Zusammenfassung
Hintergrund: Methotrexat ist essenzieller Bestandteil der Behandlung der akuten lymphoblastischen
Leukämie (ALL). Aufgrund guten Langzeitüberlebens der Patienten gewinnen die Spätfolgen
der Behandlung wie BME (bone marrow edema) und AON (aseptic osteonecrosis) zunehmend
an Interesse. Ziel der Untersuchung war es, herauszufinden, ob ein Polymorphismus
des Methylentetrahydrofolsäure-Reduktase-(MTHFR)-Gens prädisponierend für die Entstehung
von BME und/oder AON ist. Zusätzlich wurde die kumulativ verabreichte Prednisondosis
dieser Patienten errechnet und in einer Matched-pairs-Analyse verglichen. Patienten und Methoden: 87 Patienten wurden retrospektiv auf einen MTHFR-Polymorphismus hin untersucht (48
männlich, 43 weiblich). Bei 14/87 Patienten waren ein BME und/oder eine AON diagnostiziert
worden (16 %). Ergebnisse: 42/73 Patienten ohne BME und/oder AON (43 männlich, 34 weiblich, mittleres Alter
5,3 Jahre) sowie 10/14 der Patienten mit BME/AON (5 männlich, 9 weiblich, mittleres
Alter 10,2 Jahre) wiesen einen MTHFR-Polymorphismus auf (p = 0.28). 14,3 % der Patienten
mit MTHFR-Polymorphismus aber ohne BME und/oder AON (6/42) und 70 % der Patienten
mit MTHFR-Polymorphismus und mit BME und/oder AON (7/10) waren über 10 Jahre bei ALL-Diagnose
(p = 0,002). Die mittlere kumulativ verabreichte Menge an Prednison betrug in einer
Matched-pairs-Analyse 98,0 mg/kg KG respektive 100,0 mg/kg KG. Schlussfolgerung: Das Alter der Patienten bei ALL-Diagnose scheint einen Risikofaktor für die Entstehung
von BME und/oder AON darzustellen, was auch durch voran gegangene Untersuchungen bestätigt
wird. Weiterhin ergibt sich der Hinweis auf einen Zusammenhang zwischen dem MTHFR-Polymorphismus
und der Entstehung von BME/AON. Dieser Aspekt ist wert, an einer größeren Fallzahl
unter Berücksichtigung der MTX-Pharmakokinetik und der Leukovorin-Rescue überprüft
zu werden.
Abstract
Backround: Methotrexate is an essential part of the treatment of acute lymphoblastic leukaemia
(ALL). Due to an increased survival of ALL patients, complications like BME (bone
marrow edema) and AON (aseptic osteonecrosis) have become a matter of increasing importance.
The aim of the study was to find out if a polymorphism of the methylenetetrahydrofolate
reductase (MTHFR) gene predisposes to the development of BME and/or AON. Furthermore
the cumulative prednisone equivalent dose per kilogram body weight was compared in
a matched-pairs analysis. Patients and methods: A retrospective analysis of the MTHFR polymorphism of 87 patients was performed (48
male, 43 female). 14/87 patients were diagnosed with BME and/or AON (16 %). Results: 42/73 patients without BME and/or AON (43 male, 34 female, median age 5.3 yrs) and
10/14 patients with BME/AON (5 male, 9 female, median age 10.2 years) presented with
a MTHFR-polymorphism (p = 0.28). 14,3 % of the patients with MTHFR-polymorphism but
without BME and/or AON (6/42) and 70 % of the patients with MTHFR-polymorphism and
with BME and/or AON (7/10) were over 10 years of age at ALL diagnosis (p = 0.002).
The mean cumulative prednisone equivalent dose per kilogram body weight was 98.0 mg,
compared with 100.0 mg in the matched pairs group. Conclusions: The age of the patients at diagnosis seems to be a risk factor for the development
of BME and/or AON as also seen in previous studies. If MTHFR polymorphism is an additional
risk factor it was not borne out by this study, possible due to the small number of
patients analyzed. This aspect is worth to be proven with a large group of patients
considering the MTX pharmacokinetic and leucovorine rescue.
Schlüsselwörter
MTHFR-Polymorphismus - Knochenmarksödem - Aseptische Osteonekrosen - Glukokortikoide
- ALL
Key words
MTHFR-polymorphism - bone marrow edema - aseptic osteonecrosis - glucocorticoids -
ALL
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Benedikt Bernbeck, MD
Department of Paediatric Oncology, Haematology and Immunology; Children’s Hospital,
Heinrich-Heine-University, Medical Center
Moorenstr. 5
40225 Düsseldorf, Germany
Phone: +49/211/811 9108
Fax: +49/211/811 6038
Email: bernbeck@med.uni-duesseldorf.de