Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia
| Autor: | Michael C.J. Quinn, Luciano Dalla-Pozza, Georgia Chenevix-Trench, Glenn M. Marshall, Draga Barbaric, Rosemary Sutton, Daniel Catchpoole, John A. Lawson, Pasquale M Barbaro, Frank Alvaro, Stuart MacGregor, Rishi S. Kotecha, Carly George, Tamas Revesz, Jodie E. Giles, Toby Trahair, Chelsea Mayoh, Francoise Mechinaud, Marion K. Mateos |
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| Rok vydání: | 2020 |
| Předmět: |
musculoskeletal diseases
Oncology medicine.medical_specialty Lymphoblastic Leukemia Immunology Genome-wide association study 03 medical and health sciences 0302 clinical medicine immune system diseases Risk Factors Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans heterocyclic compounds Cumulative incidence Risk factor skin and connective tissue diseases Child 1102 Cardiorespiratory Medicine and Haematology Injections Spinal 030304 developmental biology First episode 0303 health sciences business.industry Incidence (epidemiology) Neurotoxicity Australia Hematology Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Methotrexate 030220 oncology & carcinogenesis business medicine.drug Genome-Wide Association Study |
| Zdroj: | Haematologica. 107(3) |
| ISSN: | 1592-8721 |
| Popis: | Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28–4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P |
| Databáze: | OpenAIRE |
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