Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia: Influence on Cure Rates and Risk of Second Cancer

• BackgroundPrevious studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMTLA) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMTWT) when treated with 6MP maintenance therapy starting doses of 75 mg/m2/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m2/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol.ProcedureWe 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.ResultsThe overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMTLA 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/m2/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 TPMTLA 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).ConclusionThis study indicates that reducing 6MP starting dose for patients with TPMTLA may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMTWT.

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ALL; late effects of cancer treatment; outcomes research; therapy

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