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Uncovering early, lineage-dependent effects of TPMT genotype in adult acute lymphoblastic leukemia by minimal residual disease

Leukemia volume 27, pages 989–992 (2013)Cite this article

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Heterozygous thiopurine methyltransferase (TPMT)-genotype conferring lower TPMT activity has been shown to be a favorable prognostic factor in acute lymphoblastic leukemia (ALL) presumably due to its modulation of mercaptopurine dose intensity.1, 2 We investigated whether this association was also measurable by minimal residual disease (MRD) in adult ALL patients as has been suggested for childhood ALL.3 Over 20 allelic variants with single nucleotide polymorphisms (SNPs) of the TPMT gene have been described, leading to a trimodal distribution of TPMT activity4 with heterozygous individuals (6–11% of caucasians) having markedly reduced and homozygous individuals (0.2–0.6% of caucasians) having virtually undectable TPMT activity.3, 5 TPMT-genotype is considered to be one of the few pharmacogenomic tests that has successfully made the transition from bench to bedside and so far is the only example of pharmacogenetic-based drug dosing in ALL.6 Nevertheless, discrepant results between studies that are discussed later in this manuscript indicate the need of more detailed information regarding the role of TPMT-genotype in relation to specific therapeutic elements, some of which may be provided by MRD analysis.

TPMT-genotype and MRD were determined in 494 patients with standard risk adult ALL treated within the GMALL 06/99 and 07/03 trials. They were therefore devoid of either clinical (leukocyte count >30,000/μl at presentation in precursor B-ALL, no complete remission (CR) after induction phase I), immunologic (pro-B, pre-T and mature T-ALL), or cytogenetic risk factors (t(9;22) and translocations involving the MLL-gene)). MRD-based risk stratification was part of the study protocol and MRD was thus measured routinely during therapy. Conversely, TPMT-genotype did not influence the risk stratification and was determined from leftover material. The patients’ informed consent was obtained at the time of entry into the trials according to the declaration of Helsinki. GMALL studies 06/99 and 07/03 were approved by the institutional review board of the University of Frankfurt and are registered at clinicaltrials.gov (NCT00199056, NCT00198991). Baseline characteristics of the patients were not different according to TPMT-genotype (see Table 1).

Table 1 Patient characteristics according to TPMT-genotype with 95% CI for difference between proportions or means
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Figure 1

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Acknowledgements

We thank all centers of the GMALL study group who have included patients in the studies reported on in this manuscript. This work was supported by Deutsche Krebshilfe Grant (Grant no. 70-2657-Ho2) (DH) and Wilhelm-Sander-Stiftung Grant (Grant no. 2001.074.2) (MB).

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  1. T Raff, M Kaiser and N Gökbuget: These authors contributed equally to this work.

Authors and Affiliations

  1. 2nd Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

    T Raff, M Kaiser, S Lüschen, M Ritgen, H Trautmann, M Kneba & M Brüggemann

  2. Department of Medicine II, Goethe University Hospital, Frankfurt, Germany

    N Gökbuget & R Reutzel

  3. Institut für Hämatopathologie, Kiel, Germany

    S Lüschen

  4. Onkologikum am Museumsufer, Frankfurt, Germany

    D Hoelzer

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Correspondence to T Raff.

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Raff, T., Kaiser, M., Gökbuget, N. et al. Uncovering early, lineage-dependent effects of TPMT genotype in adult acute lymphoblastic leukemia by minimal residual disease. Leukemia 27, 989–992 (2013). https://doi.org/10.1038/leu.2012.275

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