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Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer.
- Source :
-
Pediatric blood & cancer [Pediatr Blood Cancer] 2014 May; Vol. 61 (5), pp. 797-802. Date of Electronic Publication: 2014 Jan 03. - Publication Year :
- 2014
-
Abstract
- Background: Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMT(LA)) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMT(WT)) when treated with 6 MP maintenance therapy starting doses of 75 mg/m(2)/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m(2)/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol.<br />Procedure: We explored the pattern of SMN and relapse in the NOPHO ALL2000 protocol (n = 674) and NOPHO ALL92 protocol (n = 601) in relation to TPMT pheno- and/or genotype.<br />Results: The overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMT(LA) who experienced relapse or SMN, the risk of SMN versus leukemia relapse was significantly lower in the ALL2000 cohort for patients with a 6MP starting dose <75 mg/m(2)/day when compared to the patients in ALL92 (relapse (n = 11) and SMN (n = 0) in ALL2000 versus relapse (n = 5) and SMN (n = 4) in ALL92, P = 0.03). Furthermore, the 8-year cumulative incidence of relapse for patients with TPMT(LA) was significantly higher in the ALL2000 compared to the ALL92 cohort (19.7% (11.6-33.3%) vs. 6.7% (2.9-15.5%), P = 0.03).<br />Conclusion: This study indicates that reducing 6MP starting dose for patients with TPMT(LA) may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMT(WT).<br /> (© 2014 Wiley Periodicals, Inc.)
- Subjects :
- Adolescent
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Child
Child, Preschool
Cohort Studies
Cytogenetic Analysis
DNA, Neoplasm genetics
Dose-Response Relationship, Drug
Female
Follow-Up Studies
Genotype
Humans
Infant
Male
Mercaptopurine administration & dosage
Methotrexate administration & dosage
Methyltransferases genetics
Neoplasm Recurrence, Local diagnosis
Neoplasm Recurrence, Local drug therapy
Neoplasms, Second Primary diagnosis
Neoplasms, Second Primary drug therapy
Polymerase Chain Reaction
Precursor Cell Lymphoblastic Leukemia-Lymphoma complications
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Prognosis
Risk Factors
Antineoplastic Combined Chemotherapy Protocols adverse effects
Neoplasm Recurrence, Local etiology
Neoplasms, Second Primary etiology
Pharmacogenetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1545-5017
- Volume :
- 61
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Pediatric blood & cancer
- Publication Type :
- Academic Journal
- Accession number :
- 24395436
- Full Text :
- https://doi.org/10.1002/pbc.24921