Cytogenetic and Molecular Failure at 12 Months will be the Optimal Time Point for BCR-ABL1 Tyrosine Kinase Domain Mutation Analysis in Patients with Chronic Myeloid Leukemia: The Analysis Based on 2013 European LeukemiaNet Recommendation

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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Ponatinib induced improvement of cutaneous lesions associated to accelerated phase of Ph-positive chronic myeloid leukemia

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2016.016 ◽

2016 ◽

Vol 8 ◽

pp. 2016016

Author(s):

Massimo Breccia ◽

Gioia Colafigli ◽

Luisa Quattrocchi ◽

Elisabetta Abruzzese ◽

Giuliana Alimena

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Kinase Domain ◽

Third Generation ◽

Cutaneous Lesions ◽

Advanced Phase ◽

Kinase Domain Mutation

Ponatinib a third generation tyrosine kinase inhibitor, has been approved for all phases of disease in CML. In advanced phase, has been confirmed with a good efficacy in all type of resistance, including T315I kinase domain mutation. We here report activity of the drug in advanced phase with extramedullary localization.

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Double-Gradient–Denaturing-Gradient Gel Electrophoresis for Mutation Screening of the BCR-ABL Tyrosine Kinase Domain in Chronic Myeloid Leukemia Patients

Clinical Chemistry ◽

10.1373/clinchem.2004.047274 ◽

2005 ◽

Vol 51 (7) ◽

pp. 1263-1266 ◽

Cited By ~ 17

Author(s):

Nathalie Sorel ◽

Florence Chazelas ◽

André Brizard ◽

Jean-Claude Chomel

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Gel Electrophoresis ◽

Myeloid Leukemia ◽

Denaturing Gradient Gel Electrophoresis ◽

Mutation Screening ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Abl Tyrosine Kinase ◽

Gradient Gel Electrophoresis

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Stem cell transplantation for patients with chronic myeloid leukemia resistant to tyrosine kinase inhibitors with BCR-ABL kinase domain mutation T315I

Cancer ◽

10.1002/cncr.25092 ◽

2010 ◽

Vol 116 (15) ◽

pp. 3631-3637 ◽

Cited By ~ 19

Author(s):

Nikolai Velev ◽

Jorge Cortes ◽

Richard Champlin ◽

Dan Jones ◽

Gabriela Rondon ◽

...

Keyword(s):

Stem Cell ◽

Chronic Myeloid Leukemia ◽

Stem Cell Transplantation ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Domain ◽

Abl Kinase ◽

Kinase Domain Mutation

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Mutational Phasing: Clinical Relevance in Tyrosine Kinase Domain Mutations Using Next Generation Sequencing in Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-114130 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4269-4269

Author(s):

Seema S. Bhatwadekar ◽

Parth Shah

Keyword(s):

Next Generation Sequencing ◽

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Mutation Analysis ◽

Clinical Relevance ◽

Myeloid Leukemia ◽

Sanger Sequencing ◽

Blast Crisis ◽

Kinase Domain ◽

Generation Sequencing

Abstract Background: Tyrosine kinase mutation analysis in BCR/ABL1 gene is important for management of patients with chronic myeloid leukemia. Sanger Sequencing has been the mainstay for testing with Next Generation Sequencing (NGS) now becoming the primary technology. In this study we show a comparison between NGS versus Sanger Seqencing based ABL kinase domain mutation analysis with a likely trend of clinical relevance based on a compound versus polyclonal state of mutational distribution which may also need to be considered for patient management and therapy. Methodology: A total of 213 Imatinib-resistant patients with CML for BCR-ABL1 mutation analysis were processed on both technologies.Initial blood counts were assessed and RNA was extractedfollowed by cDNA conversion. NGS libraries were prepared with 400bp multiplexed amplicons to allow optimal phasing. Results: 179 samples were negative by both technologies. A total of only 20 samples were positive and concordant by both technologies(58.2%). Mutations in 14 other samples however were only detected in NGS(41.17%). In these 14 samples (41.17%), NGS was able to detect 23 mutations with mutation frequencies of 3-28%, which were missed by Sanger. Conclusions: Moreover 11/34 patients had 2 or >2 mutations. An inhouse script delineated mutations as compound or polyclonal from NGS data. 2/11 cases demonstrated compound mutations (Mutations in the same clone) while 7/11 cases were polyclonal per NGS. Sanger sequencing cannot differentiate between polyclonal and compound mutations. 2/11 cases appeared to have polyclonal and compound mutations. 4/11 patients presented in a blast crisis or accelerated phase CML. Interestingly, most of these patients hadat leasttwo mutations and were polyclonal(3/4). Significantly previously archived samples patients with polyclonal mutations showed polyclonality at extremely low frequency percentages in initial samples. None of the single mutation patients had presented in a blast crisis or an accelerated phase. Disclosures No relevant conflicts of interest to declare.

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Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors

Blood ◽

10.1182/blood-2008-04-149948 ◽

2008 ◽

Vol 112 (13) ◽

pp. 4839-4842 ◽

Cited By ~ 52

Author(s):

Elias Jabbour ◽

Hagop M. Kantarjian ◽

Dan Jones ◽

Neeli Reddy ◽

Susan O'Brien ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Cytogenetic Response ◽

Kinase Domain ◽

Disease Stage ◽

Kinase Domain Mutation

Abstract Mutations in codon 317 after treatment with imatinib and dasatinib have been reported. We reviewed patients with chronic myeloid leukemia and mutations after tyrosine kinase inhibitor (TKI) therapy. F317L was detected in 20, including 12/99 (12%) with mutation after imatinib failure, and 8/16 (50%) after dasatinib (P = .001). Median follow-up from mutation detection was 25 months. At the time of F317L, 8 patients were in chronic phase (CP), 6 in accelerated phase, and 6 in blast phase. There was no difference in characteristics between patients with or without F317L mutations, or with no mutations. A complete cytogenetic response was acheived in 3 of 6 patients treated with nilotinib, 2 of 2 with imatinib, and 0 of 3 with dasatinib. Survival of patients with F317L was similar to those with other mutations (P = .45). Patients in CP had better outcome, with a 2-year survival of 75%. F317L mutation is resistant to dasatinib but sensitive to other TKIs. The prognosis is dependent mostly on the disease stage.

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ABL Kinase Domain Mutation in Chronic Myeloid Leukemia - Compliance to Imatinib Matters

Blood ◽

10.1182/blood-2019-125998 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1654-1654

Author(s):

Jayachandran PK ◽

Trivadi S Ganesan ◽

Nikita Mehra ◽

Krishnarathinam Kannan ◽

Manikandan Dhanushkodi ◽

...

Keyword(s):

Next Generation Sequencing ◽

Chronic Myeloid Leukemia ◽

Mutation Analysis ◽

Myeloid Leukemia ◽

Sanger Sequencing ◽

Kinase Domain ◽

Next Generation ◽

Abl Kinase ◽

Kinase Domain Mutation ◽

Generation Sequencing

Background: Imatinib resistance mutation analysis (IRMA) or abl kinase domain mutation analysis is performed in patients with Chronic myeloid leukemia (CML) whenever the response to treatment is inadequate. We have analyzed the reports of IRMA at our centre. Methods: The clinical details of 71 patients with CML on Imatinib, who underwent IRMA testing during the period of January 2017 to March 2019 were collected from the patient records and analyzed. IRMA was performed for failure or warning or progression, anytime during the course of treatment. IRMA was done by either Sanger sequencing (n=45) or next generation sequencing (n=26, Illumina, NGS). The associations between variables were tested using Chi - Square test. Results: Median age at diagnosis of 71 patients was 44 years (Range 18 - 71 years). Males constituted 70% (n=50). At diagnosis, 92% (n=65) of patients were in chronic phase and the remainder were in accelerated phase (n=4) or blast crisis (n=2). Mutations in the abl kinase domain were detected in 26 patients (37%). Next Generation Sequencing (NGS) could identify more mutations (13/26 - 50%) compared to conventional Sanger Sequencing (13/45 - 29%), but the difference was not significant (p=0.07). NGS could identify three or more mutations in 5 patients in contrast to Sanger. All the mutations detected were those previously described except for an insertion of 35bp near the C-Terminal which was identified in 3 patients. E459K translocation was identified in 6 patients. E355G translocation was identified in 4 patients. F359V, M351T, Y253H, G250E, H396R, T315I translocations were identified in 3 patients each. Patients who were not compliant to therapy had increased frequency of mutations (14/26 - 54%) compared to those who were compliant (12/45 - 27%), which was significantly different (p=0.02). Patients who had loss of complete hematological response (CHR) had significantly higher frequency of mutations (14/21- 67%) compared to other reasons for performing the test (p=0.001). Patients who had failure to achieve targets at various time points had a significantly lower frequency of mutations (4/23 - 17%, p=0.02) compared to other reasons for performing the test. Conclusion: Patients who were not compliant for treatment were more likely to have mutations. Loss of CHR showed an increased frequency compared to other reasons. NGS could identify mutations in more number of patients. NGS identified numerically higher mutations in patients. Larger prospective data are needed to confirm these observations. Table Disclosures No relevant conflicts of interest to declare.

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