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International Journal of Clinical... Apr 2024Imatinib, a potent inhibitor of targeted protein tyrosine kinases, treats chronic myeloid leukaemia (CML). Data on imatinib-associated changes in hepatic and thyroid... (Review)
Review
BACKGROUND
Imatinib, a potent inhibitor of targeted protein tyrosine kinases, treats chronic myeloid leukaemia (CML). Data on imatinib-associated changes in hepatic and thyroid functions are limited and conflicting.
AIM
To report the prevalence of hepatic and thyroid toxicity associated with the use of imatinib in CML patients.
METHOD
Articles for the systematic review were selected from electronic databases (PubMed, CINALH, Web of Science). Readily accessible peer-reviewed full articles in English published 1st January 2000 to 18th July 2023 were included. The search terms included combinations of: imatinib, CML, liver toxicity, hepatic toxicity, thyroid toxicity. Screening of titles, abstracts, full text articles was conducted independently by two reviewers. Inclusions and exclusions were recorded following PRISMA guidelines. Detailed reasons for exclusion were recorded. Included articles were critically appraised.
RESULTS
Ten thousand one hundred and twenty-three CML patients were reported in the 82 included studies corresponding to 21 case reports, 2 case series, 39 clinical trials and 20 observational studies were selected. Excluding case studies/reports, 1268 (12.6%; n = 1268/10046) hepatotoxicity adverse events were reported, of which 64.7% were rated as mild grade I & II adverse events, 363 (28.6%) as severe, grade III and IV adverse events; some led to treatment discontinuation, liver transplantation and fatal consequences. Twenty (35.1%) studies reported discontinuation of imatinib treatment due to the severity of hepatic toxicity. Fourteen (8.4%, n = 14/167) thyroid dysfunction adverse events were reported.
CONCLUSION
High frequency of mild and severe hepatotoxicity, associated with imatinib in CML patients, was reported in the published literature. Low numbers of mild and manageable thyroid toxicity events were reported.
Topics: Humans; Imatinib Mesylate; Thyroid Gland; Prevalence; Pyrimidines; Piperazines; Benzamides; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Chemical and Drug Induced Liver Injury; Antineoplastic Agents; Protein Kinase Inhibitors
PubMed: 38147280
DOI: 10.1007/s11096-023-01671-0 -
Biomarkers in Medicine Dec 2023The present systematic review aimed to explore miRNAs as a potential biomarker for early diagnosis of chronic myeloid leukemia (CML). A systematic search was conducted...
The present systematic review aimed to explore miRNAs as a potential biomarker for early diagnosis of chronic myeloid leukemia (CML). A systematic search was conducted in three electronic databases, including Web of Science, Scopus and PubMed, to obtain relevant articles investigating the alteration of miRNA expression in patients with CML. The authors found miRNAs whose expression changes are effective in the induction of CML disease. Among them, miR-21 and miR-155 were identified as the most common miRNAs with increased expression and miR-150 and miR-146 as the most common miRNAs with decreased expression. miRNAs can be used as an indicator for the early detection and treatment of CML phase.
Topics: Humans; Biomarkers; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; MicroRNAs
PubMed: 38230979
DOI: 10.2217/bmm-2023-0575 -
Leukemia & Lymphoma May 2024
Topics: Humans; Myeloproliferative Disorders; Adolescent; Young Adult
PubMed: 38324010
DOI: 10.1080/10428194.2024.2313618 -
Clinical Drug Investigation Feb 2024The introduction and widespread use of effective and well-tolerated tyrosine kinase inhibitors for chronic myeloid leukemia have been associated with marked increments...
Maximizing the Value of Chronic Myeloid Leukemia Management Using Tyrosine Kinase Inhibitors in the USA: Potential Determinants and Consequences of Healthcare Resource Utilization and Costs, with Proposed Optimization Approaches.
BACKGROUND AND OBJECTIVES
The introduction and widespread use of effective and well-tolerated tyrosine kinase inhibitors for chronic myeloid leukemia have been associated with marked increments in life expectancy and disease prevalence. These changes have been accompanied by elevations in costs of tyrosine kinase inhibitors, which typically must be taken ad vitam after diagnosis and tend to be more expensive than medical therapies for many other hematologic malignancies. The aims of this review included evaluating the potential associations and consequences of healthcare resource utilization and costs of tyrosine kinase inhibitors and possible clinical management approaches to mitigate them.
METHODS
A PubMed search of English-language US study reports was conducted that covered the interval of 2001 (US approval of imatinib) through 17 April, 2023 augmented by manual reviews of published bibliographies from the referenced articles and searches of other databases: Google Scholar and Scopus.
RESULTS
On the basis of this analysis of chiefly real-world evidence (administrative claims database studies), healthcare resource utilization and costs can be considered indicators of ineffective chronic myeloid leukemia management, including potentially mutation-driven treatment resistance and costly tyrosine kinase inhibitor switches, non-adherence, and suboptimal tolerability, which may culminate in the progression of disease from the chronic to an accelerated or blast phase, with additional excess costs. Costs of tyrosine kinase inhibitors are also associated with reduced treatment adherence. At a willingness-to-pay threshold of $50,000-$200,000 per quality-adjusted life-year, tyrosine kinase inhibitors can be considered cost effective from a US payer perspective. Potential clinical approaches to mitigate costs include regular molecular monitoring with proactive assessments of BCR::ABL1 gene mutations to avoid costly treatment switches, as well as interventions to enhance treatment adherence and tyrosine kinase inhibitor tolerability.
CONCLUSIONS
Healthcare resource utilization and costs of chronic myeloid leukemia care may be considered barometers of ineffective management, including mutation-driven tyrosine kinase inhibitor resistance and switching as well as non-adherence and intolerance. Future prospective research is warranted to help determine whether costs can be reduced and other treatment outcomes optimized via more proactive and effective diagnostic interventions (i.e., regular molecular monitoring and proactive mutational testing) and treatment approaches. The strengths and limitations of this review include its emphasis on observational research, which, on one hand, offers a naturalistic "real-world" perspective on current chronic myeloid leukemia management, but, on the other hand, is associational in nature and cannot be used to determine causality and/or its direction.
Topics: Humans; Tyrosine Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Imatinib Mesylate; Protein Kinase Inhibitors; Delivery of Health Care; Antineoplastic Agents
PubMed: 38182963
DOI: 10.1007/s40261-023-01329-9 -
Blood Advances May 2024Cytoreductive therapy is not routinely recommended for younger patients with polycythemia vera (PV) due to concern that treatment toxicity may outweigh therapeutic... (Meta-Analysis)
Meta-Analysis
Cytoreductive therapy is not routinely recommended for younger patients with polycythemia vera (PV) due to concern that treatment toxicity may outweigh therapeutic benefits. However, no systematic data support this approach. To support objective risk/benefit assessment of cytoreductive drugs in patients with PV aged <60 years (PV<60), this systematic review and meta-analysis was conducted to evaluate toxicity and disease-related complications in PV<60 treated with interferon alfa (rIFN-α) or hydroxyurea (HU). A search of PubMed, Scopus, Web of Science and Embase identified 693 unique studies with relevant keywords, of which 14 met inclusion criteria and were selected for analysis. The weighted average age of patients treated with rIFN-α was 48 years (n = 744 patients; 12 studies) and for HU was 56 years (n = 1397; 8 studies). The weighted average duration of treatment for either drug was 4.5 years. Using a Bayesian hierarchical model, the pooled annual rate of discontinuation due to toxicity was 5.2% for patients receiving rIFN-α (n = 587; 95% confidence interval [CI], 2.2-8.2) and 3.6% for HU (n = 1097; CI, 1-6.2). The average complete hematologic response for rIFN-α and HU was 62% and 52%, respectively. Patients experienced thrombotic events at a pooled annual rate of 0.79% and 1.26%; secondary myelofibrosis at 1.06% and 1.62%; acute myeloid leukemia at 0.14% and 0.26%; and death at 0.87% and 2.65%, respectively. No treatment-related deaths were reported. With acceptable rates of nonfatal toxicity, cytoreductive treatment, particularly with disease-modifying rIFN-α, may benefit PV<60. Future randomized trials prioritizing inclusion of PV<60 are needed to establish a long-term benefit of early cytoreductive treatment in these patients.
Topics: Humans; Polycythemia Vera; Treatment Outcome; Interferon-alpha; Hydroxyurea; Adult; Middle Aged; Cytoreduction Surgical Procedures; Age Factors
PubMed: 38507746
DOI: 10.1182/bloodadvances.2023012459 -
JAMA Network Open Jun 2024Published research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors....
IMPORTANCE
Published research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors. Little is known about these practices in RCTs for hematological malignant neoplasms.
OBJECTIVE
To evaluate the prevalence of PROs as prespecified end points in RCTs of hematological malignant neoplasms, and to assess reporting of PROs in associated trial publications.
EVIDENCE REVIEW
All issues of 8 journals known for publishing high-impact RCTs (NEJM, Lancet, Lancet Hematology, Lancet Oncology, Journal of Clinical Oncology, Blood, JAMA, and JAMA Oncology) between January 1, 2018, and December 13, 2022, were searched for primary publications of therapeutic phase 3 trials for adults with hematological malignant neoplasms. Studies that evaluated pretransplant conditioning regimens, graft-vs-host disease treatment, or radiotherapy as experimental treatment were excluded. Data regarding trial characteristics and PROs were extracted from manuscripts and trial protocols. Univariable analyses assessed associations between trial characteristics and PRO collection or reporting.
FINDINGS
Ninety RCTs were eligible for analysis. PROs were an end point in 66 (73%) trials: in 1 trial (1%) as a primary end point, in 50 (56%) as a secondary end point, and in 15 (17%) as an exploratory end point. PRO data were reported in 26 of 66 primary publications (39%): outcomes were unchanged in 18 and improved in 8, with none reporting worse PROs with experimental treatment. Trials sponsored by for-profit entities were more likely to include PROs as an end point (49 of 55 [89%] vs 17 of 35 [49%]; P < .001) but were not significantly more likely to report PRO data (20 of 49 [41%] vs 6 of 17 [35%]; P = .69). Compared with trials involving lymphoma (18 of 29 [62%]) or leukemia or myelodysplastic syndrome (18 of 28 [64%]), those involving plasma cell disorders or multiple myeloma (27 of 30 [90%]) or myeloproliferative neoplasms (3 of 3 [100%]) were more likely to include PROs as an end point (P = .03). Similarly, compared with trials involving lymphoma (3 of 18 [17%]) or leukemia or myelodysplastic syndrome (5 of 18 [28%]), those involving plasma cell disorders or multiple myeloma (16 of 27 [59%]) or myeloproliferative neoplasms (2 of 3 [67%]) were more likely to report PROs in the primary publication (P = .01).
CONCLUSIONS AND RELEVANCE
In this systematic review, almost 3 of every 4 therapeutic RCTs for blood cancers collected PRO data; however, only 1 RCT included PROs as a primary end point. Moreover, most did not report resulting PRO data in the primary publication and when reported, PROs were either better or unchanged, raising concern for publication bias. This analysis suggests a critical gap in dissemination of data on the lived experiences of patients enrolled in RCTs for hematological malignant neoplasms.
Topics: Humans; Patient Reported Outcome Measures; Hematologic Neoplasms; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 38829615
DOI: 10.1001/jamanetworkopen.2024.14425 -
International Journal of Molecular... Mar 2024Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22...
Chronic myeloid leukemia is a multistep, multi-lineage myeloproliferative disease that originates from a translocation event between chromosome 9 and chromosome 22 within the hematopoietic stem cell compartment. The resultant fusion protein BCR::ABL1 is a constitutively active tyrosine kinase that can phosphorylate multiple downstream signaling molecules to promote cellular survival and inhibit apoptosis. Currently, tyrosine kinase inhibitors (TKIs), which impair ABL1 kinase activity by preventing ATP entry, are widely used as a successful therapeutic in CML treatment. However, disease relapses and the emergence of resistant clones have become a critical issue for CML therapeutics. Two main reasons behind the persisting obstacles to treatment are the acquired mutations in the ABL1 kinase domain and the presence of quiescent CML leukemia stem cells (LSCs) in the bone marrow, both of which can confer resistance to TKI therapy. In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article.
Topics: Humans; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Signal Transduction
PubMed: 38542279
DOI: 10.3390/ijms25063307 -
Annals of Diagnostic Pathology Aug 2024Philadelphia (Ph) chromosome (9;22)(q34;q11) comprises 90-95 % of chronic myeloid leukemia (CML), while 5-10 % of CML have translocations involving three or more... (Review)
Review
Does presence of complex translocations involving BCR::ABL1 in chronic myeloid leukemia affect the response rate to tyrosine kinase inhibitors? A systematic review of the literature.
Philadelphia (Ph) chromosome (9;22)(q34;q11) comprises 90-95 % of chronic myeloid leukemia (CML), while 5-10 % of CML have translocations involving three or more chromosomes. The outcome of treating patients harbouring complex Ph-positive cytogenetics with tyrosine kinase inhibitors (TKI) is unclear. In the present systematic review, we aim to summarise the response of patients with complex Ph-positive cytogenetics to treatment with TKI therapy. We collated all available literature from databases such as PubMed, Google Scholar, Web of Science database, Cochrane library, Scopus and Embase (up until January 31st, 2024), which describe cases of patients with CML, harbouring complex Ph-positive variations (three and four-way translocations), and summarised their response to TKI therapy. The studies were screened for the following criteria: documented TKI intervention and outcome (whether CR was achieved). Studies that did not report the same, were excluded. Additionally, we report a case from our center of a 55-year-old patient with CML, positive for the Ph-chromosome, harbouring a three-way translocation involving chromosome 15 i.e. 46XX, t(9;15;22) (q34;p11;q11). Identification of BCR::ABL and involvement of chromosome 15 was carried out using conventional cytogenetics, fluorescence in situ hybridization (FISH), and quantitative PCR (qPCR). Based on the inclusion criteria, a total of 15 studies were included from which a total of 87 cases were covered. Overall, we identified 38 unique complex three- and four-way translocations across 87 Ph-positive cases and found that 85 patients with complex Ph-positive cytogenetics achieved complete remission upon treatment and did not appear to have a lesser response to TKI therapy.
Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Translocation, Genetic; Protein Kinase Inhibitors; Fusion Proteins, bcr-abl; Middle Aged; Philadelphia Chromosome; Treatment Outcome; Male; Female; Tyrosine Kinase Inhibitors
PubMed: 38636337
DOI: 10.1016/j.anndiagpath.2024.152303