Related Experiment Video
Updated: Jul 1, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Long-term outcomes after upfront second-generation tyrosine kinase inhibitors for chronic myeloid leukemia: managing
Simone Claudiani1,2, Farhan Chughtai3, Afzal Khan3
1Centre for Haematology, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK. s.claudiani@imperial.ac.uk.
Abstract:
Second-generation tyrosine kinase inhibitors (2GTKI) are more effective in inducing rapid molecular responses than imatinib when used first-line in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, failure of first line-2GTKI (1L-2GTKI) still occurs and there is no consensus regarding subsequent management. We retrospectively analyzed the outcome of 106 CML-CP patients treated with 1L-2GTKI and with a median follow-up of 91 months. 45 patients (42.4%) switched to an alternative TKI, 28 for intolerance (26.4%) and 17 (16%) for resistance. Most patients who remained on 1L-2GTKI achieved deep molecular responses (DMR) and 15 (14.1%) are in treatment-free remission (TFR). Intolerant patients also obtained DMR, although most required multiple TKI changes and were slower to respond, particularly if treated with 2L-imatinib. Inferior outcomes were observed in resistant patients, who failed alternative 2L-2GTKI and required 3/4GTKI and/or allogeneic hematopoietic stem cell transplant (alloSCT). 7yr-OS was significantly lower for these individuals (66.1%) than for intolerant patients and those who remained on 1L-2GTKI (100% and 97.9%, respectively; p = 0.001). It is apparent that failure of 1L-2GTKI is a challenging problem in modern CML therapy. Intolerance can be effectively managed by switching to an alternative 2GTKI, but resistance requires early consideration of 3/4GTKI.
Insights
Second-generation tyrosine kinase inhibitors (2GTKI) improve outcomes in chronic myeloid leukemia (CML). However, managing 1L-2GTKI failure is key, with intolerance managed by switching TKIs, while resistance necessitates earlier consideration of advanced therapies.
Area of Science:
- Hematology
- Oncology
- Pharmacology
Background:
- Second-generation tyrosine kinase inhibitors (2GTKI) offer superior first-line efficacy over imatinib for chronic myeloid leukemia in chronic phase (CML-CP).
- Despite advancements, treatment failure with first-line 2GTKI (1L-2GTKI) remains a clinical challenge with no established management guidelines.
- Understanding outcomes after 1L-2GTKI failure is crucial for optimizing CML therapy.
Purpose of the Study:
- To retrospectively analyze the outcomes of CML-CP patients experiencing failure after first-line 2GTKI (1L-2GTKI) treatment.
- To compare management strategies and long-term outcomes based on the reason for 1L-2GTKI failure (intolerance vs. resistance).
- To inform clinical decision-making for subsequent therapies following 1L-2GTKI failure.
Main Methods:
- Retrospective analysis of 106 CML-CP patients treated with 1L-2GTKI.
- Patients were categorized based on switching to alternative tyrosine kinase inhibitors (TKIs) due to intolerance or resistance.
- Median follow-up of 91 months, assessing molecular responses, treatment-free remission (TFR), and overall survival (OS).
Main Results:
- 42.4% of patients switched TKIs; 26.4% for intolerance and 16% for resistance.
- Patients remaining on 1L-2GTKI or switched for intolerance achieved deep molecular responses (DMR); 14.1% achieved TFR.
- Resistant patients failing alternative 2GTKI had inferior outcomes, requiring advanced therapies (3/4GTKI, alloSCT) and exhibiting significantly lower 7-year OS (66.1%) compared to intolerant or non-switched groups (100% and 97.9%, respectively).
Conclusions:
- Failure of 1L-2GTKI presents a significant challenge in CML management.
- Switching to an alternative 2GTKI is effective for managing intolerance, enabling DMR and TFR.
- Resistance to 1L-2GTKI necessitates early consideration of third/fourth-generation TKIs (3/4GTKI) to improve survival outcomes.
More Related Videos
12:40A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
09:38Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
Related Concept Videos
02:56Treatment Resistant Cancers
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
01:26Treatment for Pulmonary Arterial Hypertension: Receptor Tyrosine Kinase Inhibitors and Calcium Channel Blockers
TKIs, such as imatinib (Gleevec), are particularly effective in tackling the growth and mitogenic factors that become upregulated in PAH patients. These factors contribute to the...
01:28Pulmonary Tuberculosis V
Latent tuberculosis infection occurs when TB bacteria are present in a person's body, but are not causing illness or symptoms. It is not contagious, and preventive treatment is crucial to avoid the...
01:19Antiasthma Drugs: Leukotriene Modifiers
Leukotriene modifiers work through two distinct mechanisms: