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Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: Influence on cure rates and risk of second cancer
Author(s) -
Levinsen Mette,
Rotevatn Elisabeth Ørskov,
Rosthøj Susanne,
Nersting Jacob,
Abrahamsson Jonas,
Appell Malin Lindqvist,
Bergan Stein,
Bechensteen AnneGrete,
HarilaSaari Arja,
Heyman Mats,
Jonsson Olafur Gisli,
Maxild Jakob Bernhard Cohn,
Niemi Mikko,
Söderhäll Stefan,
Schmiegelow Kjeld
Publication year - 2014
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.24921
Subject(s) - thiopurine methyltransferase , medicine , cumulative incidence , oncology , cohort , dosing , pediatric oncology , pediatric cancer , neuroblastoma , incidence (geometry) , cancer , azathioprine , biology , genetics , optics , cell culture , physics , disease
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 6MP 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. 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. 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). 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 . Pediatr Blood Cancer 2014;61:797–802. © 2014 Wiley Periodicals, Inc.