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Chronic Myeloproliferative Neoplasias

Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients

Leukemia volume 27, pages 1520–1526 (2013)Cite this article

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Abstract

Chronic myeloid leukemia (CML) stem cells appear resistant to tyrosine kinase inhibitors (TKIs) in vitro, but their impact and drug sensitivity in vivo has not been systematically assessed. We prospectively analyzed the proportion of Philadelphia chromosome-positive leukemic stem cells (LSCs, Ph+CD34+CD38−) and progenitor cells (LPCs, Ph+CD34+CD38+) from 46 newly diagnosed CML patients both at the diagnosis and during imatinib or dasatinib therapy (ClinicalTrials.gov NCT00852566). At diagnosis, the proportion of LSCs varied markedly (1–100%) between individual patients with a significantly lower median value as compared with LPCs (79% vs 96%, respectively, P=0.0001). The LSC burden correlated with leukocyte count, spleen size, hemoglobin and blast percentage. A low initial LSC percentage was associated with less therapy-related hematological toxicity and superior cytogenetic and molecular responses. After initiation of TKI therapy, the LPCs and LSCs rapidly decreased in both therapy groups, but at 3 months time point the median LPC level was significantly lower in dasatinib group compared with imatinib patients (0.05% vs 0.68%, P=0.032). These data detail for the first time the prognostic significance of the LSC burden at diagnosis and show that in contrast to in vitro data, TKI therapy rapidly eradicates the majority of LSCs in patients.

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Acknowledgements

We thank Sven Carlsen, Berit Bjelkåsen and Elena Ivanova (Department of Applied Clinical Research, NTNU) for data management and development of the web-based CRF, Karin Tulluan (NTNU) for the follow-up of serious adverse events, Frøydis Rikardsen (the Hospital Pharmacy in Trondheim) for the co-operation, and patients, study nurses and contributing investigators (Martin Höglund (Uppsala University Hospital, Uppsala, Sweden), Carin Lassen (Skåne University Hospital, Lund, Sweden), Kirsi Latvala (Helsinki University Central Hospital, Helsinki, Finland), Waleed Majeed (Stavanger University hospital, Stavanger, Norway), Claes Malm (Linköping University hospital, Linköping, Sweden), Ali Mosfegh (Karolinska University Hospital, Stockholm, Sweden), Lotta Ohm (Karolinska University Hospital, Stockholm, Sweden), Kari Remes (Turku University Central Hospital, Turku, Finland), Jesper Stentoft (Århus University Hospital, Århus, Denmark), Merja Suominen (Kanta-Häme Central Hospital, Hämeenlinna, Finland), Ole Weiss Bjerrum (Copenhagen University Hospital, Copenhagen, Denmark)) for their participation in this trial. This study was supported by research funding from Bristol-Myers Squibb to Nordic CML study group. BD Biosciences and Miltenyi Biotec provided study material. The trial is also listed in the European LeukemiaNet (ELN) Trial Registry (ELTR).

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Authors and Affiliations

  1. Department of Medicine, Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    S Mustjoki, S Hernesniemi, P Koskenvesa & K Porkka

  2. Skåne University Hospital, Lund, Sweden

    J Richter

  3. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

    G Barbany & S Thunberg

  4. Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden

    H Ehrencrona, T Fioretos & T Olofsson

  5. Department of Hematology, Oslo University Hospital, Oslo, Norway

    T Gedde-Dahl & I Dybedal

  6. Department of Internal Medicine, Hematology Section, Haukeland University Hospital, Bergen, Norway

    B T Gjertsen

  7. Department of Genetics, Haukeland University Hospital, Bergen, Norway

    R Hovland

  8. Department of Oncology, The Norwegian Radium Hospital, Oslo, Norway

    D Josefsen

  9. Department of Hematology, Umeå University Hospital, Umeå, Sweden

    B Markevärn

  10. Department of Hematology, Uppsala University Hospital, Uppsala, Sweden

    U Olsson-Strömberg & B Simonsson

  11. Department of Clinical Chemistry, Institute of Diagnostics, Oulu University Hospital, Oulu, Finland

    K Rapakko

  12. Department of Hematology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden

    L Stenke

  13. Department of Hematology, St Olavs Hospital, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

    H Hjorth-Hansen

  14. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

    H Hjorth-Hansen

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for the Nordic CML Study Group (NCMLSG)

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Correspondence to S Mustjoki.

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Competing interests

SM, JR, TF, BS, KP and HH-H have received honoraria and research funding from Novartis and Bristol-Myers Squibb. HE, TGD and RH have received honoraria and travel grants from Novartis and Bristol-Myers Squibb. DJ has received honoraria and travel grants from Novartis and Genzyme. ID has received honoraria from Novartis. The remaining authors declare no conflict of interest.

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Mustjoki, S., Richter, J., Barbany, G. et al. Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients. Leukemia 27, 1520–1526 (2013). https://doi.org/10.1038/leu.2013.19

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