Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics

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 ALL97. TPMT heterozygotes had significantly more frequent cytopenias and therefor...

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Main Authors:	Lennard, Lynne, Cartwright, Cher S., Wade, Rachel, Vora, Ajay
Format:	Online
Language:	English
Published:	John Wiley and Sons Inc. 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737107/

id	pubmed-4737107
recordtype	oai_dc
spelling	pubmed-47371072016-02-11 Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics Lennard, Lynne Cartwright, Cher S. Wade, Rachel Vora, Ajay Paediatrics 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 ALL97. 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 TPMT1/3A variant allele (n = 99, 5‐year EFS 88%) was better than for both wild‐type TPMT1/1 (n = 1206, EFS 80%, P = 0·05) and TPMT1/3C 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 TPMT1/3C 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, TPMT1/3A heterozygotes had a better EFS than TPMT wild‐type patients. Thiopurine induced cytopenias were not detrimental to treatment outcome. John Wiley and Sons Inc. 2014-11-29 2015-04 /pmc/articles/PMC4737107/ /pubmed/25441457 http://dx.doi.org/10.1111/bjh.13240 Text en © 2014 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Lennard, Lynne Cartwright, Cher S. Wade, Rachel Vora, Ajay
spellingShingle	Lennard, Lynne Cartwright, Cher S. Wade, Rachel Vora, Ajay Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics
author_facet	Lennard, Lynne Cartwright, Cher S. Wade, Rachel Vora, Ajay
author_sort	Lennard, Lynne
title	Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics
title_short	Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics
title_full	Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics
title_fullStr	Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics
title_full_unstemmed	Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics
title_sort	thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics
description	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 ALL97. 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 TPMT1/3A variant allele (n = 99, 5‐year EFS 88%) was better than for both wild‐type TPMT1/1 (n = 1206, EFS 80%, P = 0·05) and TPMT1/3C 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 TPMT1/3C 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, TPMT1/3A heterozygotes had a better EFS than TPMT wild‐type patients. Thiopurine induced cytopenias were not detrimental to treatment outcome.
publisher	John Wiley and Sons Inc.
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737107/
_version_	1613532271634022400

Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics

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