Finding of Kinase Domain Mutations in Patients With Chronic Phase Chronic Myeloid Leukemia Responding to Imatinib May Identify Those at High Risk of Disease Progression

2008 ◽  
Vol 26 (29) ◽  
pp. 4806-4813 ◽  
Author(s):  
Jamshid S. Khorashad ◽  
Hugues de Lavallade ◽  
Jane F. Apperley ◽  
Dragana Milojkovic ◽  
Alistair G. Reid ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Mutation Screening ◽  
Prognostic Significance ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Imatinib Resistance ◽  
Risk Of Disease

Purpose Kinase domain (KD) mutations in the BCR-ABL gene are associated with resistance to imatinib in chronic myeloid leukemia (CML) but their incidence and prognostic significance in chronic phase (CP) patients without resistance are unclear. Patients and Methods We analyzed outcome for 319 patients with CML-CP who were treated with imatinib; 171 were in early CP (ECP) and 148 were in late CP (LCP). Patients were screened routinely for mutations using direct sequencing regardless of response status. The 5-year cumulative incidence of mutations was 6.6% for ECP and 17% for LCP patients. Results Of the 319 patients, 214 (67%) achieved complete cytogenetic responses (CCyR). The identification of a mutation without other evidence of imatinib resistance was highly predictive for loss of CCyR (RR, 3.8; P = .005) and for progression to advanced phase (RR, 2.3; P = .01), though the intervals from first identification to loss of CCyR and disease progression were relatively long (median, 21 and 16 months, respectively). Mutations in the P-loop (excluding residue 244) were associated with a higher risk of progression than mutations elsewhere. Conclusion We conclude that routine mutation screening of patients who appear to be responding to imatinib may identify those at high risk of disease progression.

Mutation Analysis of ABL1 Gene and its Relation to the Achievement of Major Molecular Response in Indonesian Chronic Myeloid Leukemia Patients

2020 ◽  
Vol 17 (1) ◽  
pp. 48-54
Author(s):  
Reni Widyastuti ◽  
Melva Louisa ◽  
Ikhwan Rinaldi ◽  
Riki Nova ◽  
Instiaty Instiaty ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Cross Sectional ◽  
Imatinib Resistance

Background: Imatinib mesylate is the first tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) therapy. Imatinib is an effective drug. However, previous studies have shown that about 20-30% of patients eventually would develop resistance to imatinib. Approximately 40% of imatinib resistance is associated with BCRABL kinase domain mutation. One of the most common and serious variations account for imatinib response is T315I of ABL1 gene. Objective: The study aimed to examine the association of T315I mutation with the ABL1 gene and its relation to major molecular response (MMR) achievement in CML patients. This study also examined other mutations adjacent to T315I, i.e., F311I, F317L, and different possible variations in the ABL1 gene. Methods: This was a cross-sectional study on Indonesian CML patients in chronic phase. We analyzed 120 blood samples from patients in chronic phase who have received imatinib mesylate (IM) for ≥12 months. Results: There were no T315I, F311I, and F317L mutations found in this study. However, we found another variation, which was 36 substitutions from A to G at position 163816 of ABL1 gene (according to NG_012034.1). Conclusions: We found no T315I, F311I, and F317L mutations in this study. Our findings suggest that there might be other factors that influenced the MMR achievement in our study patients. However, there were 36 substitutions from A to G at position 163.816 (according to NG_012034.1) that needed further examination to explore the significance of this mutation in clinical practice.

The development of imatinib as a therapeutic agent for chronic myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2640-2653 ◽  
Author(s):  
Michael Deininger ◽  
Elisabeth Buchdunger ◽  
Brian J. Druker
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Chronic Phase ◽  
Initial Response ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Interferon Α ◽  
Disease Mutations ◽  
Risk Of Disease

AbstractImatinib has revolutionized drug therapy of chronic myeloid leukemia (CML). Preclinical studies were promising but the results of clinical trials by far exceeded expectations. Responses in chronic phase are unprecedented, with rates of complete cytogenetic response (CCR) of more than 40% in patients after failure of interferon-α (IFN) and more than 80% in newly diagnosed patients, a level of efficacy that led to regulatory approval in record time. While most of these responses are stable, resistance to treatment after an initial response is common in more advanced phases of the disease. Mutations in the kinase domain (KD) of BCR-ABL that impair imatinib binding have been identified as the leading cause of resistance. Patients with CCR who achieve a profound reduction of BCR-ABL mRNA have a very low risk of disease progression. However, residual disease usually remains detectable with reverse transcription–polymerase chain reaction (RT-PCR), indicating that disease eradication may pose a significant challenge. The mechanisms underlying the persistence of minimal residual disease are unknown. In this manuscript, we review the preclinical and clinical development of imatinib for the therapy of CML, resistance and strategies that may help to eliminate resistant or residual leukemia.

scholarly journals BCR-ABL Kinase Domain Mutations Exist in Few Imatinib Treated Chronic Myeloid Leukemia (CML) Patients Exhibiting Stable Cytogenetic and Hematologic Responses

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5427-5427
Author(s):  
Afia Muhammad Akram ◽  
Tanveer Akhtar ◽  
Asma Chaudhary ◽  
Muhammad Mudassar Shahzad ◽  
Ahmad Mukhtar Khalid ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Mutation Screening ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Nucleotide Substitutions ◽  
Disease Evolution ◽  
Abl Kinase

Abstract Introduction: Complete hematologic response (CHR) and complete cytogenetic response (CCyR) is observed in almost 80-90% freshly diagnosed chronic phase chronic myeloid leukemia patients treated with Imatinib, a tyrosine kinase inhibitor (TKI). The responses are usually persistent; however the residual disease may be detected molecularly by amplifying BCR-ABL transcript. Furthermore, the leukemogenic potential of the residual BCR-ABL positive cells is reflected when disease reoccurs after discontinuation of therapy. There are evidences of occurrence of mutations in patients who have achieved CCyR, which indicates their role in disease persistence and drug resistance. Patients and Methods: We performed BCR-ABL kinase domain (KD) mutation screening in 150 Imatinib treated CML patients (either resistant or sensitive to therapy) including 84 (56%) individuals manifesting CHR and and 67 (44.7%) with CCyR. For this purpose, nested reverse transcription PCR followed by direct sequence analysis was implemented as previously described. Statistical analysis was performed using SPSS version 19 (IBM, Chicago, IL, USA). Results and Conclusion: Thirty five of 150 patients exhibited mutations in BCR-ABL KD, out of which 11 (31.4%) had achieved CHR and 08 (22.9%) attained CCyR. Single rather than multiple mutated sites in ABL-KD was observed in most of mutant patients achieving CHR (27.3%) or CCyR (27.3%) (Figure 1). Eleven nucleotide substitutions were observed in more than one patient, including Imatinib sensitive individuals with CHR and CCyR (Table 1). Those include C-Helix, SH2 contact, Imatinib binding site (IBS), and A-loop mutations within ABL kinase domain. Overall survival among chronic myeloid leukemia patients achieving different levels of hematologic and cytogenetic response irrespective of mutation status show a favorable survival outcome in those attaining CHR and CCyR (Figure 2). Presence of mutations in cytogenetically stable patients of CML with good hematologic outcomes indicates a likely suboptimal response or TKI resistance during the course of treatment. It is believed by some researchers that mutations do not exist previously, but emerge after Imatinib exposure. Whereas, some believe that TKI's do not induce mutations, rather they select them. Many studies reported a rise in BCR-ABL transcript levels during follow up studies in patients who co-exhibited mutated ABL-KD and CCyR. This suggests that emergence of mutations is a disease evolution process independent of TKI therapy. Studies report that monitoring of nucleotide substitutions in optimally responding patients plays an important role in well managed therapeutic approach. Our studies reveal occurrence of ABL-KD mutations in patints with stable hematologic and cytogenetic response, therefore we suggest for regular mutation screening in CML paients irrespective of their response towards TKIs. Disclosures No relevant conflicts of interest to declare.

In Early-Chronic Phase Chronic Myeloid Leukemia Patients Treated with Imatinib, Resistance Is Rarely Mediated by Abl Kinase Domain Mutations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1934-1934 ◽  
Author(s):  
Simona Soverini ◽  
Alessandra Gnani ◽  
Sabrina Colarossi ◽  
Fausto Castagnetti ◽  
Elisabetta Abruzzese ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Point Mutations ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Line Treatment ◽  
Front Line ◽  
Imatinib Resistance

Abstract Point mutations in the kinase domain (KD) of the Bcr-Abl gene are generally regarded as the most frequent mechanism of resistance to the tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) in patients (pts) with chronic myeloid leukemia (CML). Nearly all studies, however, have focused mainly on pts with advanced disease, where resistance is most often observed. Nowadays, the great majority of pts on IM are early chronic phase (ECP) pts receiving IM as front-line treatment. If, on one hand, the IRIS study demonstrated that response rates are high and relapse is infrequent in ECP, on the other hand we still know very little on the contribution of KD mutations to resistance in this subset of pts. Between January 2005 and July 2007 we analyzed for the presence of Abl KD mutations one hundred and two ECP pts on IM who were referred to our laboratory because their response was defined either as ‘failure’ (n=70 pts) or as ‘suboptimal’ (n=32 pts) according to recently published recommendations (Baccarani et al, Blood 2006). Twenty mutations were detected in 17/70 (24%) pts who failed IM. In particular, mutations were observed in 1/2 pts who showed no hematologic response (HR) at 3 months, 1/10 (10%) pts who showed less than partial cytogenetic response (PCgR) at 12 months, 4/25 (16%) pts who showed less than complete cytogenetic response (CCgR) at 18 months, 6/23 (26%) pts who lost CCgR, 5/10 (50%) pts who lost HR. Mutations were M244V (n=2), G250E (n=1), Y253H (n=4), E255K (n=1), T277A (n=1), E279K (n=1), F311I (n=1), T315I (n=1), M351T (n=3), E355D (n=1), F359V (n=1), H396R (n=3). In 7 pts who progressed to accelerated or blastic phase shortly after, four had mutations: Y253H (n=2 pts), E255K (n=1 pt) and T315I (n=1 pt). Four mutations were detected in 4/32 (13%) pts who had a suboptimal response to IM. In particular, a mutation was observed in 1/11 (9%) pts who showed less than PCgR at 6 months and in 3/21 (14%) pts who showed less than CCgR at 12 months. Mutations were E255K, F317L, M351T, F359V. In both groups no correlation was observed between likelihood of mutation selection and Sokal risk score. We conclude that in ECP pts who receive IM as front-line treatment Abl KD mutations are not the major mechanism of drug-resistance, probably because mutations tend to accumulate during the natural course of the disease as a result of a progressively increasing genetic instability and are therefore a feature of CML clinical deterioration rather than a phenomenon observed only against a background of IM exposure. Our data highlight the need to find out which is the actual predominant mechanism(s) of resistance acting in the setting of ECP - which now gathers the overwhelming majority of CML pts on IM therapy - as a mandatory step towards the development of effective second-line treatment strategies.

scholarly journals Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2598-2605 ◽  
Author(s):  
Richard D. Press ◽  
Stephanie G. Willis ◽  
Jennifer Laudadio ◽  
Michael J. Mauro ◽  
Michael W. N. Deininger
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Mutation Screening ◽  
Progression Free Survival ◽  
Fold Increase ◽  
Kinase Domain ◽  
Characteristic Analysis ◽  
Imatinib Resistance ◽  
Kinase Domain Mutation

AbstractIn imatinib-treated chronic myeloid leukemia (CML), secondary drug resistance is often caused by mutations in the BCR-ABL kinase domain (KD). As alternative therapies are available for imatinib resistance, early identification of mutations may prevent disease progression. Because most patients are routinely monitored by BCR-ABL quantitative polymerase chain reaction (PCR), it is important to define the optimal increase in BCR-ABL that should trigger mutation testing. Expert panels have provisionally recommended a 10-fold BCR-ABL increase as the trigger for mutation screening, acknowledging the lack of consensus. To address this question, we monitored 150 CML patients by quantitative PCR and DNA sequencing. Thirty-five different mutations were identified in 53 patients, and, during 22.5 months (median) of follow-up after sequencing, mutations were significantly predictive of shorter progression-free survival. An unbiased receiver operating characteristic analysis identified a 2.6-fold increase in BCR-ABL RNA as the optimal cutoff for predicting a concomitant KD mutation, with a sensitivity of 77% (94% if including subsequent samples). The 2.6-fold threshold approximated the analytic precision limit of our PCR assay. In contrast, transcript rise cutoffs of 5-fold or greater had poor diagnostic sensitivity and no significant association with mutations. We conclude that the currently recommended 10-fold threshold to trigger mutation screening is insensitive and not universally applicable.

BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1208-1215 ◽  
Author(s):  
Simona Soverini ◽  
Andreas Hochhaus ◽  
Franck E. Nicolini ◽  
Franz Gruber ◽  
Thoralf Lange ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Abl Kinase

AbstractMutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection.

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