Present and future of molecular monitoring in chronic myeloid leukaemia

Soverini, Simona; Benedittis, Caterina De; Mancini, Manuela; Martinelli, Giovanni

doi:10.1111/bjh.13966

Cited by 13 publications

(10 citation statements)

References 102 publications

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“…If control gene copy number is adequate then the report is reliable and sensitive. The sample result must be discarded if ABL copy number is \ 10,000 or GUSB copy number is \ 24,000 regardless of BCR-ABL1 copy number [31,34]. In case of satisfactory control gene numbers amplified, the report should indicate the level of MR defined.…”

Section: Reporting Of Molecular Response (Mr)mentioning

confidence: 99%

Laboratory Monitoring of Chronic Myeloid Leukemia in Patients on Tyrosine Kinase Inhibitors

Chauhan

Sazawal

Pati

2018

Indian J Hematol Blood Transfus

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Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by translocation of genetic material from chromosome 9 to chromosome 22 to form a fusion gene (BCR-ABL1) that is responsible for abnormal tyrosine kinase activity and alteration of various downstream signaling pathways. In addition to morphological diagnosis of CML phase, it is essential to detect BCR-ABL1 fusion by either metaphase cytogenetics or reverse transcriptase polymerase chain reaction that also determines type of mRNA transcript. Once treatment begins, monitoring the response to Tyrosine Kinase Inhibitor (TKI) using standardized techniques and guidelines is important to check for failure of response and thus, plan timely intervention by increasing the dose of TKI or opting for second line TKIs. The goal is to stop evolution of CML to accelerated phase or blast crisis that has poor response to treatment. Also, it is desirable to achieve good outcomes and even treatment free remission in patients of CML on TKI. Thus, molecular monitoring by reverse transcriptase quantitative PCR (RT-qPCR) is done at regular intervals. There are international recommendations and quality control measures to standardize the reporting of fusion gene transcript levels by quantitative PCR (RT-qPCR) in CML to achieve and maintain sensitivity in molecular detection of CML disease burden. Various state-of-the-art molecular techniques have emerged to accurately determine the number of fusion-gene transcript levels. This review highlights various methodologies and their practical implications in management of CML patients on TKI.

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Section: Reporting Of Molecular Response (Mr)mentioning

confidence: 99%

Laboratory Monitoring of Chronic Myeloid Leukemia in Patients on Tyrosine Kinase Inhibitors

Chauhan

Sazawal

Pati

2018

Indian J Hematol Blood Transfus

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“…The majority of chronic phase chronic myeloid leukaemia (CP‐CML) patients achieve a complete cytogenetic response (CCyR) with tyrosine kinase inhibitors (TKIs) (Soverini et al , ). Monitoring of minimal residual disease with quantitative reverse transcription PCR (RQ‐PCR), enables definition of the depth of molecular response (MR), has prognostic relevance and may identify early resistance due to mutations that guide changes in TKI usage (Baccarani et al , ).…”

Section: Clinical Features Of the Patients Included In The Studymentioning

confidence: 99%

Long‐term impact of molecular response fluctuations in chronic myeloid leukaemia patients treated with imatinib

et al. 2017

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“…This study thus provides further evidence of how clinical actionability may be enhanced by routine DS-based BCR-ABL1 KD mutation screening and comes at a turning point witnessing a gradual transition from conventional to next-generation sequencing for the diagnostic assessment of disease (and cancer)-related genes [ 28 ]. It also contributes to build the background for implementing technical and clinical recommendations for CML monitoring and management.…”

Section: Discussionmentioning

confidence: 99%

In chronic myeloid leukemia patients on second-line tyrosine kinase inhibitor therapy, deep sequencing of BCR-ABL1 at the time of warning may allow sensitive detection of emerging drug-resistant mutants

et al. 2016

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BackgroundImatinib-resistant chronic myeloid leukemia (CML) patients receiving second-line tyrosine kinase inhibitor (TKI) therapy with dasatinib or nilotinib have a higher risk of disease relapse and progression and not infrequently BCR-ABL1 kinase domain (KD) mutations are implicated in therapeutic failure. In this setting, earlier detection of emerging BCR-ABL1 KD mutations would offer greater chances of efficacy for subsequent salvage therapy and limit the biological consequences of full BCR-ABL1 kinase reactivation. Taking advantage of an already set up and validated next-generation deep amplicon sequencing (DS) assay, we aimed to assess whether DS may allow a larger window of detection of emerging BCR-ABL1 KD mutants predicting for an impending relapse.Methodsa total of 125 longitudinal samples from 51 CML patients who had acquired dasatinib- or nilotinib-resistant mutations during second-line therapy were analyzed by DS from the time of failure and mutation detection by conventional sequencing backwards. BCR-ABL1/ABL1%IS transcript levels were used to define whether the patient had ‘optimal response’, ‘warning’ or ‘failure’ at the time of first mutation detection by DS.ResultsDS was able to backtrack dasatinib- or nilotinib-resistant mutations to the previous sample(s) in 23/51 (45 %) pts. Median mutation burden at the time of first detection by DS was 5.5 % (range, 1.5–17.5 %); median interval between detection by DS and detection by conventional sequencing was 3 months (range, 1–9 months). In 5 cases, the mutations were detectable at baseline. In the remaining cases, response level at the time mutations were first detected by DS could be defined as ‘Warning’ (according to the 2013 ELN definitions of response to 2nd-line therapy) in 13 cases, as ‘Optimal response’ in one case, as ‘Failure’ in 4 cases. No dasatinib- or nilotinib-resistant mutations were detected by DS in 15 randomly selected patients with ‘warning’ at various timepoints, that later turned into optimal responders with no treatment changes.ConclusionsDS enables a larger window of detection of emerging BCR-ABL1 KD mutations predicting for an impending relapse. A ‘Warning’ response may represent a rational trigger, besides ‘Failure’, for DS-based mutation screening in CML patients undergoing second-line TKI therapy.

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Present and future of molecular monitoring in chronic myeloid leukaemia

Cited by 13 publications

References 102 publications

Laboratory Monitoring of Chronic Myeloid Leukemia in Patients on Tyrosine Kinase Inhibitors

Laboratory Monitoring of Chronic Myeloid Leukemia in Patients on Tyrosine Kinase Inhibitors

Long‐term impact of molecular response fluctuations in chronic myeloid leukaemia patients treated with imatinib

In chronic myeloid leukemia patients on second-line tyrosine kinase inhibitor therapy, deep sequencing of BCR-ABL1 at the time of warning may allow sensitive detection of emerging drug-resistant mutants

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