Folinic-acid/furosemide/methotrexate

Abstract

Various toxicities: 3 case reports In a retrospective study, three boys (aged 11–12 years) were described, who developed drug toxicity manifesting as exanthema, anaemia, leucopenia, thrombocytopenia, leucocytosis, emesis, vomiting, abdominal pain, epistaxis, liver failure, coagulopathy or acute renal failure during treatment with methotrexate. Later, the boys exhibited lack of efficacy during treatment with folinic acid or furosemide for the methotrexate toxicity [not all routes, dosage and outcome stated; durations of treatments to reactions onset not stated]. Patient 1: An 11-year-old boy was treated for second malignant disease (an osteoblastic osteosarcoma involving the facial bones). He received the first course of high dose IV methotrexate 12 g/m2 infusion over 4 hours in accordance to the EURAMOS protocol with a short disruption because of exanthema during infusion that improved with anti-histaminics and cortisone. Methotrexate level at 4 hours was 1081 μmol/L with creatinine level of 0.81. The serum methotrexate level 24 hours following infusion was elevated and serum creatinine was 1.73 mg/dl. Subsequently, an intensification of hyperhydration, urine alkalinisation, forced diuresis with furosemide and intensification of treatment with folinic acid [leucovorin] 250 mg/m2/3 hours were carried out. Forty-eight hours following infusion and despite aggressive treatment, methotrexate levels were constantly high and he reported leucocytosis with progressive acute renal failure (elevated serum creatinine and eGFR of 21 ml/min/1.73 m2), liver failure with elevated liver enzymes and coagulopathy treated plasma and vitamin K. He was clinically stable, and besides emesis and erythema revealed no further symptoms. Subsequently, he underwent one session of charcoal haemoperfusion (CHP) which began 52 hours following start of methotrexate infusion. A dramatic decrease of methotrexate level was observed and the procedure was carried out without complications. Furthermore, he received glucarpidase, which resulted in a decrease in methotrexate level. Due to persistently elevated methotrexate levels, he received a second glucarpidase dose resulting in a sufficient decrease of methotrexate level. Later, treatment with folinic acid was maintained until day 31. Subsequently, a gradual recovery of renal function, normalisation of blood count and liver function were observed during the follow-up. Patient 2: A 12-year-old boy had pre-B lymphoblastic lymphoma. He received second high dose IV methotrexate course 5 g/m2 infusion in 24 hours that was well-tolerated according to Protocol Euro LB 02 following urine alkalinisation and adequate prehydration. During the first 24 hours following the start of methotrexate infusion, he reported non-oliguric acute renal failure. An increased methotrexate level was noted, which was managed by intensification of hydration and folinic acid 100 mg/m2/3 hours rescue . At 36 hours, methotrexate levels were persistently high and he was referred to initiate treatment with charcoal haemoperfusion (CHP). Thereafter, he was clinically stable with vomiting, abdominal pain and epistaxis. Following the first session of CHP, a reduction of methotrexate level was noted. Subsequently, anaemia and thrombocytopenia were noted requiring platelet and blood cell transfusions. He received glucarpidase that led to reduction in methotrexate levels to 0.96 μmol/L. Consequently, a recovery of renal function, remission of normal blood count and gastrointestinal symptoms was noted. Patient 3: An 11-year-old boy had T-cell acute lymphoblastic leukaemia for which he was under treatment according to protocol ALL SEHOP/PETHEMA 2013 HR. He received the first course of high dose IV methotrexate 5 g/m2 infusion in 24 hours with adequate urine alkalinisation and hydration. Increased methotrexate level was observed 24 hours following the infusion. However, despite of adequate treatment with hydration and folinic acid 30 mg/m2/6 hours rescue, he was noted with persistently elevated methotrexate levels at 36 hours and 48 hours. Additionally, non-oliguric renal failure with increased creatinine were noted. Thereafter, he received first dose of glucarpidase and second dose 96 hours following the initiation of methotrexate infusion, but an insufficient reduction in methotrexate level was noted. Methotrexate levels were persistently high despite two doses of glucarpidase, urine alkalinisation, hydration and folinic acid rescue. He presented with reduced general status. Persistent renal failure and rising creatinine were noted at the admission. Subsequently, leucopenia was noted too. Hence, charcoal haemoperfusion (CHP) was performed without complications on days 9, 10, 11, and 12. Thereafter, only slight anaemia and thrombocytopenia remained. Gradual improvement was noted with CHP treatment, with eventual decrease in methotrexate levels, normalisation of blood count and recovery of renal function.