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Hematology/oncology and Stem Cell... Mar 2022Approximately 15-20% of chronic myeloid leukemia (CML) patients fail tyrosine kinase inhibitor (TKI) therapy secondary to resistance or intolerance. In the pre-TKI era,... (Meta-Analysis)
Meta-Analysis
Approximately 15-20% of chronic myeloid leukemia (CML) patients fail tyrosine kinase inhibitor (TKI) therapy secondary to resistance or intolerance. In the pre-TKI era, front-line allogeneic hematopoietic cell transplantation (allo- HCT) represented the standard approach for patients with chronic phase-CML (CP-CML) who were deemed fit to tolerate the procedure and had a human leukocyte antigen compatible donor available. Currently, CP-CML patients are eligible for allo-HCT only if they fail more than one TKI and/or are intolerant to the drug. We performed a systematic review/meta-analysis of the available literature to assess the evidence regarding allo-HCT efficacy in CP-CML patients. Data from eligible studies were extracted in relation to benefits (overall survival [OS], progression-free survival, disease-free survival [DFS], complete remission [CR], and molecular response [MR]) and harms (nonrelapse mortality [NRM], relapse, and acute and chronic graft-versus-host disease), and stratified by age into adult and pediatric groups. For adult allo-HCT recipients, the pooled OS, DFS, CR and, MR were 84% [95% confidence interval (CI) 59-99%], 66% (95% CI 59-73%), 56% (95% CI 30-80%), and 88% (95% CI 62-98%), respectively. Pooled NRM and relapse were 20% (95% CI 15-26%) and 19% (95% CI 10-28%), respectively. For the pediatric group, the OS rate was reported in one study and was 91% (95% CI 72-99%). Our results suggest that allo-HCT is an effective treatment for TKI-resistant or TKI-intolerant CP-CML. Post-transplant strategies are still needed to further mitigate the risk of relapse.
Topics: Adult; Humans; Child; Transplantation, Homologous; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Recurrence; Protein Kinase Inhibitors
PubMed: 33789163
DOI: 10.1016/j.hemonc.2021.02.003 -
Acta Bio-medica : Atenei Parmensis Jul 2021Priapism is defined as a penile erection that persists four or more hours and is unrelated to sexual stimulation. Priapism resulting from hematologic malignancy is most...
BACKGROUND
Priapism is defined as a penile erection that persists four or more hours and is unrelated to sexual stimulation. Priapism resulting from hematologic malignancy is most likely caused by venous obstruction from microemboli/thrombi and hyperviscosity caused by the increased number of circulating leukocytes in mature and immature forms. In patients with leukemia, 50% of cases of priapism are due to Chronic Myeloid Leukemia (CML). We present a systematic review of priapism in CML. Acquisition of evidence: An extensive literature research was carried out in PubMed, Google Scholar, SCOPUS, and Science Citation Index databases... The search included cases up to 4th August 2020. Synthesis of evidence: A total of 68 articles were found and included in our review, including 3 reviews from three different centers. We found 68 articles (102 patients; figure 1) and several case reports on priapism in CML. Priapism was noticed in some patients at the first presentation of CML. However, it was infrequently reported during the start of treatment, following the stop of medication and post-splenectomy. The mean age at presentation was 27.4 years, and the mean time from onset of priapism to the time to get medical attention (presentation) was 78.2 hours. The mean white blood cell count associated with priapism was 321.29x109/L, and the mean platelet count was 569 x10 9/L. The chronic phase of CML was the most common phase where priapism occurred. Most patients were Asian (>50%). Nearly a quarter of patients (27.4%) developed permanent erectile dysfunction.
CONCLUSIONS
Priapism is a urological emergency requiring urgent multidisciplinary management to prevent erectile dysfunction. Because of the relatively rare occurrence of priapism in CML patients, there is no standard treatment protocol.
Topics: Hematologic Neoplasms; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Priapism
PubMed: 34212918
DOI: 10.23750/abm.v92i3.10796 -
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 -
Haematologica Dec 2019Hydroxyurea is the standard treatment in high-risk patients with polycythemia vera. However, estimates of its effect in terms of clinical outcomes (thrombosis, bleeding,... (Meta-Analysis)
Meta-Analysis
Hydroxyurea is the standard treatment in high-risk patients with polycythemia vera. However, estimates of its effect in terms of clinical outcomes (thrombosis, bleeding, hematologic transformations and mortality) are lacking. We performed a meta-analysis to determine the absolute risk of events in recent cases of patients under hydroxyurea treatment. We searched for relevant articles or abstracts in the following databases: Medline, EMBASE, clinicaltrials.gov, WHO International Clinical Trials Registry, LILACS. Sixteen studies published from 2008 to 2018 reporting number of events using World Health Organization diagnosis for polycythemia vera were selected. Through a random effect logistic model, incidences, study heterogeneity and confounder effects were estimated for each outcome at different follow ups. Overall, 3,236 patients were analyzed. While incidences of thrombosis and acute myeloid leukemia were stable over time, mortality and myelofibrosis varied depending on follow-up duration. Thrombosis rates were 1.9%, 3.6% and 6.8% persons/year at median ages 60, 70 and 80 years, respectively. Higher incidence of arterial events was predicted by previous cardiovascular complication. Leukemic transformation incidence was 0.4% persons/year. Incidence of transformation to myelofibrosis and mortality were significantly dependent on age and follow-up duration. For myelofibrosis, rates were 5.0 at five years and 33.7% at ten years; overall mortality was 12.6% and 56.2% at five and ten years, respectively. In conclusion, we provide reliable risk estimates for the main outcomes in polycythemia vera patients under hydroxyurea treatment. These findings can help design comparative clinical trials with new cytoreductive drugs and prove the feasibility of using critical end points for efficacy, such as major thrombosis.
Topics: Hemorrhage; Humans; Hydroxyurea; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Risk Factors; Survival Rate; Thrombosis
PubMed: 31123026
DOI: 10.3324/haematol.2019.221234 -
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 -
Clinical Oral Investigations Dec 2019To assess the association between oral mucosa hyperpigmentation in patients with leukemia and imatinib mesylate use. Additionally, we compared our data to those obtained...
OBJECTIVES
To assess the association between oral mucosa hyperpigmentation in patients with leukemia and imatinib mesylate use. Additionally, we compared our data to those obtained from a systematic review.
MATERIALS AND METHODS
A cross-sectional study was conducted with 74 patients undergoing treatment with imatinib mesylate. Sociodemographic characteristics, oral mucosa alterations, and medical history were evaluated. Oral hyperpigmentation was scored. The use of imatinib mesylate and hydroxyurea was evaluated. Association between oral hyperpigmentation and imatinib mesylate was assessed. A systematic review was also conducted to retrieve case reports or case series of patients with oral hyperpigmentation associated with imatinib mesylate.
RESULTS
Among the 74 participants, 41 were male (55.4%) and 33 were female (44.6%). Participants' mean age was 49.3 years. Sixty-six (89.2%) patients developed hyperpigmented lesions in the hard palate mucosa. In multivariate analysis, patients who had used imatinib mesylate for > 72 months had a hyperpigmentation score 1.62 times higher than those who had used this medication during a shorter period. Patients who had used hydroxyurea for > 30 days had a hyperpigmentation score 1.43 times higher than those who had used this medication during a shorter period. The systematic review retrieved 20 clinical cases of patients undergoing imatinib mesylate treatment and exhibiting oral hyperpigmentation.
CONCLUSIONS
The development of oral hyperpigmentation is associated with imatinib mesylate use. Hydroxyurea seems to increment such an association.
CLINICAL RELEVANCE
To assist providers in the differential diagnosis of hyperpigmented lesions associated with imatinib mesylate, as well as in the clinical management of such lesions.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Brazil; Cross-Sectional Studies; Female; Humans; Hyperpigmentation; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Mouth Mucosa; Young Adult
PubMed: 30968242
DOI: 10.1007/s00784-019-02886-0 -
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 -
Journal of Pediatric Hematology/oncology Jul 2023The outcomes of pediatric chronic myeloid leukemia (CML) have improved with the use of imatinib mesylate (IM). Multiple reports of growth deceleration with IM have... (Meta-Analysis)
Meta-Analysis
The outcomes of pediatric chronic myeloid leukemia (CML) have improved with the use of imatinib mesylate (IM). Multiple reports of growth deceleration with IM have raised concerns, necessitating careful monitoring and evaluation in children with CML. We systematically searched the databases of PubMed, EMBASE, Scopus, CENTRAL, and conferences-abstracts, reporting the effect of IM on growth among children with CML, and published in the English language from inception till March 2022. For observational studies, the modified Newcastle Ottawa Scale was used to assess the risk of bias. Pooled estimates were derived using a random-effects meta-analysis, and heterogeneity was assessed using Cochrane Q statistic test of heterogeneity and I2 statistic. Of the 757 studies identified through electronic search, 15 (n=265) were included in the final analysis. Six studies (n=178) were included in the meta-analysis of the primary outcome. There was a significant deleterious effect of IM on height-standardized mean difference (SMD): -0.52 (95% CI: -0.76; -0.28) ( I2 =13%). The adverse effect of IM on height was significant among studies with a follow-up period <3 years [SMD: -0.66 (95% CI: -0.93, -0.40), I2 =0%, P =0.59] but not in studies with follow-up period ≥3 years [SMD: -0.26 (95% CI: -0.63, 0.11), I2 =0, P =0.44], indicating that the effect of IM on height is a short-term effect. The effect of IM on height was not dependent upon pubertal status at the initiation of therapy. Prospective studies with adequate sample size are required to confirm the findings of the effect of IM on height in children with CML.
Topics: Humans; Child; Imatinib Mesylate; Prospective Studies; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 37027248
DOI: 10.1097/MPH.0000000000002660 -
Blood Advances Sep 2021Since the introduction of imatinib, the management of chronic myeloid leukemia (CML) has changed considerably. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML...
Since the introduction of imatinib, the management of chronic myeloid leukemia (CML) has changed considerably. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment; however, the high financial burden of TKIs can be problematic for both the patients and health care systems. After the emergence of generics, reimbursement policies of many countries have changed, and generics offered an alternative treatment option for CML patients. There are many papers published on the use of generics in CML patients with conflicting results regarding both efficacy and safety. In this paper, we systematically reviewed the current literature on generic imatinib use in CML, and 36 papers were evaluated. Both in vitro and in vivo studies of generic imatinib showed comparable results with branded imatinib in terms of bioequivalence and bioavailability. In most studies, generics were comparable with the original molecule in terms of efficacy and safety, both in newly diagnosed patients and after switching from Gleevec. Some generic studies showed contradictory findings regarding efficacy and toxicity, and these differences can be attributed to some factors including the use of different generics in different countries. Both in hypothetical models and in real life, introduction of generic imatinib caused significant reduction in health care costs. In conclusion, generics are not inferior to original imatinib in terms of efficacy with an acceptable toxicity profile. Notwithstanding the generally favorable efficacy and safety of generics worldwide to date, we most probably still need more time to draw firmer conclusions on the longer-term outcomes of generics.
Topics: Antineoplastic Agents; Drugs, Generic; Health Care Costs; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 34477815
DOI: 10.1182/bloodadvances.2021004194