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

Mirko Kroll, Kirsten Kaupat-Bleckmann, Anja Mörickel, Julia Altenl, Denis M Schewel, Martin Stanullal, Martin Zimmermann, Martin Schrappe, Gunnar Cario, Mirko Kroll, Kirsten Kaupat-Bleckmann, Anja Mörickel, Julia Altenl, Denis M Schewel, Martin Stanullal, Martin Zimmermann, Martin Schrappe, Gunnar Cario

Abstract

Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) often suffer from severe toxicities during treatment, especially with high-dose methotrexate (HD-MTX). Systematic data on methotrexate (MTX) toxicity in these patients are rare. We analyzed seven MTX-associated toxicities during consolidation therapy in 103 DS- and 1,109 non-DS-patients (NDS) with ALL (NDS-ALL) enrolled in ALL-Berlin-Frankfurt-Münster (ALL-BFM) trials between 1995-2016 and 1995-2007, respectively. Patients received four courses MTX (5 g/m2 each) plus intrathecal MTX and 6-mercaptopurine (6-MP). From 2004 onwards, a dose of 0.5 g/m2 in the first MTX course has been recommended for DS-patients. DS-patients showed higher rates of grade 3/4 toxicities after the first course with 5 g/m2 MTX compared to NDS-patients (grade 3/4 toxicities 62 in 45 DS-patients vs 516 in 1,089 NDS-patients, P<0.001). The dose reduction (0.5 g/m2) in DS-patients has 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). MTX dose escalation to 1.0 g/m2 for DS-patients who tolerated 0.5 g/m2 (n= 28 of 51 patients) did not result in an increased rate of grade 3/4 toxicities after the second course (P=0.285). Differences in MTX plasma levels at 42 and 48 hours after the start of the first methotrexate infusion did not explain higher toxicity rates in DS-patients treated with 0.5 g/m2 compared to NDS-patients treated with 5 g/m2 Within the DS cohort a higher MTX plasma level was associated with increased toxicity. In conclusion, dose reduction in the first MTX course reduced severe toxicities without increasing the risk of relapse. (ClinicalTrials.gov identifier: NTC00430118, NCT01117441).

Copyright© 2020 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Flow chart showing patient numbers in individual high-dose methotrexate courses including drop outs during high dose methotrexate consolidation.
Figure 2.
Figure 2.
Comparison of toxicities after first high-dose methotrexate (HD-MTX) course in Down syndrome acute lymphoblastic leukemia (DS-ALL) versus non-Down syndrome acute lymphoblastic leukemia (NDS-ALL) and comparison of toxicities in DS-ALL after the initial and later HD-MTX courses. (A) Comparison of grade 3/4 toxicities after application of the first HD-MTX course in DS-ALL patients who received 5 g/m2 (n=45 of 103) or 0.5 g/m2 methotrexate (MTX) (n=51 of 103) and NDS-ALL patients who received 5 g/m2 MTX (n=1,089/1,109). *P≤0.05, Fisher’s exact test. (B) Comparison of grade 3/4 toxicities after the first and second HD-MTX course in DS-ALL patients who initially received 0.5 g/m2 MTX and were escalated to a median MTX dose of 1.0 g/m2 in the second course (n=28 of 51). No significant differences according to McNemar test. (C) and (D) Comparison of grade 3/4 toxicities after the first and last HD-MTX course in all DS-ALL (C) and NDS-ALL patients (D), including patients with intermediate MTX doses. *P≤0.05 according to McNemar-test. The number on top of each bar represents the number of patients.
Figure 3.
Figure 3.
Five-year-cumulative incidence risk of relapse in Down syndrome acute lymphoblastic leukemia. (A) Comparison of the 5-year-cumulative incidence risk (5y-CIR) of Down syndrome acute lym-phoblastic leukemia (DS-ALL) patients who received a first high dose methotrexate (HD-MTX) course of 0.5 g/m2 (blue) or 5 g/m2 MTX (red). No significant differences according to Gray’s test. (B) Comparison of the 5y-CIR of DS-ALL who initially received 0.5 g/m2 MTX in the first course and were eventually dose escalated in the course of consolidation with DS-ALL who received 0.5 g/m2 MTX throughout the whole consolidation therapy. No significant differences were found according to Gray’s test.
Figure 4.
Figure 4.
Methotrexate (MTX) plasma levels at 42 and 48 hours after the start of the first high dose MTX course and grade 3/4 toxicities in Down syndrome acute lymphoblastic leukemia according to MTX plasma levels. (A) and B) MTX plasma levels at 42 h (A) and 48 h (B) after start of the first HD-MTX administration. MTX dosage subgroups are indicated. *P≤0.05, Mann-Whitney U test. (C and D) Comparison of grade 3/4 toxicities in DS-ALL according to MTX plasma level quartiles at 42 hours (C) and 48 hours (D) after the start of the first high dose MTX (HD-MTX) administration. Q1: first/lowest quartile; Q4: fourth/highest quartile; respective MTX plasma concentration is given in μmol/L. *P≤0.05, Fisher’s exact test. The number on top of each bar represents the number of patients.

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