The effect of steroid-induced hyperglycemia in early mortality during induction treatment of Philadelphia-negative acute lymphoblastic leukemia in Latino young adults

Abstract

Abstract Introduction: Acute lymphoblastic leukemia (ALL) disproportionately affects Latino populations, who also exhibit a dismal prognosis. Especifically, early death has been described to have a high frequency in Latinos and adolescents/young adults (AYAs) with ALL which is the main limitation of intensive pediatric-based treatment. Additionally, Latinos are also characterized by increased metabolic risk and particular leukemic mutational signatures such as Philadelphia-like genotypes. In this cohort, we aimed to explore the prognosis of hyperglycemia secondary to treatment in early mortality and survival of Philadelphia-negative acute lymphoblastic leukemia (Ph-negative ALL) in a cohort of Latino AYAs. Methods: We conducted a retrospective cohort study of AYAs (15–39 years) with confirmed Ph-negative ALL, diagnosed and treated at a national tertiary leukemia institution in Lima-Peru, between 2017 and 2019. All patients received the modified CALGB10403 regimen, which included standardized E. coli asparaginase doses and prednisone at 60 mg/m². Patients with a prior history of diabetes were excluded from the study. Glucose levels were monitored daily during induction treatment, with hyperglycemia defined as fasting glucose ≥126 mg/dL. Patients were grouped as based on if experienced more than seven hyperglycemia events during the induction treatment, and managed with corrective insulin therapy following standard clinical guidelines. Early death was defined as mortality occurring within the first 30 days from the initiation of induction treatment. Logistic regression and Cox regression analyses were used to assess early death and survival outcomes, respectively. Results: A total of 337 patients were included. The median age 21 years (IQR: 18-28), and 45% were female. The median BMI was 23.3 kg/m² (IQR: 20.7-27.0), 25% were classified as NCCN high-risk, and 97% mantained good performance status (ECOG 0-2). Forty-eight patients (14%) developed more than seven hyperglycemic events during induction and were classified as the persistent hyperglycemic (PHG) group. While PHG and non-PHG groups had similar baseline features, the PHG group showed significant older median age (24 vs. 20 years, p=0.003), and slightly lower hemoglobin levels (7.8 vs 8.3 g/dL, p=0.002). Liver toxicity rates were comparable between both groups. The PHG group experienced significantly higher rates of ICU admissions (37% vs. 9%, p<0.001) and lung infections (44% vs. 21%, p=0.011), with an increased trend of confirmed invasive Aspergillosis (25 vs. 13%). Although median overall survival for the entire cohort was 22 months (95% CI: 17-27) with a 5-year survival rate of 35% (95% CI: 31-41), no differences were found between groups. However, the PHG group experienced significantly higher early death rates compared to the non-PHG group (15% vs. 3.8%, p=0.007). Conclusions: In this cohort of Latino AYAs treated with pediatric-inspired regimens, persistent hyperglycemia during induction, likely related to steroid and L-asparaginase exposure, was associated with significantly high early mortality. Patients with frequent hyperglycemic episodes experienced increased rates of critical complications, including ICU admissions, pulmonary infections, and higher rates of invasive fungal infection. These findings should be validated in future prospective studies to effectively incorporate routine hyperglycemia management into standard-of-care protocols to improve early outcomes in this population.