Detection of BCR-ABL gene in Chronic Myeloid Leukemia patients treated with Tyrosine Kinase Inhibitors Drugs by Gene Expert System

2018 ◽  
Vol 9 (SPL1) ◽  
Author(s):  
Maysaa Ali Abdul Khaleq ◽  
Hussein Ali Saheb ◽  
Ahmed M Sultan ◽  
Mohsen A. N Alrodhan
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Molecular Technique ◽  
Advanced Stage ◽  
Newly Diagnosed ◽  
The Mean ◽  
One Year ◽  
Wbc Count ◽  
Rna Transcript

Chronic myeloid leukemia (CML) is one of human malignancies caused by genetic mutation and chromosomal translocation, a BCR-ABL fusion gene and as result Philadelphia chromosome is formed. The irregular tyrosine kinase activity of encoded protein by this gene causes the establishment of the disease. Nilotinib are potent and well inhibitor for BCR-ABL tyrosine kinase. This study was conducted at the period from September 2016 to February 2017,100 Iraqi CML patients were divided into two groups, first group of 50 patients were received Imatinib 400-800 mg/day, second group of another 50 patients were received 800 mg/day Nilotinib, WBC were microscopically counted using improved Neubauer ruled hemocytometer counting chamber.BCR-ABL gene RNA transcript and endogenous control (house keeping gene ) RNA transcript were extracted and purified and then reverse transcripted to cDNA after that the product was amplified and quantified by q RT-PCR. The results first group patients distribution according to the gender were 56% and 44% for males and females respectively while the mean age of the patients was 45.82 ± 16.17,the result of WBC counting of this group in regard to disease duration showed that the highest value was observed in newly diagnosed and advanced stage 98.28 ± 89.28,77.11± 2.98 respectively.The WBC count return to normal level after the period of treatment with Imatinib with significant reduction after one year at p≤ 0.0001.The results of molecular technique and BCR-ABL analysis in newly diagnosed, advanced stage and cytogenetic failure patients were 10.05 ± 4.7,3.03± 0.94 and 28.4±0.09 respectively with significant decrease after one year of treatment at p ≤ 0.002.On the other hand the results of the second group of CML patients in relation to the gender were 45% and 55% of males and femalesrespectively,while the mean age group was 36.68 ±13.51. The results of WBC count according to disease distribution in newly diagnosed and advanced stage were 87.5 ± 8.71 and43±21.72 respectively. WBC count was return to normal level after one year of treatment with Nilotinib with significant decrease at p≤0.0001. While the molecular technique and BCR-ABL analysis in newly diagnosed, advanced stage and cytogenetic failure group were 7.77±4, 1, 16.17 ± 3.78 and 2.02±0.53 after one year of treatment with Nilotinib with significant decrease at p≤ 0.0001. We conclude that treatment with Imatinib was found tough in a high extent of patients, Nilotinib is extending specific tyrosine kinaseinhibitor possess greater and selectively activity for BCR-ABL.

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.

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.

One-year and longer-term molecular responses to nilotinib and dasatinib for newly diagnosed chronic myeloid leukemia: A matching-adjusted indirect comparison.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 7072-7072
Author(s):  
James E. Signorovitch ◽  
Eric Qiong Wu ◽  
Keith A. Betts ◽  
William M. Reichmann ◽  
Darren Thomason ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Indirect Comparison ◽  
Newly Diagnosed ◽  
Molecular Responses ◽  
Adjusted Indirect Comparison ◽  
One Year

scholarly journals First-Line Second Generation Tyrosine Kinase Inhibitors in Newly Diagnosed Accelerated Phase Chronic Myeloid Leukemia Patients.

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 48-48 ◽  
Author(s):  
Marie Balsat ◽  
Vincent Alcazer ◽  
Gabriel Etienne ◽  
Gaelle Fossard ◽  
Francoise Huguet ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Board Of Directors ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Newly Diagnosed ◽  
First Line ◽  
Advisory Committees ◽  
Free Survival

Abstract Introduction Up to 10% of patients (pts) with chronic myeloid leukemia (CML) are already in accelerated phase (AP) at diagnosis and despite treatment advances in the field of tyrosine kinase inhibitors (TKIs), management of these pts is challenging. This study aims to examine the benefit of second generation BCR-ABL tyrosine kinase inhibitors (TKI2) as first-line treatment for newly diagnosed AP-CML. Methods Pts meeting criteria for AP-CML at diagnosis and treated with first-line TKI2 (i. e. Nilotinib or Dasatinib) were included in this retrospective multicenter observational national study. AP-CML were defined according to the ELN (Baccarani, Blood 2013) as hematological acceleration (HEM-AP, any of the following features: blasts in PB or marrow 15-29%, or blasts+promyelocytes in PB or marrow >30% with blasts <30%, basophils in PB ≥20%, or persistent thrombocytopenia <100×109/L (unrelated to therapy) and/or chromosomal abnormalities in addition to the Ph at diagnosis (ACA-AP). Pts initiated nilotinib at 6-800 mg BID or dasatinib at 100-140 mg QD with further dose adaptations according to toxicities or response. Overall survival (OS), progression-free survival (PFS) and failure-free survival [FFS= progression to blast crisis, death, loss of any previous response (CHR, CCyR, or MMR) discontinuation of TKI2 for toxicity], were analysed since TKI2 initiation in intention-to-treat. Results Sixty-six pts were analysed: 45 males (68%) and 21 females (32%) with a median age at diagnosis of 49 (15-78.5) years. The median follow-up of the cohort was 43.5 (1.7-117) months. We segregated the pts in HEM-AP (n=33) and ACA-AP (n=33) for further analyses. Nine pts with HEM-AP harboured ACA and were analysed in the HEM-AP group. Fusion transcripts were of the Major BCR in 57 pts, 6 pts had atypical BCR-ABL transcripts (2 e19a2, and 1 e1a2 in the HEM-AP group and 2 e19a2 and 1 Ma3 in the ACA-AP group), and 3 transcripts unknown. Not surprisingly, spleen enlargement was significantly greater in the HEM-AP group [10 (5-14.75) vs. 3 (0-10)cm, p=0.014]. PB basophils [median 10 (6-16) vs. 3 (2-5)%, p <0.001], PB blasts [median: 12.05 (7.5-15) vs. 1.5 (0-4)%, p<.001], as well as PB blasts+promyelocytes [median 14 (11-20) vs. 4 (1-7)%, p<.001]. Hemoglobin levels were significantly lower in the HEM-AP group [median 93 (6-113.5) vs 120 (100-134) g/L, p<0.001]. Neither WBC counts, platelets counts, nor BCR-ABL/ABL load differed significantly between the 2 groups. In the ACA-AP group, 10 (30%) pts harbored major route ACA and 23 (70%) pts harbored minor route ACA of whom 3 pts with i(17q) and 1 with 7q abnormalities. In the ACA-AP group, Sokal score was low in 42%, intermediate in 32% and high in 26% of pts (2 pts unknown). Dasatinib was initiated in 19/33 pts (57.5%) in the HEM-AP group and in 8/33 pts (24%) in the ACA-AP group. Treatment responses did not significantly differ between ACA-AP and HEM-AP group, regardless of the TKI2 administered, with 33/33 (100%) vs 31/33 (94%) pts achieving a CHR, 2/33 (6%) pts vs 0/33 (0%) pts achieving a MCyR, 5/33 (15%) pts vs 5/33 (15%) pts achieving CCyR, 9/33 (27%) pts vs 4/33 (12%) pts achieving a MMR respectively. However, 11/33 (33%) HEM-AP vs 22/33 (66%) ACA-AP pts achieved a deep molecular response (p=0.013, Fisher test). Median times to CHR and MMR were not significantly different between ACA-AP group and HEM-AP group with 1.05 vs 1.25 months (p=0.088) for CHR and 6 vs 7 months (p=0.156) for MMR, respectively. Overall, the estimated 7-yr FFS rate was 56.92% (95%CI: 40-81), 7-yr PFS was 83.42% (95% CI: 69.6-100%) and 7-yr OS was 87.14% (95%CI: 73.5-100%) (Figure 1.) with no significant differences between ACA-AP vs HEM-AP pts [7-yr FFS: 57.7 vs. 62%, p=0.739; 7-yr PFS: 84.7% vs. 84%, p=0.185; 7-yr OS: 88.9% vs 86.6%, p=0.132] respectively. There was also no difference in FFS, PFS and OS according to the type of TKI2. The only factors influencing negatively OS were the % of BM blasts (HR=1.17, 95%CI: 1.1-1.28, p<0.001) and the % of BM blasts+promyelocytes (HR=1.14, 95%CI: 1.06-1.22, p<0.001). We identified too few significant factors in univariate analysis to perform a multivariate analysis. Conclusion The initiation of a TKI2 in newly diagnosed AP-CML pts induces excellent response and survival rates, probably superior to that of Imatinib first-line, and counterbalances the negative impact of this advanced disease, particularly in HEM AP subgroup. Disclosures Etienne: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau. Berger:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau. Rea:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Pfizer: Honoraria. Nicolini:BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau; Sun Pharma Ltd: Consultancy.

scholarly journals Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities

Blood ◽  
2013 ◽  
Vol 121 (24) ◽  
pp. 4867-4874 ◽  
Author(s):  
Preetesh Jain ◽  
Hagop Kantarjian ◽  
Aziz Nazha ◽  
Susan O’Brien ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Treatment Modality ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Early Response ◽  
Newly Diagnosed ◽  
Key Points

Key Points This analysis demonstrates the universality of the early response in CML, regardless of the treatment modality used. Factors correlating with poor cytogenetic responses at 3-mo assessment in a multivariate analysis across all 4 TKIs.

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