Methotrexate-associated toxicity in children with Down syndrome and acute lymphoblastic leukemia during consolidation therapy with high dose methotrexate according to ALL-BFM treatment regimen

Children with Down syndrome and acute lymphoblastic leukemia often suffer from severe toxicities during treatment, especially with high-dose methotrexate. Systematic data on methotrexate toxicity in these patients are rare. We analyzed seven methotrexate-associated toxicities during consolidation therapy in 103 Down-syndrome- and 1,109 Non-Down-syndrome-patients with acute lymphoblastic leukemia enrolled in ALL-BFM trials between 1995-2016 and 1995–2007, respectively. Patients received four courses methotrexate (5 g/m2 each) plus intrathecal methotrexate and 6-mercaptopurine. From 2004 on, a dose of 0.5 g/m2 in the 1st methotrexate course was recommended for Down-syndrome-patients. Down-syndrome-patients showed higher rates of 3/4 toxicities after the 1st course with 5 g/m2 methotrexate compared to Non-Down-syndrome-patients (62 3/4 toxicities in 45 Down-syndrome- vs. 516 in 1,089 Non-Down-syndrome-patients, p<0.001). Dose reduction (0.5 g/m2) in Down-syndrome-patients reduced toxicity (39 in 51 patients, p<0.001) without increasing the relapse risk (reduced dose, 5 year cumulative relapse incidence = 0.09+/-0.04 vs. high dose, 0.10+/-0.05, p=0.51). Methotrexate dose escalation to 1.0 g/m2 for Down-syndrome-patients who tolerated 0.5 g/m2 (n= 28/51 patients) did not result in an increased rate of 3/4 toxicities after the 2nd course (p=0.285). Differences in methotrexate plasma levels at 42 h and 48 h after start of the 1st methotrexate infusion did not explain higher toxicity rates in Down-syndrome-patients treated with 0.5 g/m2 as compared to Non-Down-syndrome-patients treated with 5 g/m2. Within the Down-syndrome cohort a higher methotrexate plasma level was associated with increased toxicity. In conclusion, dose reduction in the 1st methotrexate course reduced severe toxicities without increasing the risk of relapse.