Predictors of Delayed Clearance and Toxicities from High Dose Methotrexate in Patients Receiving Hypercvad Regimen for Treatment of Lymphoid Malignancies
Authors: Ng Hong Yen , Ong Pei Shi , Loy Xue Ming , Chen Yufei , Goh Yeow Tee 
Published: October 2019

Abstract
Introduction: High dose Methotrexate (HDMTX) has been the backbone of chemotherapeutic regimens used for the treatment of lymphoid malignancies. Altered disposition of MTX may result in increased systemic exposure accompanied by severe adverse effects and organ toxicities. Diversity in toxicity profile has been shown to be associated with various clinical factors as well as genetic polymorphisms. In particular, single nucleotide polymorphisms (SNPs) in the solute carrier organic anion transporter 1B1 (SLCO1B1) gene especially rs4149056 and rs2306283 had been previously reported to be significantly associated with MTX concentration at 24 hours post-infusion, MTX AUC from 0-48 hours, MTX clearance and toxicities in the Caucasian pediatric population.
Aim: This study aimed to characterize clearance and toxicity profile [in particular acute kidney injury (AKI) and hepatotoxicity]; and identify clinical and genetic covariates associated with clearance and toxicities of HDMTX in patients receiving HyperCVAD-B regimen for treatment of lymphoid malignancies in the local setting.
Methods: This single-centered, retrospective study included all treatment-naïve patients of Asian descent who received HDMTX as part of the HyperCVAD-B regimen for treatment of lymphoid malignancies from January 2008 to December 2015 in Department of Hematology, Singapore General Hospital. Pertinent clinical data including baseline demographics, disease characteristics, treatment details, plasma MTX levels, and treatment outcomes were extracted from case notes and electronic records onto a standardized data collection form. Association between toxicities parameters and MTX levels were analyzed. Genotyping for two SNPs in the SLCO1B1 gene namely, rs2306283 and rs4146056 was using blood samples obtained from the Hematology Department Tissue Repository. Primary endpoint was incidence of delayed clearance and toxicities of HDMTX in the study population. Secondary endpoints included clinical factors and genetic covariates associated with reduced MTX clearance and toxicities.
Results: A total of 102 patients (215 treatment cycles) were included, with each patient receiving median of 2 cycles (range, 1 to 6). Median age was 45 years (range, 18 - 69), and 58 (56.9%) were male. Eighty-seven patients were diagnosed with acute lymphoblastic leukemia (ALL), whereas 12 patients had lymphoma. Sixty-one patients (59.8%) were found to have at least 1 episode of delayed clearance, occurring in 89 (41.4%) treatment cycles. Median time to MTX clearance was significantly longer in patients with delayed clearance at 69.8 hours (range, 4.5-277.2) as compared to 41 hours (range, 0 - 86.3 hours), p<0.001. Approximately 25% and 47% of the patients developed AKI and hepatotoxicity attributable to MTX, respectively. A significant association between delayed clearance and occurrence of AKI was observed, with 24% of patients with delayed clearance developing AKI vs 2% in those without delayed clearance, p<0.001. Number of treatment cycles [odds ratio (OR) = 2, 95% confidence interval (CI) 1.3 - 3.1, p = 0.002]; and age ≥ 40 (OR 3.7, 95% CI 1.4 - 9.6, p = 0.008) were found to be associated with delayed clearance. Occurrence of delayed clearance (OR = 29, 95% CI = 3.7 - 228, p = 0.001), and baseline hepatic impairment (OR = 9.5, 95% CI = 2 - 45, p = 0.005) were found to predict for AKI and hepatotoxicity, respectively. Genotyping for SLCO1B1 rs2306283 and rs4146056 was carried out for 39 patients with samples available in the repository. Frequencies and outcomes were shown in Table 1 and Table 2, respectively. Due to the small sample size, no definitive correlations between specific genotypes and clearance and outcomes could be elucidated.
Conclusion: Delayed clearance of HDMTX occurred in a substantial proportion of patients at approximately 60%, which was in turn associated with occurrence of AKI. Risk of delayed clearance seemed to increase with age (≥ 40) and number of treatment cycles. This underscores the need for more effective strategies to facilitate clearance of HDMTX especially in patients with identified risk factors. Larger sample size would be essential to determine associations between genotypes and clearance and toxicities.

Disclosures
No relevant conflicts of interest to declare.