapy resistance. Our findings underscore the prognostic impact of metabolic dysfunction during induction therapy. Targeted strategies to monitor and manage hyperglycemia may represent an opportunity to improve clinical outcomes in this high-risk population.