1,721,508 research outputs found
Tyrosine kinase inhibitors in Ph+ acute lymphoblastic leukaemia: facts and perspectives
No full textTwo tyrosine kinase inhibitors (TKIs), imatinib and dasatinib, are registered for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) in adults. Other two TKIs (nilotinib and ponatinib) have been tested in the second-line, can offer an alternative in the patients who fail the first-line, and can acquire a role also in the first-line. Here, we provide a summary of the reports of TKIs, used alone, and in combination with chemotherapy. TKIs are very effective alone and with corticosteroids and are likely to improve substantially the outcome when they are combined with standard or dose-adapted chemotherapy. While the complete haematologic remission rate is always very high, close to 100Â %, the cytogenetic and molecular remission rates are lower, so that TKIs are still considered as a complement to chemotherapy and as a bridge to allogeneic stem cell transplantation (allo-SCT). However, many patients relapse before transplant, and many patients still relapse, even if they have been submitted to allo-SCT. A proper use of TKIs, the introduction of ponatinib, and of ânew generationâ TKIs should improve further on the outcome of Ph+ ALL
Nilotinib against high dose imatinib for salvage therapy of chronic myeloid leukaemia
No full textIn 2002, the approval of the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib mesylate for the first line treatment of chronic myeloid leukaemia revolutionised therapeutic goals and led to the introduction of novel monitoring schemes and response definitions.1 In 2006–07, the introduction of second-generation TKIs dasatinib and nilotinib (developed to be more potent or more specific inhibitors for BCR-ABL1 and more tolerant of the conformational changes induced by imatinib-resistant kinase domain point mutations) for imatinib-resistant cases further increased treatment expectations
Interferon-alfa for chronic myeloid leukemia
No full textInterferon-alfa (IFNalpha) became the first-line agent for the treatment of chronic myeloid leukemia (CML) because it prolongs survival significantly compared to conventional chemotherapy (CHT). Responses to IFNalpha and the benefits from achieving a response are greater in low-risk than in high-risk patients. The best therapeutic results are obtained in low-risk patients who achieve a complete hematologic response (CHR) within 3 to 6 months, a major cytogenetic response (MCgR) within 1 year, and a complete cytogenetic response (CCgR) thereafter. Cytogenetic responses (CgRs) to IFNalpha are stable and durable, so that about 50% of complete responders become long-term survivors. Combining IFNalpha with other drugs, like arabinosyl cytosine (AC), and with other treatments, like autologous stem cell transplantation (autoSCT), may provide additional benefit, although this has not been proven. The biologic and molecular bases of the action of IFNalpha are still poorly understood, but are worth investigating further to determine whether it will still have a therapeutic role when used in combination with the protein tyrosine kinase inhibitors and other new agents
New tyrosine kinase inhibitors in chronic myeloid leukemia
No full textThe deregulated activity of BCR-ABL tyrosine kinase originating from the t(9;22) chromosomal translocation has been shown to be necessary and sufficient for the transformed phenotype of chronic myeloid leukemia (CML) cells. This peculiarity has paved the way for the development of novel therapies specifically targeting the BCR-ABL gene product. The first BCR-ABL inhibitor to come into use in clinical practice, imatinib mesylate, is now the first-choice treatment for all newly diagnosed CML patients, but the initial striking efficacy of this drug has been overshadowed by the development of clinical resistance. The most common mechanisms of resistance include (i) BCR-ABL overexpression, and (ii) BCR-ABL kinase domain mutations disrupting critical contact points between imatinib and BCR-ABL or inducing a transition to a conformation to which imatinib is unable to bind. Several approaches to overcoming resistance have been studied both in vitro and in vivo. They include dose escalation of imatinib, the combination of imatinib with chemotherapeutic drugs, alternative BCR-ABL inhibitors, and inhibitors of kinases acting downstream of BCR-ABL such as Src kinases. Various novel tyrosine kinase inhibitors (TKI) have been synthesized and have now reached the pre-clinical or clinical phase. This review highlights the development of new TKI as specific molecularly targeted therapy and as the principal mechanisms for overcoming imatinib resistance
A review of the European LeukemiaNet recommendations for the management of CML
No full textSeveral guidelines and recommendations on the management of chronic myeloid leukemia (CML) have been prepared by several scientific societies. The European LeukemiaNet (ELN) appointed a panel of experts who submitted their recommendations to peer-reviewed scientific journals in 2006, 2009, and 2013. Here, we make a critical review of the last, 2013, ELN recommendations, concerning the use of the five available tyrosine kinase inhibitors (TKIs), the evaluation of cytogenetic and molecular response, and the strategy of treatment. Three TKIs (imatinib, nilotinib, dasatinib) are recommended first-line. Bosutinib and ponatinib are available second-line; ponatinib is particularly indicated in case of the T315I mutation. Achieving an optimal response, not only for survival but also for a deeper, stable, treatment-free remission, requires a BCR-ABL transcripts level ≤ 10 % at 3 months, ≤ 1 % at 6 months, ≤ 0.1 % at 1 year, and ≤ 0.01 % later on. Molecular monitoring must include mutational analysis in every case of failure. A successful treatment of accelerated and blastic phase requires TKIs, and in many cases also allogeneic stem cell transplantation
Dual tyrosine kinase inhibitors in chronic myeloid leukemia.
No full textThe Bcr-Abl inhibitor imatinib mesylate induces complete hematologic and cytogenetic remissions in most newly diagnosed chronic myeloid leukemia (CML) patients, but relatively few of them achieve molecular remission. In addition, imatinib is much less effective in advanced phase-CML as well as in Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL), mainly due to the development of drug resistance. The challenge for the future is to improve current clinical results with kinase inhibitors in CML, developing strategies that can eradicate residual disease and overcome or prevent resistance. 'Dual' Src and Abl kinase inhibitors are an attractive class of compounds, since (a) these molecules are able to bind Bcr-Abl with less stringent conformational requirements with respect to imatinib, therefore allowing for efficient inhibition of several, resistance-associated mutant forms of Bcr-Abl; (b) Src kinases have been shown to be involved in Bcr-Abl-mediated leukemogenesis as well as upregulated in some patients resistant to imatinib. Here, we review the development, the mode of action and the preclinical or early clinical evaluation of several novel dual Src and Abl kinase inhibitors
Safety profiles of first-line TKIS and managing adverse effects
No full textThe treatment armamentarium of chronic myeloid leukemia (CML) is based on at least five TKIs, employed either in first-line CP (imatinib, dasatinib, and nilotinib) and in second and third line (dasatinib, nilotinib, bosutinib, and ponatinib). These drugs share the same target of interest (BCR-ABL) but have profound different off-target effects. In turn, the general spectrum of adverse events experienced by the treated patients, either clinical symptoms, biochemical abnormalities, or severe AEs (or âcomplicationsâ), varies considerably. SAEs are more frequent with second- and third-generation TKIs, and from this point of view, imatinib remains the safest drug. The early identification of CML patient candidates to experience more frequently SAEs with second (and third)-generation TKIs is of course part of the treatment decision process where the right balance between risk and benefit should be accomplished. Second-generation TKIs, nilotinib and dasatinib, are considered generally to be better tolerated than imatinib. However, two types of complications are described more frequently with nilotinib and ponatinib (cardiovascular, in general, and PAOD in particular) and with dasatinib (pleural effusions and pulmonary hypertension) if compared with imatinib. These two types of complications deserve a particular attention
Tyrosine kinase inhibitors in chronic myeloid leukaemia: Which, when, for whom?
No full textThe therapeutic armamentarium for chronic myeloid leukaemia (CML) comprises mainly tyrosine kinase inhibitors (TKIs), with several agents available for frontline treatment, or for the treatment of disease resistance or intolerance to the first-choice or second-choice drug. The availability of different drugs is a major achievement, but means that choices must be made-which can be difficult and questionable at times. The most important end point considered in decision-making regarding treatment for any cancer is overall survival, but additional factors (such as age, prognostic category, safety, or the possibility of achieving treatment-free remission) should be considered when selecting an agent for frontline treatment. Regardless of the TKI selected for first-line treatment, guidelines that define the importance of reaching specific response indicators and procedures for vigilant follow-up monitoring are established to ensure timely implementation of second-line TKIs. Herein, we discuss the benefits and risks of the different TKIs available for the treatment of patients with CML, and how to decide when to employ these agents at different treatment settings
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