Minimal residual disease is an independent predictor for 10-year survival in CLL

The approval of venetoclax, a “BH3-mimetic” antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received “breakthrough” designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are the main determinants of resistance to venetoclax. This opens up possibilities for rationally combining venetoclax with other targeted agents to circumvent resistance. Here, we summarize the most promising combinations, and highlight those already in clinical trials. There is also increasing recognition that different tumors display different degrees of addiction to individual BCL-2 family proteins, and of the need to refine current “BH3 profiling” techniques. Finally, the successful clinical development of potent and selective antagonists of BCL-XL and MCL-1 is eagerly awaited.

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“…[1, 2] MRD negativity has been shown to be a powerful predictor of long-term outcome in CLL, irrespective of line and type of therapy. [4]…”

Section: Introductionmentioning

confidence: 99%

Pathways and mechanisms of venetoclax resistance

Bose

Gandhi²,

Konopleva

2017

Leukemia & Lymphoma

230

195

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“…[4][5][6][7] It is important to note that there is no a one-size-fits-all set of predictive biomarkers, which are therapy-dependent. [4][5][6][7] It is important to note that there is no a one-size-fits-all set of predictive biomarkers, which are therapy-dependent.…”

Section: Importance Of Predictive Biomarkersmentioning

confidence: 99%

Predicting the outcome of patients with chronic lymphocytic leukemia: Progress and uncertainty

Montserrat

Gale

2019

Cancer

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Because chronic lymphocytic leukemia is a heterogeneous disease, there are considerable efforts underway to develop increasingly accurate and precise analytics with which to estimate the probability of future events such as the need for and probability of response to therapy, progression‐free survival, and survival. These analytics typically are constructed from clinical and laboratory variables. These variables often are combined into scores or staging systems, some of which are prognostic (therapy‐independent), whereas others are predictive (therapy‐dependent). Predictive variables differ with different therapies. Because response to therapy is a necessary condition for the improvement of survival, predictive biomarkers are extremely important. However, despite some progress to identify new predictive biomarkers, del(17p)/TP53 mutation remains the only widely accepted variable used to guide therapy. New laboratory techniques and analytical tools may contribute to improvements in the precision and accuracy of outcome indicators. However, there are inherent limitations when applying cohort‐based estimates to individuals within the cohort. The accuracy and precision of prediction also are limited by measurement error and chance. Ultimately, estimating outcomes requires a careful balance between clinical experience, imperfect prediction, and uncertainty.

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“…A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course [37]. Finally, biomarker and minimal residual disease assessment may ultimately be useful to guide the targeted agent or regimen of choice and the duration of treatment [38]. …”

Section: Recent Landmark Trial In Chronic Lymphocytic Leukaemia (Cll)mentioning

confidence: 99%

Spotlight on landmark oncology trials: the latest evidence and novel trial designs

Earl

Molica

Rutkowski

2017

BMC Med

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The era of precision oncology is marked with prominent successes in the therapy of advanced soft tissue sarcomas, breast cancer, ovarian cancer and haematological neoplasms, among others. Moreover, recent trials of immune checkpoint inhibitors in melanoma, non-small cell lung carcinoma, and head and neck cancers have significantly influenced the therapeutic landscape by providing promising evidence for immunotherapy efficacy in the adjuvant setting in high-risk locoregional disease. To speed up the introduction of targeted therapy for cancer patients, novel phase II trials are being designed, and may likely form the basis for the ‘landmark trials’ of the future. A special article collection in BMC Medicine, “Spotlight on landmark oncology trials”, features articles from invited experts on recent clinical practice-changing trials.

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Minimal residual disease is an independent predictor for 10-year survival in CLL

Cited by 120 publications

References 22 publications

Pathways and mechanisms of venetoclax resistance

Pathways and mechanisms of venetoclax resistance

Predicting the outcome of patients with chronic lymphocytic leukemia: Progress and uncertainty

Spotlight on landmark oncology trials: the latest evidence and novel trial designs

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