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A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response

Leukemia volume 23, pages 1199–1201 (2009)Cite this article

The treatment of chronic myeloid leukaemia (CML) with imatinib mesylate (IM, Glivec) results in complete cytogenetic response (CCyR) for most patients in the chronic phase of the disease. For the majority of patients in CCyR, persisting low-level disease is demonstrable by sensitive real-time quantitative PCR (RQ-PCR) for BCR-ABL in peripheral blood.1 We have shown an IM-resistant, quiescent (G0) population of BCR-ABL+ leukaemic stem cells in primary CD34+-selected populations from CML patients at diagnosis that persist following IM treatment in vivo.2 In contrast, BCR-ABL+ CD34+ cells that are actively cycling are killed by IM in-vitro. Furthermore, IM seems to exert an antiproliferative effect on the G0 population leading to accumulation of drug-resistant, quiescent malignant progenitor cells.2 It is possible that this population is responsible for persistently positive BCR-ABL RQ-PCR and also for the rapid relapse observed in patients in CCyR who cease to undergo IM therapy.3 To eradicate this population, we hypothesized that a valid strategy might involve a pulsed IM (pIM) schedule plus recombinant granulocyte-colony stimulating factor (G-CSF) to push the clonal G0 population into cell cycle and restore IM sensitivity. In light of these data, we developed a pilot, randomized, three-arm phase II study to determine the safety and toxicity of pIM with or without G-CSF in patients with chronic phase CML who had achieved CCyR (EudraCT 2004-000179-33).

Chronic phase CML patients ⩾18 years of age, already established on IM and having achieved a CCyR (but not a complete molecular response), were eligible for this study. RQ-PCR was performed according to a standard protocol at the Adult Leukaemia Unit, Hammersmith Hospital.4 At trial entry, patients received IM according to their established dose level (400 mg for all patients). After informed consent was obtained, patients were randomized to receive either Lenograstim (rHu-G-CSF, 263 μg, provided by Chugai Pharma UK and France) on days 24, 26 and 28 of each cycle in combination with pIM (pIM-G) therapy, pIM therapy alone or continuous IM (cIM) therapy alone (IM given at earlier dose level). For the group receiving pIM and pIM-G, IM was continued for days 1–21, and stopped until day 28 of each 4-week cycle. G-CSF was given every 48 h during the IM-free week as preclinical studies had shown a more dramatic effect with pulsed G-CSF compared with continuous G-CSF.5 The 7-day break in IM therapy was considered long enough for drug and metabolite washout to allow reversal of the antiproliferative effects of IM on leukaemic stem cells, but short enough to be safe from the point-of-view of disease control. Treatment was administered in 4-week cycles up until a maximum of 12 cycles. Monthly BCR-ABL RQ-PCR was performed. The primary end points were: (1) safety of the combination of rHu-G-CSF plus IM. For the purposes of the trial, this was defined as ⩾2 patients in either of the two experimental arms experiencing severe adverse events or Grade 3/4 toxicity (according to National Cancer Institute (NCI) toxicity criteria) attributable to the study treatment, (2) safety of IM interruption, that is, no apparent loss of molecular, CCyR or complete haematological response above that seen in the control arm (proportion of patients progressing). The secondary end point was molecular response to IM interruption +/− G-CSF.

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References

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Acknowledgements

This research was supported by the Leukaemia Research Fund CTAP (UK), Chugai Pharmaceutical Co. Ltd, Chugai Pharma, France and Novartis Pharmaceuticals (UK). We are grateful to Lindsay Mitchell and Karen Stewart for their help with recruitment and assessment of patients. We thank the ‘Délégation à la recherche clinique des Hospices Civils de Lyon’ for their support in setting up this trial in France and Elodie Gadolet, CRA, for her help in collecting the data for the French patients. Drs Steve O'Brien, Heather Jorgensen and Alex McMahon assisted in reviewing the data.

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Authors and Affiliations

  1. Department of Haematology, Beatson West of Scotland Cancer Centre, Glasgow, UK

    M W Drummond

  2. Section of Experimental Haematology, University of Glasgow, Glasgow, UK

    N Heaney, G Wilson, L McLintock & T L Holyoake

  3. Department of Haematology, Hammersmith Hospital, London, UK

    J Kaeda

  4. Haematology Department, Hôpital Edouard Herriot, Lyon, France

    F E Nicolini

  5. Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK

    R E Clark

  6. Department of Haematology, Western General Hospital, Edinburgh, UK

    P Shepherd

  7. Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, UK

    J Tighe

  8. Institute of Medical Veterinary Science, University of Adelaide, Adelaide, Australia. E-mail: mark.drummond@ggc.scot.nhs.uk,

    T Hughes

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  1. M W Drummond
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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Drummond, M., Heaney, N., Kaeda, J. et al. A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response. Leukemia 23, 1199–1201 (2009). https://doi.org/10.1038/leu.2009.43

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