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ABL kinase domain mutations in patients with chronic myeloid leukemia in Jordan.

ABSTRACT: Mutations of the BCR-ABL tyrosine kinase domain constitute a major cause of resistance to tyrosine kinase inhibitors in patients with chronic myelogenous leukemia (CML). In this study, we analyzed peripheral blood samples from 185 Jordanian CML patients for ABL mutations, who were on imatinib for a minimum of 6 months regardless of their disease status and over a period of 5 years. Mutations were detected by nested RT-polymerase chain reaction, followed by direct sequencing of the ABL kinase domain. Twelve different point mutations were detected 25 times in 21 patients. The resultant mutations were as follows: four patients have T315I, three of each of the following: L248V, F317L, and G250E, two of each of the following: H396R, M244V, and T277A, and one of each of the following: F311I, M318T, Q252H, F359A, F359I, and Y326H. After patient follow-up, the mutation had disappeared in 12 patients; 3 patients died; 3 patients were not retested; and 3 patients had persistent mutation. The finding of our study is in line with what has been described in the literature. Detecting ABL mutations in chronic phase may lead to positive outcome by modifying treatment.

SUBMITTER: Awidi A

PROVIDER: S-EPMC3483047 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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ABL kinase domain mutations in patients with chronic myeloid leukemia in Jordan.

Awidi Abdalla A Ababneh Nidaa N Magablah Ahmad A Bsoul Nazzal N Mefleh Razan R Marei Lina L Abbasi Salah S

Genetic testing and molecular biomarkers 20120925 11

Mutations of the BCR-ABL tyrosine kinase domain constitute a major cause of resistance to tyrosine kinase inhibitors in patients with chronic myelogenous leukemia (CML). In this study, we analyzed peripheral blood samples from 185 Jordanian CML patients for ABL mutations, who were on imatinib for a minimum of 6 months regardless of their disease status and over a period of 5 years. Mutations were detected by nested RT-polymerase chain reaction, followed by direct sequencing of the ABL kinase dom ...[more]

PMID: 23009571

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Project description:BackgroundAsciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown.MethodsIn this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months.ResultsPatients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.ConclusionsAsciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).

Project description:BackgroundAdditional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain are probably the most common mechanisms of imatinib resistance.Design and methodsWe assessed the influence of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure. Standard cytogenetic analysis of metaphases was performed to detect additional chromosomal aberrations and the BCR-ABL kinase domain was sequenced to detect point mutations.ResultsAmong 53 patients with a median follow-up of 16 months, of whom 38, 5 and 10 were in chronic phase, accelerated phase and blast crisis, respectively, 19 (36%) had additional chromosomal aberrations and 20 (38%) had BCR-ABL kinase domain mutations. The 2-year overall survival rate of all patients with-out additional chromosomal aberrations (89%) was higher than that of patients with such aberrations (54%) (P=0.0025). Among patients with chronic phase disease, overall survival at 2 years was 100% and 62% for patients without or with additional chromosomal aberrations, respectively (P=0.0024). BCR-ABL kinase domain mutations were associated with lower remission rates in response to nilotinib, with 9 of 20 (45%) of these patients achieving a major cytogenetic remission as compared to 26 of 33 (79%) patients without mutations (P<0.05). However, overall survival was not affected by BCR-ABL kinase domain mutations.ConclusionsWhereas BCR-ABL kinase domain mutations may confer more specific resistance to nilotinib, which will predominantly affect response rates, the presence of additional chromosomal aberrations may reflect genetic instability and, therefore, intrinsic aggressiveness of the disease which will be less amenable to subsequent alternative treatments and thus negatively affect overall survival. Conventional cytogenetic analyses remain mandatory during follow-up of patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy.

Dataset Information

ABL kinase domain mutations in patients with chronic myeloid leukemia in Jordan.

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ABL kinase domain mutations in patients with chronic myeloid leukemia in Jordan.

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