scholarly journals Proteomics Analysis Reveals Protein Panels That Are Associated with Prediction to Tyrosine Kinase Inhibitors Response, Bone Marrow Transplant, Survival and Disease Outcome of Chronic Myeloid Leukemia Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5434-5434
Author(s):  
Ayodele Alaiya ◽  
Mahmoud Aljurf ◽  
Zakia Shinwari ◽  
Fahad Z. Alsharif ◽  
Hazza A. Alzahrani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Personalized Medicine ◽  
Tyrosine Kinase ◽  
Treatment Response ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
The Other ◽  
Disease Outcome

Abstract Clinical and molecular diagnosis of most hematological malignancies including Chronic Myeloid Leukemia (CML) can be accurately made. However, prediction of treatment response and estimation of disease survival period eludes the currently available tools for patient care. Quantitative expression proteomics can potentially be developed as effective tool to monitor therapy response towards achieving personalized medicine for CML patients. We have over 10 years follow up period for some of the CML patients, and the majorities of them are alive and doing well on Imatinib. On the other hand, a small fraction of the patients were switched to alternative Tyrosine Kinase Inhibitors (TKI) and some underwent bone marrow transplants (BMT). Our follow up results stratified all 37 analyzed newly diagnosed CP-CML patients into 5 distinct cohorts including 52% on Imatinib, 12% on Nilotinib, 9% on Dasatinib, and 15% BMT, while 12% of the patients had disease-related mortality. Kaplan-Meier survival curve showed no significant difference between all patients on TKI and BMT that were alive under a follow up period of 4-11 years compared. On the other hand 3 of 4 patients had disease related deaths less than 2 years of diagnosis. Only one patient survived for almost 10 years (Figure 1). Besides survival analysis, peripheral blood samples obtained from the patients at time of diagnosis were subjected to expression proteome analysis using label-free quantitative liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). A subset of significantly differentially expressed proteins was able to distinctively discriminate samples into their respective treatment response and disease outcome groups based on unique protein expression signatures (P<0.05 and > 2- ∞- fold change, (Figure 2). Some of the identified proteins were implicated in hematological diseases including CML as potential biomarkers using Ingenuity Pathway Analysis. These protein signatures once validated in larger sample cohorts might be capable of prediction of molecular response, choice of therapy and disease outcome for CML patients. Therefore; allowing for identification of would be high risk patients that might potentially benefit from aggressive treatment at point of diagnosis pre initiation of conventional therapy. Altogether our findings indicate that analysis of panel of protein markers have the potential of clinical utility for prediction of response to therapy, disease survival and objective prognostication of disease outcome, thus bringing personalized medicine closer to CML patients. Disclosures No relevant conflicts of interest to declare.

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.

Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: A case report

2012 ◽  
Vol 18 (4) ◽  
pp. 440-444 ◽  
Author(s):  
Prathima Prodduturi ◽  
Anamarija M Perry ◽  
Patricia Aoun ◽  
Dennis D Weisenburger ◽  
Mojtaba Akhtari
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Bone Marrow Aplasia ◽  
Line Therapy ◽  
Grade 3

Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.

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.

Role of ABL Gene Mutations in Chronic Myeloid Leukemia Patients Resistant to Imatinib and Results of Treatment Shift to Second-Generation Tyrosine Kinase Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4442-4442
Author(s):  
Silvia Marce ◽  
Lurdes Zamora ◽  
Marta Cabezon ◽  
Blanca Xicoy ◽  
Concha Boqué ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
The Other ◽  
Molecular Response ◽  
Imatinib Resistant

Abstract Abstract 4442 Introduction: Chronic myeloid leukemia (CML) is a model of disease in the development of targeted therapies. Tyrosine kinase inhibitors (TKIs) have transformed the approach to management of CML and have dramatically improved patients' outcome. Clinical response is obtained in the majority of patients. However, a significant proportion of patients do not achieve the optimal desirable outcome or are completely resistant to this treatment. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKIs has produced high rates of hematologic and cytogenetic response in mutated ABL patients. The aim of this study was analyzed the presence of ABL mutations in imatinib resistant patients and determine the importance of changing to second-generation TKIs treatment as soon as failure or suboptimal response is recognized. Patients and methods: From 420 CML patients diagnosed in 6 centers between 2004 and 2010, we have amplified and sequenced the ABL1 domain from BCR-ABL1 amplicon of 45 imatinib resistant patients (23 patients with suboptimal response, 14 with treatment failure, 4 who lost the molecular response and 4 patients who progressed to blast phase). The obtained sequences were compared with the published ABL1 sequence, GenBank U07563, using BLAST 2 software. Results: We have detected mutations in 15 of 45 patients (33%), some of them with more than one mutation (Table 1). Seven of these patients were treated with second-generation TKIs as a single treatment. Three of them achieve a major molecular response (MMR), one patient is in complete cytogenetic response (CCyR) and the other two patients are in major (MCyR) and partial (PCyR) cytogenetic response. Another patient received nilotinib followed by hematological stem cell transplantation (HSCT) and is in MMR. Two patients were submitted to a HSCT and achieve MMR. Only one patient treated with nilotinib as second option has not reach a cytogenetic response one year after detection of the mutation. Two of the patients with the T315I mutation were treated with IFN and nilotinib achieving PCyR and MCyR, respectively, and are still alive. The other T315I patient, and two patients in blast-crisis (BC) disease with the F317L mutation who received dasatinib prior to the study of ABL mutations, died before a change of treatment could have been performed. Conclusions: Disclosures: No relevant conflicts of interest to declare.

Evaluation of the Risk of Hepatitis B Reactivation Among Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5429-5429 ◽  
Author(s):  
Ohad Benjamini ◽  
Maya Zlotnick ◽  
Elena Ribakovsky ◽  
Meirav Kedmi ◽  
Adrian Duek ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Hepatitis B ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Hbv Reactivation ◽  
Positive Serology ◽  
Hepatitis B Reactivation

Abstract Background: Immunosuppressive therapy is a known risk factor for hepatits B reactivation. The highest risk is reported in hematologic patients treated with anti-CD20 monoclonal antibodies, glucocorticoids and hematopoietic stem cell transplantation. Currently, treatment with tyrosine kinase inhibitors (TKIs) in the vast majority of chronic myeloid leukemia (CML) patients is life-long. Recently healthcare professionals were advised to test for hepatitis B infection before initializing therapy with TKIs and closely monitor HBV carriers. The risk is considered class effect with all TKIs and recommendations are based on case reports. Aim: The aim of the current study was to evaluate the risk of hepatitis B reactivation in patients with CML treated with TKIs. Methods: The records of patients with CML treated with TKIs from a single center were systematically reviewed for hepatitis B serology and serum biochemistry. Results: One hundred eighty one patients diagnosed with CML between the years 1983 and 2016 were evaluated. The median age at diagnosis was 49.7 years (range 18-89), 117/181 (65%) males, with median duration of follow up with TKI therapy of 5.3 years (range 0.4 to 33 years). Over a total of 1195 years of therapy with TKIs no cases of HBV reactivation were identified. Among 114 patients with hepatitis serology, 11 patients (10%) had evidence of prior resolved HBV infection (HBsAg negative/anti-HBc positive). Two of them had anti-HBs positive serology, one had negative PCR for HBV DNA and other two patients received lamivudine prophylaxis. Only one patient had HBsAg positive serology. None of the patients with positive hepatitis serology had clinical or biochemistry evidence of hepatitis B reactivation. The 67 patients without available hepatitis serology had normal liver transaminases at 6 months of TKI therapy and at last day of follow up, confirming that no overt hepatitis B reactivation occurred. Conclusions: We evaluated hepatitis B reactivation in a rather large cohort of CML patients, treated with TKIs. Although there were no cases of HBV reactivation during long term follow up, it should be emphasized that even a low incidence may exert a significant risk due to the long duration of treatment in a chronic disease with lifelong therapy. Our study infers that patients with serology of prior resolved HBV infection are at low risk for hepatitis B reactivation. Larger cohorts of patients with positive hepatitis B serology in a multicenter long term evaluation should be performed in order to address current recommendations for patients' safety and concerns. Disclosures No relevant conflicts of interest to declare.

scholarly journals Patterns of Tyrosine Kinase Inhibitor Utilization in Newly Treated Patients With Chronic Myeloid Leukemia: An Exhaustive Population-Based Study in France

2021 ◽  
Vol 11 ◽  
Author(s):  
Marie Pajiep ◽  
Cécile Conte ◽  
Françoise Huguet ◽  
Martin Gauthier ◽  
Fabien Despas ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Antihypertensive Agents ◽  
Female Ratio ◽  
Increased Risk ◽  
Incident Cases

We analyzed demographic characteristics, comorbidities and patterns of treatment with tyrosine kinase inhibitors (TKIs) in a cohort of 3,633 incident cases of chronic myeloid leukemia (CML) identified across France from 1 January 2011 to 31 December 2014. Patients were identified through a specific algorithm in the French Healthcare Data System and were followed up 12 months after inclusion in the cohort. The estimated incidence rate of CML for this period in France was 1.37 per 100,000 person-years (95% Confidence Interval 1.36-1.38) and was higher in men, with a peak at age 75-79 years. At baseline, the median age of the cohort was 60 years (Inter Quartile Range 47-71), the Male/Female ratio was 1.2, and 25% presented with another comorbidity. Imatinib was the first-line TKI for 77.6% of the patients, followed by nilotinib (18.3%) and dasatinib (4.1%). Twelve months after initiation, 86% of the patients remained on the same TKI, 13% switched to another TKI and 1% received subsequently three different TKIs. During the follow-up, 23% discontinued and 52% suspended the TKI. Patients received a mean of 16.7 (Standard Deviation (SD) 9.6) medications over the first year of follow-up, and a mean of 2.7 (SD 2.3) concomitant medications on the day of first TKI prescription: 24.4% of the patients received allopurinol, 6.4% proton pump inhibitors (PPI) and 6.5% antihypertensive agents. When treatment with TKI was initiated, incident CML patients presented with comorbidities and polypharmacy, which merits attention because of the persistent use of these concomitant drugs and the potential increased risk of drug-drug interactions.

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