ALL-406: Comparison of Safe Delivery of 2 and 5 g/m2 of High-Dose Methotrexate to Children with Acute Lymphoblastic Leukemia in Sri Lanka without Availability of Methotrexate Levels

Abstract

<h3>Context</h3> In many low- and middle-income countries (LMICs), there are barriers to delivery of chemotherapy based on international protocols. For higher-risk Acute Lymphoblastic Leukemia (ALL) in children and adolescents, most protocols mandate four courses of high-dose methotrexate (HDMTX) at 5 g/m². However, because of the risk of toxicity, many patients in LMICs receive lower doses. <h3>Design</h3> We retrospectively reviewed management and outcomes of patients treated for ALL using HDMTX (2 or 5 g/m²) as a 24-hour infusion to determine whether the higher dose had unacceptable toxicity. <h3>Setting</h3> At the National Cancer Institute Sri Lanka, delivery of HDMTX is challenging due to shortage of nurses, large numbers of patients, crowded conditions, and inability to measure methotrexate levels. Our team disagrees about the optimal dose of HDMTX, with some physicians using 2 and others 5 g/m². <h3>Patients</h3> Ninety-three consecutive patients with ALL treated on protocols containing HDMTX. <h3>Intervention</h3> Two doses of HDMTX were used, based on clinician preference. Each clinician used a uniform strategy for all her/his patients; toxicity risk was not used to determine the dose. <h3>Main outcome measures</h3> We compared methotrexate toxicities, including acute kidney injury, mucositis, infections, hemorrhage, hospital length-of-stay and delay of subsequent treatment cycles. Patient outcomes were also assessed, but with the short follow-up time, no difference in survival would be expected unless toxicities were extreme. <h3>Results</h3> Toxicities were uncommon in all patients (age 3 months to 19 years) who received 330 courses of HDMTX (103 courses of 2 g/m² and 227 courses of 5 g/m²). There was one death in the 5 g/m² arm due to severe mucositis. Mucositis in 5 g/m² was 6/227 (2.6%) and in 2 g/m² was 1/103 (0.97%) (p=0.34). Two courses were complicated by acute kidney injury (1 in each group, p=1.0), and infections occurred in 32/227 (14.1%) higherdose courses versus 8/103 (7.7%) lower-dose courses (p=0.1). Length of stay was 4.8 days in both groups (p=0.88). <h3>Conclusions</h3> HDMTX up to 5 g/m² can be safely delivered, even in a limited-resource setting and no access to methotrexate levels. One death with severe mucositis suggests that monitoring methotrexate levels could improve safety even more.