scholarly journals Metabolomics Profile of Patients with Chronic Myeloid Leukemia and Cardiovascular Adverse Events after Treatment with Tyrosine Kinase Inhibitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4144-4144
Author(s):  
Giovanni Caocci ◽  
Martino Deidda ◽  
Antonio Noto ◽  
Christian Cadeddu ◽  
Marianna Greco ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Dissecting Aneurysm ◽  
Metabolomic Profile ◽  
The Mean

Background. Cardiovascular adverse events (CV-AE) are emerging complications in chronic myeloid leukemia (CML) patients treated with second and third generation tyrosine kinase inhibitors (TKIs). Despite the importance of CV risk factors,predictive CV-AE biomarkers are still lacking. Further understanding of the molecular pathways underlying CV-AE may promote novel strategies to prevent its initiation prior to clinical disease. In this scenario, the use of a novel tool such as metabolomics may be useful for the identification of new metabolic pathways related to CV-AE. Metabolites are the output of cellular metabolism, accounting for expression and activity of genes, transcripts, and proteins, and offering unique insights into small molecule regulation. For the first time we evaluated the correlation between CV-AE and metabolomic profile in CML patients treated with TKIs. Methods. We considered 39 adult CP-CML patients (mean age 49, range 24-70), without comorbidity at baseline, consecutively diagnosed and treated with imatinib, dasatinib nilotinib and ponatinib, at the Haematology Unit of "Businco Hospital", Cagliari, Italy. All patients underwent a metabolomic profile detection, after CV-AE or during follow-up, and were stratified in 2 groups (with or without CV-AE). Plasma samples were collected and acquired chromatogram was analysed by means of the free software AMDIS (Automated Mass Spectral Deconvolution and Identification System; http://chemdata.nist.gov/mass-spc/amdis) that identified each peak by comparison of the relative mass spectra and the retention times with those stored in an in-house made library comprising 255 metabolites. Data were investigated by applying the supervised multivariate statistical approach OPLS-DA (Orthogonal partial least square discriminant analysis) (SIMCA, version 13.0, Umetrics, Umea, Sweden). Results. The mean follow-up since CML diagnosis was 3.7 years (range 0.9-5); 22 (56.4%) patients were treated frontline, while 17 (43.5%) underwent second or subsequent TKI lines of treatments. The reason for switching was inefficacy in 15.3% and intolerance in 28.2%. At CV-AE or last follow-up 16 (41%) patients were treated with imatinib, 8 (20.5%) with dasatinib, 14 (35.8%) with nilotinib and 1 patient with ponatinib (2.7%). Overall, 17 CV-AE were recorded: 7 cases of hypercholesterolemia, 5 pleural or pericardial effusions, one episode of hypertension and 4 cardiac events (atrial fibrillation,ST-segment elevation myocardial infarction, reduction of cardiac ejection fraction and dissecting aneurysm of the aorta); 7 CV-AE were graded as 3 according to the common toxicity criteria and one patient died from dissecting aneurysm of the aorta). The 60-month cumulative CV-AE incidence was 54.4±9.1%. The mean time between the start of the treatment and the occurrence of a CV-AE was 44.4 months (range 19-60). OPLS-DA showed that patient's samples were clearly separated into 2 groups indicating that CV-AE patients (blue dots) presented a markedly distinct metabolic profile compared with patients without CV-AE (green dots); (figure 1). The parameters of the model were R2Y = 0.76 and Q2 = 0.44. To validate the OPLS-DA model, a permutation was performed resulting statistically significant (p=0,002). The main discriminant metabolites were tyrosine, lysine, ornithine, glutamic acid, 2-piperdincarboxylic acid, proline, citric acid, phenylalanine, mannitol, threonine, leucine, creatine, serine, 4-hydroxyproline, and alanine (more represented in CV-AE group); while unknown 204, myristic acid, arabitol, oxalic acid, 4-deoxyrithronic acid, elaidic acid and ribose resulted less expressed in CV-AE group. Conclusions. This exploratory study showed different metabolomic profile of CML patients with CV-AE underwent TKI treatment, suggesting possible mechanisms of endothelial damage mediated by the accumulation of metabolites. Tyrosine, highly expressed in the CV-AE CML group, is a reliable marker of oxidative stress in various acute and chronic diseases.Metabolomics research has considerable potential for translating the metabolic fingerprint into personalized therapeutic strategies. These preliminary data should be confirmed in prospective clinical trials. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1643
Author(s):  
Prahathishree Mohanavelu ◽  
Mira Mutnick ◽  
Nidhi Mehra ◽  
Brandon White ◽  
Sparsh Kudrimoti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Gastrointestinal Adverse Events

Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib. Examination of combined TKI average GI AE incidence found diarrhea most prevalent (22.5%), followed by nausea (20.6%), and vomiting (12.9%). Other TKI GI AEs included constipation (9.2%), abdominal pain (7.6%), gastrointestinal hemorrhage (3.5%), and pancreatitis (2.2%). Mean GI AE incidence was significantly different between TKIs (p < 0.001): bosutinib (52.9%), imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). Diarrhea was the most prevalent GI AE with bosutinib (79.2%) and dasatinib (28.1%), whereas nausea was most prevalent with imatinib (33.0%) and nilotinib (13.2%). Incidence of grade 3 or 4 severe GI AEs was ≤3% except severe diarrhea with bosutinib (9.5%). Unsupervised clustering revealed treatment efficacy measured by the complete cytogenetic response, major molecular response, and overall survival is driven most by disease severity, not TKI type. For patients with chronic phase CML without resistance, optimal TKI selection should consider TKI AE profile, comorbidities, and lifestyle.

scholarly journals Metabolomic Analysis of Patients with Chronic Myeloid Leukemia and Cardiovascular Adverse Events after Treatment with Tyrosine Kinase Inhibitors

2020 ◽  
Vol 9 (4) ◽  
pp. 1180 ◽  
Author(s):  
Giovanni Caocci ◽  
Martino Deidda ◽  
Antonio Noto ◽  
Marianna Greco ◽  
Maria Pina Simula ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Endothelial Damage ◽  
Gas Chromatography Mass Spectrometry ◽  
Metabolomic Analysis

Background: Cardiovascular adverse events (CV-AEs) are considered critical complications in chronic myeloid leukemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (TKIs). The aim of our study was to assess the correlation between metabolic profiles and CV-AEs in CML patients treated with TKIs. Methods: We investigated 39 adult CML patients in chronic-phase (mean age 49 years, range 24–70 years), with no comorbidities evidenced at baseline, who were consecutively identified with CML and treated with imatinib, nilotinib, dasatinib, and ponatinib. All patients performed Gas-Chromatography-Mass-Spectrometry-based metabolomic analysis and were divided into two groups (with and without CV-AEs). Results: Ten CV-AEs were documented. Seven CV-AEs were rated as 3 according to the Common Toxicity Criteria, and one patient died of a dissecting aneurysm of the aorta. The patients’ samples were clearly separated into two groups after analysis and the main discriminant metabolites were tyrosine, lysine, glutamic acid, ornithine, 2-piperdinecarboxylic acid, citric acid, proline, phenylalanine, threonine, mannitol, leucine, serine, creatine, alanine, and 4-hydroxyproline, which were more abundant in the CV-AE group. Conversely, myristic acid, oxalic acid, arabitol, 4-deoxy rithronic acid, ribose, and elaidic acid were less represented in the CV-AE group. Conclusions: CML patients with CV-AEs show a different metabolic profile, suggesting probable mechanisms of endothelial damage.

scholarly journals Specificity of dermatological adverse events of BCR-ABL tyrosine kinase inhibitors and their effect on quality of life of patients with chronic myeloid leukemia

2020 ◽  
pp. 72-76
Author(s):  
E. A. Shatokhina ◽  
A. G. Turkina ◽  
E. Yu. Chelysheva ◽  
O. A. Shukhov ◽  
A. N. Petrova ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Maculopapular Rash ◽  
Abl Tyrosine Kinase

Introduction. BCR-ABL tyrosine kinase inhibitors are currently used to successfully treat chronic myeloid leukemia (CML). Drug therapy is carried out in a continuous daily mode throughout the patient’s life. Treatment with this group of drugs is associated with specific dermatological adverse events (dAE), which can lead to a change in the regimen of effective, vital therapy for CML patients.Purpose. To study the characteristics of dermatological adverse events, the severity and influence on the quality of life of BCR-ABL tyrosine kinase inhibitors.Patients and methods. The observational study included 93 patients. The clinical manifestations of dAE, their severity were evaluated, their photographs and pathomorphological studies of skin biopsy samples were performed, cases of dose reduction or drug withdrawal due to dAE were recorded. The quality of life of patients with dAE was determined based on the assessment of the dermatological index of quality of life.Results. Imatinib therapy was accompanied by a maculopapular rash in 43.3 % of patients, nilotinib caused follicular keratosis in 12.9 % of patients. In 3.2 % of patients, dasatinib caused hyperpigmentation, in 2.2 % of patients lichenoid rashes of the II degree occurred during treatment with bosutinib. Ponatinib treatment was followed by dAE in 9.7 % of patients. All dAE have an impact on the quality of life of patients, but the maculopapular rash and dyskeratotic changes are most pronounced. In a pathomorphological study, these dAE have specific features corresponding to immuno-mediated dermatitis.Conclusions. The most frequent and pronounced dAE that significantly affect the quality of life of patients with CML are a maculopapular rash and dyskeratotic skin changes: psoriasiform and lichenoid dermatitis. Clinical and pathomorphological characteristics of skin reactions make it possible in the future to determine effective methods of supportive therapy for dAE.

Medical Costs of Adverse Events in Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors: Canadian Perspective.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5178-5178
Author(s):  
Nick Newton ◽  
Khalid El Ouagari ◽  
Mireille M. Goetghebeur
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Medical Costs ◽  
Icd 10 ◽  
Grade 3

Abstract Background: Imatinib (Gleevec) is recommended first-line therapy for treatment of chronic myeloid leukemia (CML). A relatively small group of patients treated with imatinib develop resistance or are intolerant to the treatment. Dose escalation of imatinib may be used in some cases. Recently, two treatment options, nilotinib (Tasigna) and dasatinib (Sprycel), have become possible alternatives for patients resistant or intolerant to imatinib. Current data indicates that nilotinib and dasatinib have a different side effect profile. Objectives: This study investigated the costs of adverse events (AEs) in patients receiving nilotinib or dasatinib for chronic and accelerated CML. Methods: Incidence rates of grade 3/4 AEs treated with nilotinib or dasatinib were obtained from nilotinib Phase II Summary of Clinical Safety: 120-Day Safety Update Report and dasatinib product information, respectively. Costs for non-hematological AEs were obtained from the Ontario Case Costing Initiative (OCCI) acute inpatient databases, using ICD-10 codes cross-referenced with AEs described in product monographs. For ICD 10 codes identified for this study, there were not enough cases in CML patients (a minimum of five cases is required to access data) and therefore OCCI costs used in this study were those of AEs in oncology patients. These costs were considered a good approximation of costs of AEs in CML patients by the clinical expert. Costs for grade 3 anemia and thrombocytopenia, and non-febrile neutropenia, were assumed to be outpatient costs and were based on literature, expert validation of treatment pathways and resource utilization in the Canadian context. Costs for grade 4 anemia and thrombocytopenia, and febrile neutropenia, were obtained from the OCCI. Multivariate sensitivity analyses were conducted on costs of AEs. The analysis was developed from a payer perspective considering direct medical costs only. Costs are reported in 2006 Canadian dollars. Results: Cost of treatment-related AEs for CML patients was higher for dasatinib than nilotinib. For both treatments, total costs for AEs associated with the accelerated phase were higher than those associated with the chronic phase: $19,902 versus $7,653 for dasatinib; $8,645 versus $3,790 for nilotinib; respectively. Cost attributable to hematological AEs represented between 45% and 71% of total cost of AEs. Ranking observed among treatments for base case costs of AEs was maintained for both high and low cost estimates, indicating that the model was robust to variation in cost of AEs. Conclusions: For patients resistant or intolerant to imatinib, costs of dasatinib-related AEs were approximately twice the costs of nilotinib-related AEs in both chronic and accelerated phases, highlighting the importance of considering the cost of AEs in economic evaluation of new tyrosine kinase inhibitors. Further research is needed to comprehensively evaluate the impact of AEs on healthcare expenditures.

Molecular Response to Tyrosine Kinase Inhibitors (TKIs) for Chronic Myeloid Leukemia (CML), the Experience At Tawam Hospital, Abudhabi, UAE

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4458-4458
Author(s):  
Arif Alam ◽  
Sabir Hussain ◽  
Amar Lal ◽  
Donna Lee ◽  
Jorgen Kristensen
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Technique ◽  
Molecular Response ◽  
Female Ratio

Abstract Abstract 4458 Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a balanced reciprocal translocation involving the long arms of chromosomes 9 and 22. The fusion gene that is created by this translocation (BCR-ABL1) encodes for a constitutively active protein tyrosine kinase that is primarily responsible for the leukemic phenotype. Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) has become the recommended first-line treatment for patients with CML. Monitoring of the CML is done with quantification of the BCR-ABL transcripts by RQ-PCR–based molecular technique. Twenty nine patients were diagnosed with CML in chronic phase between January 2009 till June 2012. The median age was 32 years (range 22–68 years). Male to female ratio was4.14:1. Three patients were lost from follow up after diagnosis and are excluded. Molecular response is available for 16 patients. Nine patients were treated with Imatinib 400 mg daily, four with Dasatinib 100 mg daily and three with Nilotinib 400 mg BID daily as upfront therapy. Twelve patients have achieved MMR/CMR (75 %) within 18months of starting therapy. Four patients have failed to achieve MMR by 24 months. All non responders were on Imatinib. Interestingly six (37.5%) patients achieved MMR/CMR within 9 months of starting TKIs. Of these only 1 was on Imatinib while the rest were on 2nd generation TKIs (Nilotinib 3 and Dasatinib 2). MMR report from Enestnd trial is 67–71% in favor of Nilotinib as compared to Imatinib 44%, while the Dasision trial reported a MMR of 44 % in favor of Dasatinib with faster rate to response. Our results mirror the results of these phase 3 randomized trial with MMR/CMR of 75 %. Until today there has been no case of progressive disease. Our data is limited but shows that the median age is much lower compared to Western countries, just reflecting differences in the age distribution of the population in the UAE with 80% being below the age of 65 years. Expatriates accounts for approximately 80% of the population in the UAE and many are temporary employed, having limited health care coverage, limited financial means as well as limited possibilities to attend regular follow-ups. This leads to compliance problems, loss from follow-up and suboptimal management and monitoring of their disease. Disclosures: Alam: BMS/Novartis: Consultancy, Honoraria. Hussain:BMS: Consultancy, Honoraria.

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