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Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics
Author(s) -
Lennard Lynne,
Cartwright Cher S.,
Wade Rachel,
Vora Ajay
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13240
Subject(s) - thiopurine methyltransferase , medicine , pharmacogenetics , oncology , genotype , azathioprine , biology , genetics , disease , gene
Summary The impact of thiopurine methyltransferase ( TPMT ) genotype on thiopurine dose intensity, myelosuppression and treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia ( ALL ) trial ALL 97. TPMT heterozygotes had significantly more frequent cytopenias and therefore required dose adjustments below target levels significantly more often than TPMT wild‐type patients although the average dose range was similar for both genotypes. Event‐free survival ( EFS ) for patients heterozygous for the more common TPMT *1/*3A variant allele ( n = 99, 5‐year EFS 88%) was better than for both wild‐type TPMT *1/*1 ( n = 1206, EFS 80%, P = 0·05) and TPMT *1/*3C patients ( n = 17, EFS 53%, P = 0·002); outcomes supported by a multivariate Cox regression analysis. Poor compliance without subsequent clinician intervention was associated with a worse EFS ( P = 0·02) and such non‐compliance may have contributed to the poorer outcome for TPMT *1/*3C patients. Patients prescribed escalated doses had a worse EFS ( P = 0·04), but there was no difference in EFS by dose intensity or duration of cytopenias. In contrast to reports from some USA and Nordic trials, TPMT heterozygosity was not associated with a higher rate of second cancers. In conclusion, TPMT *1/*3A heterozygotes had a better EFS than TPMT wild‐type patients. Thiopurine induced cytopenias were not detrimental to treatment outcome.