Page 171 - Haematologica April 2020

Acute Lymphoblastic Leukemia
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,1 Kirsten Kaupat-Bleckmann,1 Anja Mörickel,1 Julia Altenl,1 Denis M. Schewel,1 Martin Stanullal,2 Martin Zimmermann,2
Martin Schrappe1 and Gunnar Cario1
1Department of Pediatrics I, University Hospital Schleswig-Holstein, Kiel and 2Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
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 ana- lyzed 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 toxic- ities 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 toxi- cities 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 tox- icities without increasing the risk of relapse. (ClinicalTrials.gov identifier: NTC00430118, NCT01117441).
Introduction
Children and adolescents with Down syndrome (DS) DS have an approximately 10-fold higher risk of acquiring acute lymphoblastic leukemia (ALL)1 and have shown an inferior outcome compared to children with NDS-ALL.2-5 The worse out- come for DS-ALL has been attributed to a higher risk of relapse as well as higher levels of chemotherapy-associated toxicities and treatment-related mortality.2,6-8 Severe toxicities may eventually lead to chemotherapy dose reduction which in turn might increase the risk of relapse.2,5,6
Methotrexate (MTX is a folate antagonist that interferes with the de novo synthe- sis of nucleotides in proliferating cells and plays a crucial role in the treatment of pediatric ALL in which MTX is administered in high doses (HD-MTX, ≥ 0.5 g/m2 per intravenous [i.v.] application).9 Many patients with DS-ALL suffer from severe side effects after receiving HD-MTX. Common MTX-associated side effects in DS- ALL are severe mucositis and stomatitis, infections, bone marrow suppression, hepato-, nephro- and neurotoxicity.2,6-8
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):1013-1020
In order to extend our knowledge on MTX-associated toxicities in DS-ALL, we
Correspondence:
GUNNAR CARIO
gunnar.cario@uksh.de
Received: April 15, 2019. Accepted: July 24, 2019. Pre-published: August 1, 2019.
doi:10.3324/haematol.2019.224774
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/1013
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