Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia

Kjeld Schmiegelow; Olle Björk; Anders Glomstein; Göran Gustafsson; Niels Keiding; Jon Kristinsson; Anne Mäkipernaa; Susanne Rosthøj; Carol Szumlanski; Tine M Sørensen; Richard Weinshilboum

Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia

Kjeld Schmiegelow, Olle Björk, Anders Glomstein, Göran Gustafsson, Niels Keiding, Jon Kristinsson, Anne Mäkipernaa, Susanne Rosthøj, Carol Szumlanski, Tine M Sørensen, Richard Weinshilboum

85 Citations (Scopus)

Abstract

PURPOSE: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). RESULTS: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P =.002), and high average neutrophil counts during maintenance therapy (P =.0009), with a significant interaction between sex and randomization group (P =.0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P =.001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P <.0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P =.03; boys 19.3 v 18.0 U/mL, P =.04). CONCLUSION: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

Original language	English
Journal	Journal of Clinical Oncology
Volume	21
Issue number	7
Pages (from-to)	1332-9
Number of pages	7
ISSN	0732-183X
Publication status	Published - 2003

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Schmiegelow, K., Björk, O., Glomstein, A., Gustafsson, G., Keiding, N., Kristinsson, J., Mäkipernaa, A., Rosthøj, S., Szumlanski, C., Sørensen, T. M., & Weinshilboum, R. (2003). Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. Journal of Clinical Oncology, 21(7), 1332-9.

Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. / Schmiegelow, Kjeld; Björk, Olle; Glomstein, Anders et al.

In: Journal of Clinical Oncology, Vol. 21, No. 7, 2003, p. 1332-9.

Research output: Contribution to journal › Journal article › Research › peer-review

Schmiegelow, K, Björk, O, Glomstein, A, Gustafsson, G, Keiding, N, Kristinsson, J, Mäkipernaa, A, Rosthøj, S, Szumlanski, C, Sørensen, TM & Weinshilboum, R 2003, 'Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia', Journal of Clinical Oncology, vol. 21, no. 7, pp. 1332-9.

@article{a5fd8da09eaa11debc73000ea68e967b,

title = "Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia",

abstract = "PURPOSE: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). RESULTS: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P =.002), and high average neutrophil counts during maintenance therapy (P =.0009), with a significant interaction between sex and randomization group (P =.0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P =.001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P <.0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P =.03; boys 19.3 v 18.0 U/mL, P =.04). CONCLUSION: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.",

author = "Kjeld Schmiegelow and Olle Bj{\"o}rk and Anders Glomstein and G{\"o}ran Gustafsson and Niels Keiding and Jon Kristinsson and Anne M{\"a}kipernaa and Susanne Rosth{\o}j and Carol Szumlanski and S{\o}rensen, {Tine M} and Richard Weinshilboum",

note = "Keywords: 6-Mercaptopurine; Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Erythrocytes; Female; Humans; Infant; Leukocyte Count; Male; Methotrexate; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Sex Factors; Thioguanine",

year = "2003",

language = "English",

volume = "21",

pages = "1332--9",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "American Society of Clinical Oncology",

number = "7",

}

TY - JOUR

T1 - Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia

AU - Schmiegelow, Kjeld

AU - Björk, Olle

AU - Glomstein, Anders

AU - Gustafsson, Göran

AU - Keiding, Niels

AU - Kristinsson, Jon

AU - Mäkipernaa, Anne

AU - Rosthøj, Susanne

AU - Szumlanski, Carol

AU - Sørensen, Tine M

AU - Weinshilboum, Richard

N1 - Keywords: 6-Mercaptopurine; Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Erythrocytes; Female; Humans; Infant; Leukocyte Count; Male; Methotrexate; Neutrophils; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Sex Factors; Thioguanine

PY - 2003

Y1 - 2003

N2 - PURPOSE: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). RESULTS: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P =.002), and high average neutrophil counts during maintenance therapy (P =.0009), with a significant interaction between sex and randomization group (P =.0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P =.001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P <.0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P =.03; boys 19.3 v 18.0 U/mL, P =.04). CONCLUSION: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

AB - PURPOSE: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). RESULTS: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P =.00003), high WBC at diagnosis (P =.03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P =.002), and high average neutrophil counts during maintenance therapy (P =.0009), with a significant interaction between sex and randomization group (P =.0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P =.001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P <.0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P =.03; boys 19.3 v 18.0 U/mL, P =.04). CONCLUSION: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

M3 - Journal article

C2 - 12663723

SN - 0732-183X

VL - 21

SP - 1332

EP - 1339

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

IS - 7

ER -

Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia

Abstract

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