Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline.
TL;DR: This study highlighted that the rate of BCR-ABL1 decline may be a critical prognostic discriminator of the patients with very poor outcome among those >10% at 3 months.
About: This article is published in Blood.The article was published on 2014-07-24. It has received 173 citations till now. The article focuses on the topics: Imatinib mesylate.
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University of Alabama at Birmingham1, University of South Florida2, Vanderbilt University3, City of Hope National Medical Center4, Fox Chase Cancer Center5, University Of Tennessee System6, Brigham and Women's Hospital7, Seattle Cancer Care Alliance8, Case Western Reserve University9, Roswell Park Cancer Institute10, Northwestern University11, Harvard University12, University of Nebraska Medical Center13, University of Utah14, Memorial Sloan Kettering Cancer Center15
TL;DR: This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
Abstract: Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.
1,545 citations
TL;DR: Describing ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia, shows similar cellular potencies but distinct patterns of resistance mutations.
Abstract: Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.
347 citations
TL;DR: Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML‐CP who have failed at least two TKIs, and for all patients in advanced phase disease.
Abstract: Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL oncoprotein. Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Although second and third generation TKIs are potent and selective TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients’ comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least two TKIs, and for all patients in advanced phase disease. Am. J. Hematol. 91:253–265, 2016. © 2015 Wiley Periodicals, Inc.
148 citations
Cites background from "Prognosis for patients with CML and..."
...Furthermore, a 3-month value of 10% [IS] may not be accurate: in a recent report in 1 sample collected at 3 months and tested 96 times, the mean value was 11% (range, 5-16%), with only 31% of tests being 10% [61]....
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TL;DR: This paper reviews the incidences and highlights potential mechanisms of vascular and metabolic perturbations associated with 3 classes of commonly used kinase inhibitors that target the vascular endothelial growth factor signaling pathway, the ABL kinase, and the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathway.
148 citations
Cites background from "Prognosis for patients with CML and..."
...The 4year overall survival rate for CML patients is as high as 95% (83), and survival rates of CML patients who experience a complete cytogenetic response is comparable to their age-matched control subjects (84)....
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TL;DR: A critical review of the last, 2013, ELN recommendations concerning the use of the five available tyrosine kinase inhibitors (TKIs), the evaluation of cytogenetic and molecular response, and the strategy of treatment is made.
Abstract: Several guidelines and recommendations on the management of chronic myeloid leukemia (CML) have been prepared by several scientific societies. The European LeukemiaNet (ELN) appointed a panel of experts who submitted their recommendations to peer-reviewed scientific journals in 2006, 2009, and 2013. Here, we make a critical review of the last, 2013, ELN recommendations, concerning the use of the five available tyrosine kinase inhibitors (TKIs), the evaluation of cytogenetic and molecular response, and the strategy of treatment. Three TKIs (imatinib, nilotinib, dasatinib) are recommended first-line. Bosutinib and ponatinib are available second-line; ponatinib is particularly indicated in case of the T315I mutation. Achieving an optimal response, not only for survival but also for a deeper, stable, treatment-free remission, requires a BCR-ABL transcripts level ≤10 % at 3 months, ≤1 % at 6 months, ≤0.1 % at 1 year, and ≤0.01 % later on. Molecular monitoring must include mutational analysis in every case of failure. A successful treatment of accelerated and blastic phase requires TKIs, and in many cases also allogeneic stem cell transplantation.
133 citations
Cites background from "Prognosis for patients with CML and..."
...Two recent retrospective analyses of the dynamics of the early molecular response have shown that it may be more important than the molecular response at 3 months [38, 39]....
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References
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TL;DR: In this article, the product-limit (PL) estimator was proposed to estimate the proportion of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t).
Abstract: In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed. For random samples of size N the product-limit (PL) estimate can be defined as follows: L...
52,450 citations
"Prognosis for patients with CML and..." refers methods in this paper
...Survival analyses were performed using the Kaplan-Meier method.(31) Events were defined for OS, PFS (accelerated phase or blast crisis [BC]), and FFS according to ELN recommendations....
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TL;DR: The analysis of censored failure times is considered in this paper, where the hazard function is taken to be a function of the explanatory variables and unknown regression coefficients multiplied by an arbitrary and unknown function of time.
Abstract: The analysis of censored failure times is considered. It is assumed that on each individual arc available values of one or more explanatory variables. The hazard function (age-specific failure rate) is taken to be a function of the explanatory variables and unknown regression coefficients multiplied by an arbitrary and unknown function of time. A conditional likelihood is obtained, leading to inferences about the unknown regression coefficients. Some generalizations are outlined.
28,264 citations
TL;DR: This article proposes methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation, but these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function.
Abstract: With explanatory covariates, the standard analysis for competing risks data involves modeling the cause-specific hazard functions via a proportional hazards assumption Unfortunately, the cause-specific hazard function does not have a direct interpretation in terms of survival probabilities for the particular failure type In recent years many clinicians have begun using the cumulative incidence function, the marginal failure probabilities for a particular cause, which is intuitively appealing and more easily explained to the nonstatistician The cumulative incidence is especially relevant in cost-effectiveness analyses in which the survival probabilities are needed to determine treatment utility Previously, authors have considered methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation However, these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function In this article we pro
11,109 citations
"Prognosis for patients with CML and..." refers methods in this paper
...Fine and Gray models implemented in R(27,28) were used to examine the association between each of the baseline risk factors and the molecular responses.(29,30) Relative risks and their 95% confidence intervals (CIs)were calculated from these regressionmodels, and significance was determined with the Wald test....
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TL;DR: pROC as mentioned in this paper is a package for R and S+ that contains a set of tools displaying, analyzing, smoothing and comparing ROC curves in a user-friendly, object-oriented and flexible interface.
Abstract: Receiver operating characteristic (ROC) curves are useful tools to evaluate classifiers in biomedical and bioinformatics applications. However, conclusions are often reached through inconsistent use or insufficient statistical analysis. To support researchers in their ROC curves analysis we developed pROC, a package for R and S+ that contains a set of tools displaying, analyzing, smoothing and comparing ROC curves in a user-friendly, object-oriented and flexible interface. With data previously imported into the R or S+ environment, the pROC package builds ROC curves and includes functions for computing confidence intervals, statistical tests for comparing total or partial area under the curve or the operating points of different classifiers, and methods for smoothing ROC curves. Intermediary and final results are visualised in user-friendly interfaces. A case study based on published clinical and biomarker data shows how to perform a typical ROC analysis with pROC. pROC is a package for R and S+ specifically dedicated to ROC analysis. It proposes multiple statistical tests to compare ROC curves, and in particular partial areas under the curve, allowing proper ROC interpretation. pROC is available in two versions: in the R programming language or with a graphical user interface in the S+ statistical software. It is accessible at http://expasy.org/tools/pROC/
under the GNU General Public License. It is also distributed through the CRAN and CSAN public repositories, facilitating its installation.
8,052 citations
"Prognosis for patients with CML and..." refers methods in this paper
...Receiver operating characteristic (ROC) curves were generated using the pROC statistical package for R.(33) Optimal thresholds along the ROC curves were calculated using the Youden index....
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TL;DR: In this paper, a class of tests developed for comparing the cumulative incidence of a particular type of failure among different groups is presented. The tests are based on comparing weighted averages of the hazards of the subdistribution for the failure type of interest.
Abstract: In this paper, for right censored competing risks data, a class of tests developed for comparing the cumulative incidence of a particular type of failure among different groups. The tests are based on comparing weighted averages of the hazards of the subdistribution for the failure type of interest. Asymptotic results are derived by expressing the statistics in terms of counting processes and using martingale central limit theory. It is proposed that weight functions very similar to those for the $G^p$ tests from ordinary survival analysis be used. Simulation results indicate that the asymptotic distributions provide adequate approximations in moderate sized samples.
4,469 citations
"Prognosis for patients with CML and..." refers methods in this paper
...Fine and Gray models implemented in R(27,28) were used to examine the association between each of the baseline risk factors and the molecular responses.(29,30) Relative risks and their 95% confidence intervals (CIs)were calculated from these regressionmodels, and significance was determined with the Wald test....
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