Improving the safety of high-dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin.

Abstract

A lack of access to methotrexate levels is common in low- and middle-income countries (LMIC), relevant for 80% of children with cancer worldwide. We evaluated whether high-dose methotrexate (HD-MTX) can be administered safely with extended hydration and leucovorin rescue, with monitoring of serum creatinine and urine pH. The prospective study was conducted at a single centre in Chandigarh, India in 2015. Patients with B-cell acute lymphoblastic leukemia (ALL) or with T-cell ALL or non-Hodgkin lymphoma (T-NHL) were administered 3 and 5 gm/m2 of MTX (24hr infusion), respectively. Six doses of leucovorin (15mg/m2 /dose), instead of recommended three (for optimally reduced levels) at standard timing (42hr from start of HD-MTX) were administered. Hydration (125ml/m2 /hr) was continued for 72hr, instead of the recommended 30hr. Hydration fluid consisted of 0.45% sodium chloride, 5% dextrose, 7.5% sodium bicarbonate (50 mmol/l) and potassium chloride (20 mmol/l). Serum creatinine and urine pH were measured at baseline, 24 and 48hr. The volume of hydration was increased (200ml/m2 /hr) for a serum creatinine>1.25 times the baseline. The study included 100 cycles of HD-MTX in 53 patients: B-ALL 25 patients (51 cycles), T-ALL 16 patients (28 cycles), T-NHL 10 patients (18 cycles), and relapsed ALL 2 patients (3 cycles). The mean age was 6.8±3.2 years. Patients were underweight in 15 (15%) cycles. Patients in 23% of cycles had a rise in creatinine to >1.25 times the baseline. Toxicities (NCI CTCAE v4.0) included mucositis (32%), diarrhoea (10%), and febrile neutropenia (9%). One patient died from dengue shock syndrome. It is safe to administer 3 or 5 gm/m2 of MTX (24hr infusion) without measuring MTX levels, with extended hydration, additional doses of leucovorin, and monitoring of serum creatinine and urine pH.