1,721,041 research outputs found
Asciminib in chronic myeloid leukemia
No full text: Despite the fact that, in the last years, life expectancy of chronic myeloid leukemia (CML) patients has reached that of the normal population, a significant proportion of CML patients is likely to fail treatment with first- or second-generation tyrosine kinase inhibitors (TKIs). Failure to first-line treatment is commonly due to molecular resistance or unbearable toxicity. New specific compounds are tested in this setting to fulfill this unmet clinical need in CML; of these, asciminib has shown efficacy based on allosteric inhibition which allows to overcome resistance and off-target toxicity. This review aims to cover how asciminib will change the therapeutic scenario of CML, highlighting its mechanism of action, pharmacokinetics, efficacy and toxicity. Asciminib will be a possible option as third-line therapy for patients carrying resistant mutations, such as T315I, and/or not eligible for treatment with other TKIs
Asciminib as a third line option in chronic myeloid leukemia
No full textUnmet needs remain in the treatment of chronic phase chronic myeloid leukemia (CML) in later lines. Sequential use of tyrosine kinase inhibitors (TKIs) is associated with decreased overall survival and emergence of new mutations, particularly the T315I mutation. Among the new drugs developed to overcome resistance and intolerance, the STAMP inhibitor asciminib (which specifically targets the ABL myristoyl pocket) is the first example of a drug that works by allosteric inhibition. This review focuses on its mechanism of action, pharmacokinetic, efficacy, and toxicity, as well as how this drug will change the therapeutic approach for CML patients not eligible to receive other available drugs
Optimizing health-related quality of life in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors
No full textIntroduction: The current treatment landscape of chronic myeloid
leukemia (CML) is challenging for several reasons, and health-related
quality of life (HRQOL) data may be of critical importance to help
physicians and patients make more informed decisions.
Areas covered: A systematic literature search was performed in PubMed to
identify the most recent studies (between April 2016 and June 2020)
assessing the impact of tyrosine kinase inhibitors (TKIs) on adult CML
patients' HRQOL. Studies assessing treatment discontinuation were also
considered. For each study, we evaluated characteristics of CML patients
included, treatment information and basic HRQOL data, including
questionnaires used, and summary findings.
Expert opinion: Valuable information can be gleaned from recent CML
studies including a HRQOL assessment; however, major gaps remain in our
knowledge. These include, for example, a better understanding of the
impact of second- and third-generation TKIs on patients' HRQOL compared
to imatinib therapy. Also, the benefits of TKI treatment
discontinuation, in terms of symptom burden and HRQOL, are yet to be
fully elucidated. More research efforts are needed in this area to
generate high-quality evidence that can facilitate decision-making
Future Management of Chronic Myeloid Leukemia: From Dose Optimization to New Agents
No full textBackground: The outcome of chronic myeloid leukemia (CML) patients in chronic phase has changed after the introduction of tyrosine kinase inhibitors (TKIs). The life expectancy is actually similar to that of the general population. Although outstanding results were achieved, about 20-30% of patients failed to achieve molecular milestones or experienced a severe toxicity and needed to switch to a second line. Objective: The aim of this review is to report on possible future management in CML, from dose optimization to avoid long-term off-target events to new agents for the treatment of resistant and/or intolerant patients. Methods: Broad research on Medline, Embase and archives from EHA and ASH congresses was performed. Results: New TKIs have been developed to counteract resistance and/or intolerance in the setting of T315I mutated patients. The benefits of ponatinib dose optimization have been recently reported in the OPTIC trial. New trials to test the dose optimization are ongoing. Conclusion: Reduction of the standard dose could be performed to reduce the specific TKI toxicity. Selective TKIs could be prescribed in the future as third line treatment
Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia
No full textThere are five tyrosine kinase inhibitors (TKIs) that are currently
approved (in the European Union and the United States) for the treatment
of chronic myeloid leukaemia (CML) in the chronic phase (CP) and each of
them has its own efficacy and toxicity profile. Oral ponatinib
(Iclusig((R))) is a third-generation TKI structurally designed to
inhibit native BCR-ABL1 tyrosine kinase and several BCR-ABL1 mutants,
including T315I. Ponatinib is now approved for patients with CML who are
resistant or intolerant to prior TKI therapy (European Union) or for
whom no other TKI therapy is indicated (United States). Despite
achieving results in heavily treated patients, which led to its
approval, the drug may induce cardiovascular events, requiring a careful
baseline assessment of predisposing risk factors and specific management
during treatment. Pharmacokinetic analysis has indicated the possibility
of reducing the starting dose of ponatinib to 15 mg/day and preliminary
data showed advantages in terms of safety while maintained its efficacy.
This review summarizes the results achieved and drug-related side
effects reported in all clinical trials and real-life experiences,
testing ponatinib in patients with CP-CML. In addition, we focus on the
appropriate use of ponatinib in clinical practice suggesting some useful
recommendations on the proper management of this drug
Insights into the optimal use of ponatinib in patients with chronic phase chronic myeloid leukaemia
No full textThere are five tyrosine kinase inhibitors (TKIs) that are currently approved (in the European Union and the United States) for the treatment of chronic myeloid leukaemia (CML) in the chronic phase (CP) and each of them has its own efficacy and toxicity profile. Oral ponatinib (Iclusig((R))) is a third-generation TKI structurally designed to inhibit native BCR-ABL1 tyrosine kinase and several BCR-ABL1 mutants, including T315I. Ponatinib is now approved for patients with CML who are resistant or intolerant to prior TKI therapy (European Union) or for whom no other TKI therapy is indicated (United States). Despite achieving results in heavily treated patients, which led to its approval, the drug may induce cardiovascular events, requiring a careful baseline assessment of predisposing risk factors and specific management during treatment. Pharmacokinetic analysis has indicated the possibility of reducing the starting dose of ponatinib to 15 mg/day and preliminary data showed advantages in terms of safety while maintained its efficacy. This review summarizes the results achieved and drug-related side effects reported in all clinical trials and real-life experiences, testing ponatinib in patients with CP-CML. In addition, we focus on the appropriate use of ponatinib in clinical practice suggesting some useful recommendations on the proper management of this drug
Hemorrhagic Complications in Patients Treated With Azacitidine and Direct Oral Anticoagulants
No full textHemorrhagic Complications in Patients Treated With Azacitidine and Direct Oral Anticoagulant
Asciminib: an investigational agent for the treatment of chronic myeloid leukemia
No full textIntroduction: Tyrosine kinase inhibitors (TKIs) have drastically changed the outcome of chronic myeloid leukemia (CML) patients. However, a subset of patients experienced resistance and/or intolerance and need to switch to other agents. Resistance to second-generation TKIs used in first-line treatment is less of an issue when compared to imatinib in first line. New drugs that are able to improve efficacy, without long-term off-target effects are needed. Allosteric inhibitors such as asciminib (ABL001) were created to overcome resistance and off-target toxicity. Areas covered: In this review, we report the mechanism of action, pharmacokinetic data, and the clinical trial results of asciminib tested in chronic phase CML patients. Expert Opinion: Asciminib, the first example of allosteric inhibition, could be a promising approach as third-line therapy and in the subset of patients with T315I mutation that, for coexistent comorbidities, cannot receive other drugs. Future results will probably help to move the drug to earlier lines of treatment
Tyrosine kinase inhibitor discontinuation in the management of chronic myeloid leukemia: a critical review of the current practice
No full textIntroduction: Tyrosine kinase inhibitors (TKIs), which target BCR-ABL1 kinase activity, have significantly prolonged the overall survival of patients affected by chronic myeloid leukemia (CML) and changed drastically the outcome. Evidences from several studies suggest that in patients who have achieved a sustained, stable and deep molecular response, TKI treatment can be safely discontinued with a close subsequent monitoring. Thus, a stable deep molecular response (DMR) has become a feasible treatment goal in CML. Areas covered: In this review, the main findings extrapolated from sponsored and real-life evidences regarding TKI discontinuation were discussed, through a broad research on Medline, Embase and archives from EHA and ASH congresses (including words such as discontinuation, treatment-free remission, TFR, etc). Moreover, suggestions emerged from international guidelines about treatment-free remission (TFR) are presented. Expert opinion: With the growing availability of clinical trials and real-life data on TFR, in recent years the possibility of offering to CML patients a safe, informed and shorter path to TFR, through the achievement of a stable deep molecular response (DMR), has become an increasing option. However, many controversial aspects remain regarding treatment choices and timings, predictive factors, patient communication and optimal strategies aimed at achieving a successful TFR
Pharmacotherapeutic advances for chronic myelogenous leukemia: beyond tyrosine kinase inhibitors
No full textIntroductionDespite the notable success of tyrosine kinase inhibitors
(TKIs) in treating chronic myeloid leukemia (CML), a subset of patients
experiences resistance, or relapse after discontinuation. This challenge
is attributed to the Ph+ leukemia stem cells (LSCs) pool not fully
involved in the inhibition process due to the current therapeutic
approach.Areas coveredCurrent pharmacological advancements in CML
therapy focus on targeting LSCs, intervening in self-renewal pathways,
and exploiting biological vulnerabilities. Beyond BCR::ABL1 inhibition,
innovative approaches include immunotherapy, epigenetic modulation, and
interference with microenvironmental mechanisms.Expert opinionDiverse
therapeutic strategies beyond TKIs are under investigation.
Immunotherapy with interferon-alpha (IFN-alpha) shows some biological
effects, although further research is needed for optimal application in
enhancing discontinuation rates. Other compounds were able to mobilize
Ph+ LSCs from the bone marrow niche (DPP-IV inhibitor vildagliptin or
PAI-1 inhibitor TM5614) increasing the LSC clearance or target the CD26,
a Ph+ specific surface receptor. It is noteworthy that the majority of
these alternative strategies still incorporate TKIs. In conclusion,
novel therapeutic perspectives are emerging for CML, holding the
potential for substantial advancements in disease treatment
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