AraC-based pharmacotherapy of chronic myeloid leukaemia

In interferon-α (IFN) treated chronic phase chronic myeloid leukaemia (CML) patients, survival depends on individual risk profile and achievement of a complete haematological response (CHR) and a major cytogenetic response (MCR) (< 35% Philadelphia-chromosome-positive metaphases). The highest cytogenetic response rates have been achieved with the combination of IFN and low-dose sc. AraC (10 mg daily to 10 - 20 mg/m² for 10 - 14 days/month). Whether the higher cytogenetic response rates are also associated with a significant improvement of survival still remains controversial. The different results obtained from large randomised and observational trials may be due to the numbers of patients enrolled, distribution of risk profiles and the treatment schedule, which is influenced greatly by the haematological and gastrointestinal toxicity of AraC. An oral formulation (YNK01), which is lipophilic and resistant to deamination, is currently under investigation. Clinically, it has similar activity, but toxicity leads to discontinuation of treatment in a considerable proportion of patients. The clinical benefits may therefore be outweighed by the dose-limiting toxicity for both application forms. Combinations with other drugs, e.g., STI571 or homoharringtonine, have shown promising early results in vitro and in vivo.     

Imatinib mesylate in the treatment of chronic myeloid leukaemia

Imatinib mesylate (Gleevec, Glivec), formerly STI571; Novartis Pharmaceuticals) is an inhibitor of the Bcr-abl tyrosine kinase that is central to the pathogenesis of chronic myeloid leukaemia (CML). The remarkable results of imatinib mesylate in clinical trials have rapidly and profoundly changed the management of patients with CML. This article will review the development of this molecularly targeted agent. The clinical trials with imatinib mesylate will be summarised along with the pharmacology of this agent. Despite the impressive responses seen in chronic-phase patients, numerous questions remain. For example, how durable will responses to imatinib mesylate be and is it necessary or possible to improve upon these results? Ongoing efforts to address these issues will be discussed.     

Targeting survival pathways in chronic myeloid leukaemia stem cells

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a fusion oncogene BCR-ABL, which encodes a protein with constitutive TK activity. The implementation of tyrosine kinase inhibitors (TKIs) marked a major advance in CML therapy; however, there are problems with current treatment. For example, relapse occurs when these drugs are discontinued in the majority of patients who have achieved a complete molecular response on TKI and these agents are less effective in patients with mutations in the BCR-ABL kinase domain. Importantly, TKI can effectively target proliferating mature cells, but do not eradicate quiescent leukaemic stem cells (LSCs), therefore allowing disease persistence despite treatment. It is essential that alternative strategies are used to target the LSC population. BCR-ABL activation is responsible for the modulation of different signalling pathways, which allows the LSC fraction to evade cell death. Several pathways have been shown to be modulated by BCR-ABL, including PI3K/AKT/mTOR, JAK-STAT and autophagy signalling pathways. Targeting components of these survival pathways, alone or in combination with TKI, therefore represents an attractive potential therapeutic approach for targeting the LSC. However, many pathways are also active in normal stem cells. Therefore, potential targets must be validated to effectively eradicate CML stem cells while sparing normal counterparts. This review summarizes the main pathways modulated in CML stem cells, the recent developments and the use of novel drugs to target components in these pathways which may be used to target the LSC population.

Linked Articles

This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8     

Metabolic characteristics of imatinib resistance in chronic myeloid leukaemia cells

Background and purpose:

Early detection of resistance development is crucial for imatinib-based treatment in chronic myeloid leukaemia (CML) patients. We aimed to distinguish metabolic markers of cell resistance to imatinib.

Experimental approach:

Two human imatinib-sensitive CML cell lines: LAMA84-s and K562-s, and their resistant counterparts: LAMA84-r and K562-r (both resistant to 1 µM imatinib), and K562-R (5 µM) were analysed by nuclear magnetic resonance spectroscopy to assess global metabolic profiling, including energy state, glucose and phospholipid metabolism.

Key results:

We found, by Western blotting and flow cytometry, that the levels of Bcr-Abl tyrosine kinase and multi-drug resistance p-glycoprotein were inconsistent among resistant clones. On the other hand, phospholipid metabolism and lactate production were highly predictive for cell response to imatinib. As previously reported, sensitive cells showed significantly decreased glycolytic activity (lactate) and phospholipid synthesis (phosphocholine) as well as increased phospholipid catabolism (glycerophosphocholine) after 24 h of 1 µM imatinib treatment, which correlated with inhibition of cell proliferation and induction of apoptosis. In contrast to their sensitive counterparts, the K562-r, K562-R and LAMA84-r maintained increased phospholipid synthesis and glycolytic lactate production in the presence of 1 µM (K562-r and LAMA84-r) and 5 µM (K562-R) imatinib.

Conclusions and implications:

Specific metabolic markers for early detection of imatinib resistance, including increased glycolytic activity and phospholipid turnover, can be identified in resistant clones. Once validated in human isolated leukocytes, they may be used to monitor the responsiveness of CML patients to treatment.     

Imatinib: a review of its use in chronic myeloid leukaemia

Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia (CML). It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL) fusion protein that results from the chromosomal abnormality known as the Philadelphia chromosome. CML is characterised by this abnormality, which leads to abnormalities of the peripheral blood and bone marrow including an increase in the number of granular leukocytes. Imatinib is approved in numerous countries worldwide for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase CML, Ph+ accelerated-phase or blast-crisis CML, and in patients with Ph+ chronic-phase CML who have failed to respond to interferon-alpha therapy. It is also indicated in paediatric patients with newly diagnosed Ph+ chronic-phase CML, in accelerated-phase or blast-crisis CML, or in chronic-phase CML after failure of interferon-alpha therapy or when the disease has recurred after haematopoietic stem cell transplantation (HSCT). Approved indications, however, may vary by country.Imatinib is effective and generally well tolerated in patients with Ph+ CML. In patients with newly diagnosed chronic-phase CML, imatinib was more effective than interferon-alpha plus cytarabine in preventing progression of the disease and in achieving haematological and cytogenetic responses. Overall survival rates remain high after 5 years of follow-up, and historical comparisons with other treatments demonstrate improved overall survival with imatinib in the long term. Patients with accelerated-phase or blast-crisis CML, or those who have not responded to prior interferon-alpha therapy also benefit from imatinib treatment. Some patients become resistant or intolerant to imatinib therapy; management strategies to overcome these problems include dosage adjustment, other treatments, or combination therapy with imatinib and other agents. Allogeneic HSCT is currently the only potentially curative treatment, but it is associated with high rates of morbidity and mortality and is not suitable for all patients. The introduction of imatinib has had a marked impact on outcomes in patients with CML. It remains a valuable treatment for all stages of the disease, especially initial treatment of newly diagnosed Ph+ chronic-phase CML, and is endorsed by European and US treatment guidelines as a first-line option.     

Nilotinib: in the first-line treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase

Nilotinib is an effective first-line treatment for newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase. It is an aminopyrimidine-based, high-affinity inhibitor of the tyrosine kinase activity of BCR-ABL. It thus decreases ABL-associated cell proliferation and kinase autophosphorylation. At 12 months, a significantly greater proportion of nilotinib 300?mg twice daily recipients experienced a major molecular response (primary endpoint) than those receiving imatinib 400?mg once daily, in the randomized, open-label, multicentre ENESTnd study in adults with newly diagnosed Philadelphia chromosome-positive CML in chronic phase. Moreover, a significantly greater proportion of nilotinib 300?mg twice daily than imatinib recipients had a complete molecular response at 12 months. Complete cytogenetic response rates were also significantly higher in the nilotinib 300?mg twice daily group than in the imatinib group at 12 months. Treatment differences in molecular response rates remained significant in an updated analysis, with data from a minimum follow-up of 24 months. Nilotinib 300?mg twice daily was generally well tolerated in the ENESTnd study. While nilotinib is associated with an increase in corrected QT interval (QTc), the incidence of cardiac-related adverse events in nilotinib recipients in the ENESTnd study was low.     

Dasatinib: a review of its use in the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia

Dasatinib (Sprycel?) is an orally administered small molecule inhibitor of multiple tyrosine kinases, including BCR-ABL and SRC family kinases, which is indicated for the treatment of adults with newly diagnosed chronic-phase chronic myeloid leukaemia (CML), CML (chronic-, accelerated- or blast-phase) with resistance or intolerance to prior therapy, including imatinib, or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) with resistance or intolerance to prior therapy. Dasatinib is ≈325-fold more active than imatinib in inhibiting wild-type ABL kinase in vitro and is active against a wide variety of imatinib-resistant BCR-ABL mutants, except for T315I. This article reviews the efficacy and tolerability of dasatinib in the treatment of patients with newly diagnosed chronic-phase CML or imatinib-resistant or -intolerant CML or Ph+ ALL, as well as summarizing its pharmacological properties. In clinical trials, oral dasatinib was effective in achieving major or complete cytogenetic responses in both newly diagnosed and imatinib-resistant or -intolerant chronic-phase CML. Dasatinib was likewise effective in achieving major or overall haematological responses in imatinib-resistant or -intolerant, accelerated- or blast-phase CML, or Ph+ ALL. Responses were rapidly achieved within 1-3 months and were durable over 1-5 years of follow-up. The majority of adverse events with dasatinib were of mild to moderate severity. Fluid retention (including pleural effusion) was the most common adverse event. Haematological abnormalities were common and cytopenias were the most common grade 3/4 adverse events. Dasatinib 100?mg administered once daily was as effective as dasatinib 70?mg administered twice daily, and was better tolerated, being associated with lower incidences of pleural effusion and grade 3/4 thrombocytopenia, in particular. Dasatinib was more effective than high-dose imatinib in the treatment of patients with imatinib-resistant chronic-phase CML and was more effective than standard dosages of imatinib, as well as being associated with less frequent fluid retention, in patients with newly diagnosed chronic-phase CML. Dasatinib was generally equally effective in patients with or without BCR-ABL mutations at baseline. Therefore, oral dasatinib is a highly effective once-daily therapy for the first-line treatment of newly diagnosed patients with chronic-phase CML, as well as for the treatment of patients with imatinib-resistant or -intolerant chronic- and advanced-phase CML or Ph+ ALL.