Suboptimal molecular response to tyrosine kinase inhibition associated with acquisition of a T240A ABL1 kinase domain mutation in a patient with chronic myeloid leukemia

2019 ◽  
Author(s):  
S.E. Langabeer ◽  
◽  
K. Haslam ◽  
M. Crampe ◽  
B. MacDonagh ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Molecular Response ◽  
Kinase Inhibition ◽  
Tyrosine Kinase Inhibition ◽  
Kinase Domain Mutation

scholarly journals ETV6-ABL1-positive "chronic myeloid leukemia": clinical and molecular response to tyrosine kinase inhibition

Haematologica ◽  
2010 ◽  
Vol 96 (2) ◽  
pp. 342-343 ◽  
Author(s):  
F. Perna ◽  
O. Abdel-Wahab ◽  
R. L. Levine ◽  
S. C. Jhanwar ◽  
K. Imada ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Molecular Response ◽  
Kinase Inhibition ◽  
Tyrosine Kinase Inhibition

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

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.

Molecular Monitoring and Mutations in Chronic Myeloid Leukemia: How to Get the Most out of Your Tyrosine Kinase Inhibitor

2014 ◽  
pp. 167-175 ◽  
Author(s):  
Michele Baccarani ◽  
Simona Soverini ◽  
Caterina De Benedittis
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Sanger Sequencing ◽  
Mutational Analysis ◽  
Residual Disease ◽  
Kinase Domain ◽  
Response To Treatment ◽  
Molecular Response ◽  
Therapeutic Decisions

The course of chronic myeloid leukemia (CML) and the response to treatment with tyrosine kinase inhibitors (TKIs) are best monitored and assessed using two molecular tests: the first is real-time quantitative reverse transcription-polymerase chain reaction (RQ-PCR), which measures the size of residual disease that is expressed as BCR-ABL1% (the ratio between BCR-ABL1 and a control gene) and the other is mutational analysis by Sanger sequencing, which checks for the presence of BCR-ABL1 kinase domain point mutations. Both tests are technically demanding and require a high level of specialization and standardization. RQ-PCR, when performed on a regular basis, allows for the defining of molecular response (MR) levels as log reduction from a standardized baseline: major molecular response (MMR or MR3) that is the best predictor of survival; and the deeper molecular response (MR4, MR4.5, and MR5) that is necessary to enroll a patient in a trial aiming at treatment-free remission (TFR). Mutational analysis, to be performed in case of failure or warning by Sanger sequencing, allows for screening of the BCR-ABL1 kinase domain for mutations conferring resistance to TKIs. Since different mutations have different degrees of sensitivity to each of the currently available TKI, the knowledge of BCR-ABL1 kinase domain–mutation status is necessary for subsequent treatment choice. Optimal patient management requires that MR and mutational information be rationally interpreted at both the technical and at the biologic level, and put into context—therapeutic decisions also take into account other factors, such as age, comorbidities, side effects, compliance, and treatment-related complications.

Chronic myeloid leukemia with p190BCR-ABL: prevalence, morphology, tyrosine kinase inhibitor response, and kinase domain mutation analysis

Blood ◽  
2009 ◽  
Vol 114 (16) ◽  
pp. 3502-3503 ◽  
Author(s):  
Animesh Pardanani ◽  
Ayalew Tefferi ◽  
Mark R. Litzow ◽  
Clive Zent ◽  
William J. Hogan ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Kinase Domain ◽  
Kinase Domain Mutation

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

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4839-4842 ◽  
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.

scholarly journals ID: 2036 Next-generation sequencing to evaluate frequency of BCR-ABL1 kinase domain Imatinib-resistance mutations

2017 ◽  
Vol 4 (S) ◽  
pp. 67
Author(s):  
Chinh Q. Duong ◽  
Trang T. Nguyen ◽  
Lam V. Nguyen ◽  
Huy Q. Pham ◽  
Hien T. T. Trinh ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Next Generation Sequencing ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Kinase Domain ◽  
Imatinib Resistance ◽  
Kinase Domain Mutation ◽  
Generation Sequencing

Chronic myeloid leukemia is a clonal myeloproliferative neoplasm, characterized by the presence of chromosomal translocation t(9; 22)(q34; q11). This is found in over 95% of the cases and results in the BCR-ABL1 fusion gene with high tyrosine kinase activity. During the last decades, imatinib and other generation of tyrosine kinase inhibitors have been used effectively for target therapy of the disease. However, many of the drug resistance cases have been reported recently, due to the mutation within kinase domain of the BCR-ABL1 fusion gene. In this work, we performed a retrospective study of 141 imatinib-resistance chronic myeloid leukemia patients to analyze kinase domain mutation by deep sequencing. Another group of 20 untreated patients were added as control. RNA from bone marrow cells was extracted and deeply sequenced utilizing Illumina MiSeq. Bioinformatics pipeline was applied for variant calling and annotation. And the Sanger sequencing was used to validate those mutations. The results showed that nearly one-fourth of patients harboring mutations that resist to Imatinib, among those, Y253F/H, M351T, G250E, F359V/I and M244V were the most frequent mutations. There were also a number of samples harboring multiple substitutions and new variations. Thus, Next-generation sequencing could be the sensitive and effective method to detect kinase domain mutation and our results could provide further information about the drug-resistance mutation in chronic myeloid leukemia.

scholarly journals Late Emergence of an Imatinib-Resistant ABL1 Kinase Domain Mutation in a Patient with Chronic Myeloid Leukemia

2017 ◽  
Vol 2017 ◽  
pp. 1-3
Author(s):  
Mireille Crampe ◽  
Claire Andrews ◽  
Anne Fortune ◽  
Stephen E. Langabeer
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Molecular Response ◽  
Late Emergence ◽  
Kinase Domain Mutation

The introduction of the tyrosine kinase inhibitor (TKI) imatinib has revolutionised the outlook of chronic myeloid leukemia (CML); however, a significant proportion of patients develop resistance through several mechanisms, of which acquisition of ABL1 kinase domain mutations is prevalent. In chronic-phase patients, these mutations become evident early in the disease course. A case is described of a chronic-phase CML patient who achieved a sustained, deep molecular response but who developed an Y253H ABL1 kinase domain mutation nearly nine years after commencing imatinib. Switching therapy to bosutinib resulted in a rapid reachievement of a major molecular response. Long-term TKI treatment impacts on quality of life and late losses of responses are usually due to lack of adherence. This case highlights the requirement for ABL1 kinase domain mutation analysis in those CML patients on long-term imatinib who lost their molecular response, regardless of whether nonadherence is suspected.

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