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Imatinib dose escalation for chronic phase–chronic myelogenous leukaemia patients in primary suboptimal response to imatinib 400 mg daily standard therapy

Leukemia volume 23, pages 1193–1196 (2009)Cite this article

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Imatinib mesylate (IM) at 400 mg daily has now become the standard of care for newly diagnosed Philadelphia-positive (Ph+) chronic phase–chronic myelogenous leukaemia (CP-CML), and a vast majority of patients show optimal responses translating into high rates of long-term survival. Despite these unprecedented results, up to 23% of patients are reported to discontinue IM treatment, because of an insufficient therapeutic effect.1 Although a lot of progress has been made for patients showing IM resistance, there is no consensus regarding the management of patients with suboptimal responses. Current options in this setting include continuation of IM at the initial dose, dose escalation of the drug or enrolment into investigational trials. In this study, we retrospectively analyzed the impact of IM dose escalation in 23 newly diagnosed CP-CML patients treated with first-line IM, which showed cytogenetic or primary molecular suboptimal responses as defined by Baccarani et al.2 It is not clear to date whether these patients need to be considered as primary-resistant to IM or solely insufficient responders for pharmacological reasons, excluding non-compliance.

In primary suboptimal molecular responders (n=13), the dose of IM was increased after a median duration of exposure to initial IM 400 of 27 months (21–58) (Table 1). The median duration of IM treatment after dose escalation of the drug was 24 months (5–51). No spontaneous decline in the leukaemic burden had occurred within 12 months before IM dose escalation (not shown). Among 8/13 patients with mutational analysis, only one harboured a BCR–ABL mutation (M244V). At the time of IM dose escalation, monitoring of the residual disease showed a median BCR–ABL % (IS) ratio of 0.784 (0.25–3.16) (Figure 1c). A significant decrease in BCR–ABL transcripts occurred during the following 6 months, with a median BCR–ABL % (IS) at 6 months of 0.243 (0.02–1.2), but not at later time points (Figure 1c). Intensification of IM therapy led to a MMR on at least once in 5/13 patients (38%) after a median duration of high-dose IM treatment of 11 months (3–25) (Figure 1b). MMR remained stable in four patients over a median observation time of 18 months (7–26). The patient harbouring an M244V mutation prior to dose escalation of IM showed a molecular response lightly fluctuating between major and less than major over a period of 23 months. Comparing primary suboptimal molecular responders reaching MMR and those failing to do so did not reveal significant differences in terms of demography (except for age), disease characteristics, duration of initial and high-dose IM treatment and IM dose issue (data not shown). There was only a trend toward higher BCR–ABL transcripts levels at dose escalation of IM in patients who did not reach MMR. The emergence of a BCR–ABL kinase domain mutation was a rare event, which was thereby not likely to account for the differential effect of dose escalation on the residual disease among patients. Lastly, dose escalation of IM in patients who failed to obtain MMR increased trough drug levels above the so-called therapeutic threshold of 1000 ng/ml,6 with median concentrations before and after dose increase of 451 (325–1940) and 1422 ng/ml (988–2219), respectively (P=0.012) (Table 1). Whether this threshold is satisfactory in all patients remains questionable. Another explanation may relate to the differential functional activity of OCT-1 among primary suboptimal molecular responders. White et al.8 indeed found that in patients with insufficient molecular responses, the impact of IM dose escalation on the residual leukaemic burden was dependent on OCT-1 activity: IM dose escalation had no effect in high OCT-1 activity patients ,whereas patients with low OCT-1 activity achieved satisfactory molecular responses. Thus, we could hypothesize that primary suboptimal molecular responders to IM 400 might represent a heterogeneous group of patients: some might respond well to IM dose-increase because of insufficient plasmatic and/or intracellular IM levels, whereas the majority might show a more intrinsic resistance of the residual leukaemic burden, which is likely to benefit from different therapeutic strategies. These last statements rely on a small cohort of patients and our hypothesis should be confirmed in a randomized trial.

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Authors and Affiliations

  1. Service des Maladies du Sang et Unité de Thérapie Cellulaire, Hôpital Saint-Louis, AP-HP, Paris, France

    D Rea

  2. FI-LMC group (France Inter Groupe des Leucémies myéloïdes chroniques), Service d’Oncologie Hématologique et de Thérapie Cellulaire, CHU la Milétrie, Poitiers, France

    D Rea, G Etienne, S Corm, P Cony-Makhoul, M Gardembas, L Legros, V Dubruille, S Hayette, F-X Mahon, J-M Cayuela & F E Nicolini

  3. Service d’Hématologie, Institut Bergonié, Bordeaux, France

    G Etienne & F-X Mahon

  4. Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France

    S Corm

  5. Service d’Hématologie, CH d’Annecy, Pringy, France

    P Cony-Makhoul

  6. Service des Maladies du Sang, CHU, Angers, France

    M Gardembas

  7. Hématologie Clinique, Hôpital de L’Archet, Nice, France

    L Legros

  8. Service d’Hématologie, CHU Hôtel Dieu, Nantes, France

    V Dubruille

  9. Laboratoire de Biologie Moléculaire, CH Lyon Sud, Pierre-Bénite, France

    S Hayette

  10. Laboratoire d’Hématologie, Hôpital Pellegrin, Bordeaux, France

    F-X Mahon

  11. Laboratoire Central d’Hématologie, Hôpital Saint-Louis, Paris, France

    J-M Cayuela

  12. Service d’Hématologie, Hôpital Edouard Herriot, Lyon, France

    F E Nicolini

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Correspondence to D Rea.

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Rea, D., Etienne, G., Corm, S. et al. Imatinib dose escalation for chronic phase–chronic myelogenous leukaemia patients in primary suboptimal response to imatinib 400 mg daily standard therapy. Leukemia 23, 1193–1196 (2009). https://doi.org/10.1038/leu.2009.32

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