A Study to Evaluate the Effectiveness and Safety of Prephase Steroid Treatment before Remission Induction Chemotherapy in Patients with Pediatric Acute Lymphoblastic Leukemia Using Common Data Model-Based Real World Data

Abstract

Introduction: Remission induction chemotherapy (RIC) is a primary treatment strategy for pediatric acute lymphoblastic leukemia (ALL), aiming to rapidly reduce leukemic cells in the bone marrow. However, this swift reduction can lead to significant complications such as tumor lysis syndrome (TLS). Pretreatment with steroids such as prednisolone or dexamethasone a week before initiating multi-agent RIC can potentially prevent TLS, but the effectiveness and utility of this approach remains unclear. We investigated whether steroid pretreatment before RIC can decrease TLS incidence and improve overall survival. Methods: We utilized clinical databases from two university-affiliated tertiary-care hospitals in Seoul, South Korea, constructed according to the OMOP Common Data Model (CDM) specifications. Eligible patients were children with ALL aged <18 who received RIC consisting of vincristine, prednisolone, L-asparaginase with or without daunorubicin between 2012 and 2021. Patients who received steroid pretreatment ≥7 days before RIC constituted the treated group, whereas those who didn't receive any steroid pretreatment or received it <7 days before were the untreated group. We used propensity score (PS) matching to make baseline characteristics comparable between the groups, based on logistic regression model that incorporated the following covariates: age at ALL diagnosis, sex, presence of Down syndrome, risk group, and baseline laboratory measurements including white blood cell count, hemoglobin, platelet count, absolute neutrophil count, uric acid, phosphorus, potassium, calcium, blood urea nitrogen, creatinine, and lactate dehydrogenase. The primary and secondary outcomes were the incidence of TLS within 14 days of starting RIC and overall survival (OS), respectively. Sensitivity analyses were performed to evaluate if unmeasured confounders resulted in any difference in the main results. Likewise, a rule-out approach and a negative control method was applied to adjust for confounders like immunophenotype and genetic alterations and for other residual confounding, respectively. Results: The study included 574 pediatric patients with ALL, with 275 in the treated group and 299 in the untreated group. After PS matching, each group included 142 patients with all baseline characteristics being comparable. Among the untreated patients, TLS was observed 32 out of 299 (10.7%), whereas in the treated group, 6 out of 275 (2.2%) developed TLS. The significant association between the treatment and reduced TLS risk persisted after adjusting for potential confounders (adjusted OR = 0.08, 95% CI: 0.01-0.31, p = 0.01). OS was numerically greater in the treated group that in the untreated group although it failed to reach statistical significance (HR 0.78, 95% CI 0.35-1.71, p=0.53). Sensitivity analyses including a rule-out approach and a negative control method indicated no substantial impact from unmeasured confounders such as immunophenotype, genetic alterations, or other residual factors. Conclusions: Steroid pretreatment ≥7 days before RIC significantly reduced the risk of TLS in pediatric patients with ALL although no significant reduction in OS was seen in the treated group than in the untreated group, partly because median OS was not reached. Because prospective randomized studies are ethically challenging to assess the efficacy and safety of steroid pretreatment before RIC, our results can provide its critical real-world evidence.