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Journal ArticleDOI: 10.1182/BLOOD.2020005514

Early BCR-ABL1 kinetics are predictive of subsequent achievement of treatment-free remission in chronic myeloid leukemia.

04 Mar 2021-Blood (American Society of Hematology)-Vol. 137, Iss: 9, pp 1196-1207
Abstract: With treatment-free remission (TFR) rapidly becoming the ultimate goal of therapy in chronic myeloid leukemia (CML), there is a need to develop strategies to maximize sustained TFR by improving our understanding of its key determinants. Chronic-phase CML patients attempting TFR were evaluated to identify the impact of multiple variables on the probability of sustained TFR. Early molecular response dynamics were included as a predictive variable, assessed by calculating the patient-specific halving time of BCR-ABL1 after commencing tyrosine kinase inhibitor (TKI) therapy. Overall, 115 patients attempted TFR and had ≥12 months of follow-up. The probability of sustained TFR, defined as remaining in major molecular response off TKI therapy for 12 months, was 55%. The time taken for the BCR-ABL1 value to halve was the strongest independent predictor of sustained TFR: 80% in patients with a halving time of 21.85 days (last quartile) (P < .001). The e14a2 BCR-ABL1 transcript type and duration of TKI exposure before attempting TFR were also independent predictors of sustained TFR. However, the BCR-ABL1 value measured at 3 months of TKI was not an independent predictor of sustained TFR. A more rapid initial BCR-ABL1 decline after commencing TKI also correlated with an increased likelihood of achieving TFR eligibility. The association between sustained TFR and the time taken for BCR-ABL1 to halve after commencing TKI was validated using an independent dataset. These data support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.

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14 results found


Open accessJournal Article
01 Jan 2003-Leukemia
Abstract: Detection of minimal residual disease (MRD) has proven to provide independent prognostic information for treatment stratification in several types of leukemias such as childhood acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute promyelocytc leukemia. This report focuses on the accurate quantitative measurement of fusion gene (FG) transcripts as can be applied in 35–45% of ALL and acute myeloid leukemia, and in more than 90% of CML. A total of 26 European university laboratories from 10 countries have collaborated to establish a standardized protocol for TaqMan-based real-time quantitative PCR (RQ-PCR) analysis of the main leukemia-associated FGs within the Europe Against Cancer (EAC) program. Four phases were scheduled: (1) training, (2) optimization, (3) sensitivity testing and (4) patient sample testing. During our program, three quality control rounds on a large series of coded RNA samples were performed including a balanced randomized assay, which enabled final validation of the EAC primer and probe sets. The expression level of the nine major FG transcripts in a large series of stored diagnostic leukemia samples (n=278) was evaluated. After normalization, no statistically significant difference in expression level was observed between bone marrow and peripheral blood on paired samples at diagnosis. However, RQ-PCR revealed marked differences in FG expression between transcripts in leukemic samples at diagnosis that could account for differential assay sensitivity. The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels. This is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.

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Topics: Fusion gene (58%)

34 Citations


Book ChapterDOI: 10.1007/978-3-030-71913-5_15
01 Jan 2021-
Abstract: Response to tyrosine kinase inhibitor (TKI) therapy in CML can be measured by haematological, cytogenetic and molecular criteria. Achieving haematological and cytogenetic response is still a desirable early measure of response. However measurement of the level of BCR-ABL1 transcripts in the blood by qRT-PCR, adjusted to the international scale (IS), is now the primary means of monitoring response. Achieving time-dependent molecular targets is a strong predictor of survival as well as indicating the longer-term prospects of achieving eligibility for treatment-free remission (TFR). Optimal response can be determined solely by the achievement and maintenance of time-dependent molecular response levels. Likewise, treatment failure is largely defined by a failure to achieve molecular milestones or loss of that molecular response, except in cases where treatment failure is evident by progression to advanced-phase disease. Treatment failure mandates a switch in therapy, usually to a more potent TKI, if possible. In between optimal response and treatment failure, there is a “warning category” where outcomes are generally inferior and therapeutic decisions are more complex. Recently, the importance of determining the dynamics of response, not just the BCR-ABL1 level at one specified time point, has been recognized, particularly when determining the probability of achieving sustained TFR in eligible patients.

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Topics: Molecular Response (59%)

3 Citations


Journal ArticleDOI: 10.1016/J.EXPHEM.2020.11.006
Ingo Roeder1, Ingmar Glauche1Institutions (1)
Abstract: Prognostic or therapeutic classification of diseases is often based on clinical or genetic characteristics at diagnosis or response landmarks determined at a certain time point of treatment. On the other hand, there are more and more means, such as molecular markers and sensor data, that allow for quantification of disease or therapeutic parameters over time. Although a general value of time-resolved disease monitoring is widely accepted, the full potential of using the available information on disease and treatment dynamics in the context of outcome prediction or individualized treatment optimization still seems to be, at least partially, overlooked. Within this Perspective, we summarize the conceptual idea of using dynamic information to obtain a better understanding of complex pathophysiological processes within their particular "host environment," which also allows us to intrinsically map patient-specific heterogeneity. Specifically, we discuss to which extent treatment alterations can provide additional information to understand a patient's individual condition and use this information to further adapt the therapeutic strategy. This conceptual discussion is illustrated by using examples from myeloid leukemias to which we recently applied this concept using statistical and mathematical modeling.

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2 Citations


Open access
23 Nov 2020-
Abstract: 疾病的预后或治疗分类通常基于在特定治疗时间点确定的诊断或反应标志的临床或遗传特征。另一方面,越来越多的手段,例如分子标记和传感器数据,可以随着时间的推移量化疾病或治疗参数。尽管时间分辨疾病监测的一般价值已被广泛接受,但使用有关疾病和治疗的现有信息的全部潜力dynamics在结果预测或个体化治疗优化的背景下,似乎仍然至少部分地被忽视了。在此观点中,我们总结了使用动态信息以更好地理解其特定范围内的复杂病理生理过程的概念。"host environment,"这也使我们能够固有地映射患者特定的异质性。具体来说,我们讨论到什么程度治疗改变可以提供其他信息来了解患者'并根据这些信息进一步调整治疗策略。通过使用髓样白血病的例子说明了这一概念性讨论,我们最近通过统计学和数学建模将其应用到了髓性白血病。

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Journal ArticleDOI: 10.1097/MOH.0000000000000630
Abstract: Purpose of review Despite unprecedented challenges during the preceding year, there have been a wide range of significant advances in the field of chronic myeloid leukaemia. In this review article we highlight papers reporting on some of the most important developments over the last year, both with regards to the clinical management of patients with chronic myeloid leukaemia, as well as studies that help to increase our understanding of the pathophysiology of the disease. We have performed a PubMed search to identify important papers and abstracts listed over the last year and have included additional papers published prior to this, where relevant, to provide context. Recent findings We comment on novel biomarkers for treatment free remission as well as recent results from second generation Tyrosine Kinase Inhibitor (TKI) discontinuation studies. We discuss new techniques that are being used to assess TKI resistance as well as reviewing novel and emerging approaches to the management of resistant patients, including the use of combination therapies. Summary This review highlights some of the most important research to have been reported over the last year in the field of chronic myeloid leukaemia, encompassing emerging diagnostic techniques, biomarkers and novel therapeutic options.

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References
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60 results found


Journal ArticleDOI: 10.1001/JAMA.1982.03320430047030
14 May 1982-JAMA
Abstract: A method is presented for evaluating the amount of information a medical test provides about individual patients. Emphasis is placed on the role of a test in the evaluation of patients with a chronic disease. In this context, the yield of a test is best interpreted by analyzing the prognostic information it furnishes. Information from the history, physical examination, and routine procedures should be used in assessing the yield of a new test. As an example, the method is applied to the use of the treadmill exercise test in evaluating the prognosis of patients with suspected coronary artery disease. The treadmill test is shown to provide surprisingly little prognostic information beyond that obtained from basic clinical measurements.

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Topics: Medical test (56%), Test (assessment) (51%), Physical examination (51%)

2,173 Citations


Open accessJournal ArticleDOI: 10.1038/SJ.LEU.2403135
Jean Gabert, Emmanuel Beillard, V H J van der Velden1, Wanli Bi2  +16 moreInstitutions (9)
01 Dec 2003-Leukemia
Abstract: Detection of minimal residual disease (MRD) has proven to provide independent prognostic information for treatment stratification in several types of leukemias such as childhood acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and acute promyelocytc leukemia. This report focuses on the accurate quantitative measurement of fusion gene (FG) transcripts as can be applied in 35-45% of ALL and acute myeloid leukemia, and in more than 90% of CML. A total of 26 European university laboratories from 10 countries have collaborated to establish a standardized protocol for TaqMan-based real-time quantitative PCR (RQ-PCR) analysis of the main leukemia-associated FGs within the Europe Against Cancer EAC) program. Four phases were scheduled: (1) training, (2) optimization, (3) sensitivity testing and (4) patient sample testing. During our program, three quality control rounds on a large series of coded RNA samples were performed including a balanced randomized assay, which enabled final validation of the EAC primer and probe sets. The expression level of the nine major FG transcripts in a large series of stored diagnostic leukemia samples (n = 278) was evaluated. After normalization, no statistically significant difference in expression level was observed between bone marrow and peripheral blood on paired samples at diagnosis. However, RQ-PCR revealed marked differences in FG expression between transcripts in leukemic samples at diagnosis that could account for differential assay sensitivity. The development of standardized protocols for RQ-PCR analysis of FG transcripts provides a milestone for molecular determination of MRD levels. This is likely to prove invaluable to the management of patients entered into multicenter therapeutic trials.

... read more

Topics: Minimal residual disease (61%), Myeloid leukemia (56%), Leukemia (53%) ... read more

1,385 Citations


Journal ArticleDOI: 10.1016/S1470-2045(10)70233-3
01 Nov 2010-Lancet Oncology
Abstract: Summary Background Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib. Methods In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR–ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with ClinicalTrials.gov, number NCT00478985. Findings 100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1–30), and 69 patients had at least 12 months follow-up (median 24 months, range 13–30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29–52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR–ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge. Interpretation Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors. Funding French Ministry of Health (Programme Hospitalier de Recherche 2006 grants), Institut National du Cancer (INCA).

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Topics: Imatinib mesylate (63%), Imatinib (51%), Transplantation (51%) ... read more

1,252 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA1609324
Abstract: BackgroundImatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy. MethodsIn this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. Long-term analyses included overall survival, response to treatment, and serious adverse events. ResultsThe median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall s...

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Topics: Imatinib mesylate (61%), Crossover study (53%), Interferon alfa (53%) ... read more

581 Citations


Journal ArticleDOI: 10.1182/BLOOD-2013-02-483750
25 Jul 2013-Blood
Abstract: Most patients with chronic myeloid leukemia (CML) treated with imatinib will relapse if treatment is withdrawn. We conducted a prospective clinical trial of imatinib withdrawal in 40 chronic-phase CML patients who had sustained undetectable minimal residual disease (UMRD) by conventional quantitative polymerase chain reaction (PCR) on imatinib for at least 2 years. Patients stopped imatinib and were monitored frequently for molecular relapse. At 24 months, the actuarial estimate of stable treatment-free remission was 47.1%. Most relapses occurred within 4 months of stopping imatinib, and no relapses beyond 27 months were seen. In the 21 patients treated with interferon before imatinib, a shorter duration of interferon treatment before imatinib was significantly associated with relapse risk, as was slower achievement of UMRD after switching to imatinib. Highly sensitive patient-specific BCR-ABL DNA PCR showed persistence of the original CML clone in all patients with stable UMRD, even several years after imatinib withdrawal. No patients with molecular relapse after discontinuation have progressed or developed BCR-ABL mutations (median follow-up, 42 months). All patients who relapsed remained sensitive to imatinib re-treatment. These results confirm the safety and efficacy of a trial of imatinib withdrawal in stable UMRD with frequent, sensitive molecular monitoring and early rescue of molecular relapse.

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Topics: Imatinib mesylate (63%), Minimal residual disease (53%), Imatinib (53%) ... read more

553 Citations