Dose Escalation of Imatinib in Chronic-Phase CML Patients
Dose Escalation of Imatinib in Chronic-Phase CML Patients
Suboptimal response or treatment failure to standard-dose imatinib are relevant problems in chronic-phase chronic myeloid leukemia patients. Insufficient adherence is one of the main causes of insufficient response but biological reasons also have to be considered. Various mechanisms of resistance have been described in the past, some of them mediating absolute resistance and others, relative resistance, to imatinib. The latter can be overcome by dose intensification of imatinib. However, the availability of second-generation tyrosine kinase inhibitors means these patients can be switched to these novel agents. Thus, which strategy is most appropriate for the individual patient with insufficient response to standard-dose imatinib remains elusive. Moreover, it remains unclear whether dose intensification of imatinib in the first-line setting might allow a more rapid and deeper response rate. This article will summarize data on imatinib dose intensification and will make recommendations about which patients imatinib dose intensification is most appropriate for.
Imatinib mesylate (Imatinib, Glivec®) is currently approved and recommended for first-line treatment of chronic myeloid leukemia (CML) in chronic phase (CML-CP). Recent data on nilotinib (Tasigna®) and dasatinib (Sprycel®) in this setting suggest that in the near future this standard will eventually be displaced by the more potent second-generation tyrosine kinase inhibitors (TKIs). However, optimization of dosing schedules of TKIs is a reasonable approach to achieve the best possible therapeutic response, especially when patients do not optimally respond to standard-dose therapy. Up-front dose intensification might induce a more rapid reduction of the leukemic burden, which we already know from the imatinib studies is linked to an improved long-term outcome. As an example, patients treated within the International Randomized IFN versus STI571 (IRIS) trial showed a considerable inter-individual variability with respect to the time to complete cytogenetic remission (CCyR). None of the patients achieving a CCyR and major molecular remission (MMR) after 18 months of therapy had progressed during the follow-up phase, which impressively underscores the relevance of an early and a deep remission (CCyR at 12 months, MMR at 18 months). It also emphasizes the need for frequent and early molecular monitoring to select patients not achieving these treatment goals, thus identifying candidates for treatment intensification (e.g., by dose intensification or by switch to an alternative TKI).
Thus, whether the approved dosing schedules for TKI are optimal in terms of achieving a maximum therapeutic response remains a critical issue. Recent data from conventional chemotherapeutics in acute myeloid leukemia underline the importance of dose-optimization trials, even when using conventional chemotherapeutics, as dose intensification of daunorubicin from 45mg/m to 90mg/m in younger patients when combined with standard-dose arabinosylcytosine improves the rate of complete remission and the duration of overall survival, while preserving tolerability of the combination therapy.
At the beginning of the imatinib era, the optimal dosing schedule was not extensively studied, as the maximum tolerated dose was not achieved in the initial Phase I study. In the relatively small dose-finding study (83 CML-CP patients), hematologic and cytogenetic response rates were not different in patients receiving doses above 300 mg per day. As a consequence, the dose of 400 mg was used to test the efficacy of the drug in the subsequent Phase II studies. Obviously, the outstanding clinical activity of standard-dose imatinib caused a relatively long delay until further dose intensification schedules were systematically tested in patients not optimally responding to the standard dosing schedule. However, the option of a dose increase to 400 mg twice daily in this Phase II study already suggested a potential role for a dose increase with the aim to optimize response rates in patients not achieving a sufficient response. The decision to use 400 mg per day for the initial clinical trials was further underscored by pharmacokinetic data showing that upon oral administration of imatinib, a mean steady state concentration of 2.3 µg/ml (4.6 µM) is reached, which far exceeds the concentration required to inhibit cellular phosphorylation by BCR-ABL (0.25 µM for 50% inhibition) and causes cell death of BCR-ABL positive cell lines in vitro. However, in the clinical setting, a considerable number of patients do not sufficiently profit from standard-dose (SD) imatinib in the first-line setting, which is, at least in part, due to the appearance of point mutations (the most important mechanisms of relative and absolute imatinib resistance are shown in Figure 1). These patients (i.e., those with suboptimal response or failure according the second European Leukemia Net [ELN] recommendations) might be candidates for dose intensification to achieve an optimal response. In clinical practice, approximately 50% of resistant patients develop point mutations within the BCR-ABL molecule and some of these mutations are sensitive to an imatinib dose increase (e.g., M351T, V299L, L384M, G398R, M244V, M244I, Q252H, E355G, L387M), while others are not (e.g., G250E, E255K, E255V, T315I, F486S, Y253H, Y253F, F317L, F311L). In the latter, a switch to a second-generation TKI, such as dasatinib or nilotinib, should be performed. In the case of an T315I mutation, none of the TKIs that have been approved so far are effective, and those patients should be treated within clinical trials, testing T315I-targeting drugs (i.e., ponatinib/AP24534) and the option of a stem cell transplantation should be carefully evaluated. In this article, clinical data dealing with dose optimization in CML-CP patients will be discussed and critically evaluated to finally provide an expert recommendation for cases in which dose escalation of imatinib might be of clinical benefit.
(Enlarge Image)
Figure 1.
Reasons for resistance or refractoriness to imatinib.
CML: Chronic myeloid leukemia.
There are two different scenarios in which dose escalation has been tested. First, in patients not achieving an optimal response while on standard-dose imatinib or in TKI treatment-naive patients with de novo CML (early CP), as well as in patients having received prior non-TKI-based therapies (including hydroxyurea, IFN-α and busulfan).
Abstract and Introduction
Abstract
Suboptimal response or treatment failure to standard-dose imatinib are relevant problems in chronic-phase chronic myeloid leukemia patients. Insufficient adherence is one of the main causes of insufficient response but biological reasons also have to be considered. Various mechanisms of resistance have been described in the past, some of them mediating absolute resistance and others, relative resistance, to imatinib. The latter can be overcome by dose intensification of imatinib. However, the availability of second-generation tyrosine kinase inhibitors means these patients can be switched to these novel agents. Thus, which strategy is most appropriate for the individual patient with insufficient response to standard-dose imatinib remains elusive. Moreover, it remains unclear whether dose intensification of imatinib in the first-line setting might allow a more rapid and deeper response rate. This article will summarize data on imatinib dose intensification and will make recommendations about which patients imatinib dose intensification is most appropriate for.
Introduction
Imatinib mesylate (Imatinib, Glivec®) is currently approved and recommended for first-line treatment of chronic myeloid leukemia (CML) in chronic phase (CML-CP). Recent data on nilotinib (Tasigna®) and dasatinib (Sprycel®) in this setting suggest that in the near future this standard will eventually be displaced by the more potent second-generation tyrosine kinase inhibitors (TKIs). However, optimization of dosing schedules of TKIs is a reasonable approach to achieve the best possible therapeutic response, especially when patients do not optimally respond to standard-dose therapy. Up-front dose intensification might induce a more rapid reduction of the leukemic burden, which we already know from the imatinib studies is linked to an improved long-term outcome. As an example, patients treated within the International Randomized IFN versus STI571 (IRIS) trial showed a considerable inter-individual variability with respect to the time to complete cytogenetic remission (CCyR). None of the patients achieving a CCyR and major molecular remission (MMR) after 18 months of therapy had progressed during the follow-up phase, which impressively underscores the relevance of an early and a deep remission (CCyR at 12 months, MMR at 18 months). It also emphasizes the need for frequent and early molecular monitoring to select patients not achieving these treatment goals, thus identifying candidates for treatment intensification (e.g., by dose intensification or by switch to an alternative TKI).
Thus, whether the approved dosing schedules for TKI are optimal in terms of achieving a maximum therapeutic response remains a critical issue. Recent data from conventional chemotherapeutics in acute myeloid leukemia underline the importance of dose-optimization trials, even when using conventional chemotherapeutics, as dose intensification of daunorubicin from 45mg/m to 90mg/m in younger patients when combined with standard-dose arabinosylcytosine improves the rate of complete remission and the duration of overall survival, while preserving tolerability of the combination therapy.
At the beginning of the imatinib era, the optimal dosing schedule was not extensively studied, as the maximum tolerated dose was not achieved in the initial Phase I study. In the relatively small dose-finding study (83 CML-CP patients), hematologic and cytogenetic response rates were not different in patients receiving doses above 300 mg per day. As a consequence, the dose of 400 mg was used to test the efficacy of the drug in the subsequent Phase II studies. Obviously, the outstanding clinical activity of standard-dose imatinib caused a relatively long delay until further dose intensification schedules were systematically tested in patients not optimally responding to the standard dosing schedule. However, the option of a dose increase to 400 mg twice daily in this Phase II study already suggested a potential role for a dose increase with the aim to optimize response rates in patients not achieving a sufficient response. The decision to use 400 mg per day for the initial clinical trials was further underscored by pharmacokinetic data showing that upon oral administration of imatinib, a mean steady state concentration of 2.3 µg/ml (4.6 µM) is reached, which far exceeds the concentration required to inhibit cellular phosphorylation by BCR-ABL (0.25 µM for 50% inhibition) and causes cell death of BCR-ABL positive cell lines in vitro. However, in the clinical setting, a considerable number of patients do not sufficiently profit from standard-dose (SD) imatinib in the first-line setting, which is, at least in part, due to the appearance of point mutations (the most important mechanisms of relative and absolute imatinib resistance are shown in Figure 1). These patients (i.e., those with suboptimal response or failure according the second European Leukemia Net [ELN] recommendations) might be candidates for dose intensification to achieve an optimal response. In clinical practice, approximately 50% of resistant patients develop point mutations within the BCR-ABL molecule and some of these mutations are sensitive to an imatinib dose increase (e.g., M351T, V299L, L384M, G398R, M244V, M244I, Q252H, E355G, L387M), while others are not (e.g., G250E, E255K, E255V, T315I, F486S, Y253H, Y253F, F317L, F311L). In the latter, a switch to a second-generation TKI, such as dasatinib or nilotinib, should be performed. In the case of an T315I mutation, none of the TKIs that have been approved so far are effective, and those patients should be treated within clinical trials, testing T315I-targeting drugs (i.e., ponatinib/AP24534) and the option of a stem cell transplantation should be carefully evaluated. In this article, clinical data dealing with dose optimization in CML-CP patients will be discussed and critically evaluated to finally provide an expert recommendation for cases in which dose escalation of imatinib might be of clinical benefit.
(Enlarge Image)
Figure 1.
Reasons for resistance or refractoriness to imatinib.
CML: Chronic myeloid leukemia.
There are two different scenarios in which dose escalation has been tested. First, in patients not achieving an optimal response while on standard-dose imatinib or in TKI treatment-naive patients with de novo CML (early CP), as well as in patients having received prior non-TKI-based therapies (including hydroxyurea, IFN-α and busulfan).