Kinase domain mutations and responses to dose escalation in chronic myeloid leukemia resistant to standard dose imatinib mesylate

The chronic myeloid leukemia (CML) development is associated with the formation of the BCR/ABL1 fusion gene and the BCR/ABL1 protein with increased tyrosine kinase activity. Despite the high efficiency of targeted therapy, up to 30% of patients do not respond on such therapy i.e. are primary resistant. The presence of BCR/ABL1 kinase domain mutations is considered to be one of the reasons of tyrosin kinase inhibitors resistance. To evaluate the frequency of BCR/ABL1 kinase domain mutations in Ukrainian cohort of CML patients with primary resistance to imatinib therapy, we retrospectively studied BCR/ABL1 kinase domain mutations in peripheral blood of 107 CML patients. The nucleotide sequence was determined by direct sequencing by Sanger. Mutations were reported in 45 of 107 (41.7%) CML patients. Two mutations at a time were revealed in 8 patients. So a total of 53 mutations were found out. Among them 49 were missense-mutations and 4 - deletions of different regions of the BCR/ABL1 kinase domain gene. The missense-mutations F359I/V (12 patients), T315I (8 patients) and G250E (6 patients) were most common. By localization, the mutations majority (23 of 53) was in the P-loop, 10 mutations - in the contact site, 13 mutations - in the catalytic domain and 6 – in the A-loop. Of the detected mutations, 26 (49%) resulted in a disruption of the hydrogen bond between BCR/ABL1-tyrosine kinase and imatinib. Significant reduction in overall survival was found in patients with BCR/ABL1 kinase domain mutations compared with patients with wild-type of BCR/ABL1 gene (p=0.018). The estimated 3-year overall survival was 83.4% (95% CI: 77.0%-89.8%) and 94.3% (95% CI: 91.0%-97.3%), respectively. Therefore, mutations of the BCR/ABL1 kinase domain are one of the mechanisms of primary resistance in CML patients on imatinib therapy. The occurrence of BCR/ABL1 gene mutations impairs the prognosis of imatinib therapy response.

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

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692117666190925115852 ◽

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.

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Detection of BCR-ABL Kinase Domain Mutations in Chronic Myeloid Leukemia Patients

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2016.07.087 ◽

2016 ◽

Vol 16 ◽

pp. S60

Author(s):

Nancy Escobar ◽

Mariana Herrera ◽

Luisa Rosales ◽

Silvana Torselli ◽

Julio Caceres ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Domain ◽

Abl Kinase ◽

Kinase Domain Mutations

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Correlation of plasma concentration and adverse effects of bosutinib: standard dose or dose-escalation regimens of bosutinib treatment for patients with chronic myeloid leukemia

Experimental Hematology and Oncology ◽

10.1186/s40164-018-0101-1 ◽

2018 ◽

Vol 7 (1) ◽

Cited By ~ 6

Author(s):

Akiko Mita ◽

Maiko Abumiya ◽

Masatomo Miura ◽

Takenori Niioka ◽

Saori Takahashi ◽

...

Keyword(s):

Plasma Concentration ◽

Chronic Myeloid Leukemia ◽

Adverse Effects ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Standard Dose

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PB1920 BCR-ABL GENE ABL KINASE DOMAIN MUTATIONS IN IMATINIB RESISTANT CHRONIC MYELOID LEUKEMIA PATIENTS FROM AZERBAIJAN

HemaSphere ◽

10.1097/01.hs9.0000566180.59245.28 ◽

2019 ◽

Vol 3 (S1) ◽

pp. 873-874

Author(s):

C. Asadov ◽

A. Hasanova ◽

A. Shirinova ◽

N. Karimova ◽

Z. Alimirzoeva

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Domain ◽

Abl Kinase ◽

Imatinib Resistant ◽

Kinase Domain Mutations

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Novel Illumina‐based next generation sequencing approach with one‐round amplification provides early and reliable detection of BCR‐ABL1 kinase domain mutations in chronic myeloid leukemia

British Journal of Haematology ◽

10.1111/bjh.16382 ◽

2020 ◽

Vol 189 (3) ◽

pp. 469-474

Author(s):

Marianna Romzova ◽

Dagmar Smitalova ◽

Nikola Tom ◽

Tomas Jurcek ◽

Martin Culen ◽

...

Keyword(s):

Next Generation Sequencing ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Kinase Domain ◽

Next Generation ◽

Reliable Detection ◽

Kinase Domain Mutations ◽

Generation Sequencing

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Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽

10.1182/blood.v114.22.3302.3302 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3302-3302

Author(s):

Massimo Breccia ◽

Fabio Stagno ◽

Roberto Latagliata ◽

Paolo Vigneri ◽

Laura Cannella ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Standard Dose ◽

Acquired Resistance ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. Disclosures No relevant conflicts of interest to declare.

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