Growth dynamics in naturally progressing chronic lymphocytic leukaemia

Gruber, Michaela; Božić, Ivana; Leshchiner, Ignaty; Livitz, Dimitri; Stevenson, Kristen E.; Rassenti, Laura Z.; Rosebrock, Daniel; Taylor-Weiner, Amaro; Olive, Oriol; Goyetche, Reaha; Fernandes, Stacey M.; Sun, Jing; Stewart, Chip; Wong, Alicia; Cibulskis, Carrie; Zhang, Wandi; Reiter, Johannes G.; Gerold, Jeffrey M.; Gribben, John G.; Kanti, R.; Keating, Michael J.; Brown, Jennifer R.; Neuberg, Donna; Kipps, Thomas J.; Nowak, Martin A.; Getz, Gad; Wu, Catherine J.

doi:10.1038/s41586-019-1252-x

Cited by 108 publications

(168 citation statements)

References 33 publications

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“…These two different patterns of growth associate with peculiar molecular features. CLL cases with an exponential growth are mainly IGHV-unmutated CLL and have a higher frequency of clonal and subclonal somatic genetic lesions compared to patients with a logistic growth pattern [6]. These different growth patterns, as well as the association between exponential growth, unmutated IGHV genes, and additional genetic lesions, have been validated in an independent cohort of CLL patients [6].…”

Section: Management Of Asymptomatic Cll Patientsmentioning

confidence: 88%

“…Two different patterns of growth have been identified. The exponential growth pattern is characterized by a rapid proliferation of the CLL clone, whereas the logistic growth pattern displays a lower rate of progression [6]. These two different patterns of growth associate with peculiar molecular features.…”

Section: Management Of Asymptomatic Cll Patientsmentioning

confidence: 99%

“…An extensive body of molecular studies has deciphered the molecular landscape of CLL [2][3][4][5][6][7]. CLL is not characterized by a unique and unifying genetic lesion, but rather displays a variety of molecular abnormalities that are responsible for disease pathogenesis, progression, and transformation.…”

Section: Genomics and Biology Of Cll As The Backbone For A Precision mentioning

confidence: 99%

“…Recent studies have tried to identify the clinical and molecular features of early stage CLL patients managed with a watch and wait approach and who might manifest treatment requirement soon after diagnosis [6,[55][56][57][58]. The pattern of tumor growth of untreated CLL has been investigated by analyzing serial longitudinal samples collected between diagnosis and the time of treatment requirement [6]. Two different patterns of growth have been identified.…”

Section: Management Of Asymptomatic Cll Patientsmentioning

confidence: 99%

“…Chronic lymphocytic leukemia (CLL) is one of the most frequent B-cell malignancies and the most frequent leukemia in Western countries [1,2]. The extensive body of molecular studies in CLL has allowed a better understanding of the disease pathogenesis and have led to the identification of has allowed a better understanding of the disease pathogenesis and have led to the identification of molecular biomarkers that help clinicians in the precision management of individual patients [2][3][4][5][6][7]. The identification of molecular predictors, coupled with the introduction of innovative and highly efficacious drugs in the therapeutic armamentarium, allows optimization of the treatment strategy for CLL in individual patients.…”

Section: Introductionmentioning

confidence: 99%

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Precision Medicine Management of Chronic Lymphocytic Leukemia

Moia

Patriarca

Schipani

et al. 2020

Cancers

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Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in western countries, with an incidence of approximately 5.1/100,000 new cases per year. Some patients may never require treatment, whereas others relapse early after front line therapeutic approaches. Recent whole genome and whole exome sequencing studies have allowed a better understanding of CLL pathogenesis and the identification of genetic lesions with potential clinical relevance. Consistently, precision medicine plays a pivotal role in the treatment algorithm of CLL, since the integration of molecular biomarkers with the clinical features of the disease may guide treatment choices. Most CLL patients present at the time of diagnosis with an early stage disease and are managed with a watch and wait strategy. For CLL patients requiring therapy, the CLL treatment armamentarium includes both chemoimmunotherapy strategies and biological drugs. The efficacy of these treatment strategies relies upon specific molecular features of the disease. TP53 disruption (including both TP53 mutation and 17p deletion) is the strongest predictor of chemo-refractoriness, and the assessment of TP53 status is the first and most important decisional node in the first line treatment algorithm. The presence of TP53 disruption mandates treatment with biological drugs that inhibit the B cell receptor or, alternatively, the B-cell lymphoma 2 (BCL2) pathway and can, at least in part, circumvent the chemorefractoriness of TP53-disrupted patients. Beside TP53 disruption, the mutational status of immunoglobulin heavy variable (IGHV) genes also helps clinicians to improve treatment tailoring. In fact, patients carrying mutated IGHV genes in the absence of TP53 disruption experience a long-lasting and durable response to chemoimmunotherapy after fludarabine, cyclophosphamide, and rituximab (FCR) treatment with a survival superimposable to that of a matched general population. In contrast, patients with unmutated IGHV genes respond poorly to chemoimmunotherapy and deserve treatment with B cell receptor inhibitors. Minimal residual disease is also emerging as a relevant biomarker with potential clinical implications. Overall, precision medicine is now a mainstay in the management and treatment stratification of CLL. The identification of novel predictive biomarkers will allow further improvements in the treatment tailoring of this leukemia.

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Section: Management Of Asymptomatic Cll Patientsmentioning

confidence: 88%

Section: Management Of Asymptomatic Cll Patientsmentioning

confidence: 99%

Section: Genomics and Biology Of Cll As The Backbone For A Precision mentioning

confidence: 99%

Section: Management Of Asymptomatic Cll Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Precision Medicine Management of Chronic Lymphocytic Leukemia

Moia

Patriarca

Schipani

et al. 2020

Cancers

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Population PK‐PD Modeling of Circulating Lymphocyte Dynamics in Chronic Lymphocytic Leukemia Patients Under Ibrutinib Treatment

Gallais

Ysebaert

Despas

et al. 2021

Clin Pharma and Therapeutics

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Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL). Absolute lymphocyte count (ALC) is a clinical criterion used for the monitoring of CLL. Ibrutinib has several effects on lymphocytes, and has highly variable pharmacokinetics (PK). The objective of this work was to build a PK‐pharmacodynamic (PD) model describing ALC dynamics under ibrutinib treatment in patients with CLL. ALC observations before and after ibrutinib treatment initiation in patients with CLL were included in the analysis. A population PK‐PD model was developed based on physio‐pharmacological knowledge. Individual PK concentrations at each hospital visit were included in the model. The association between PD parameters and lymphocytosis, and between PD parameters and response to treatment were assessed. A total of 94 patients, 658 ALC and 1,501 PK observations were included in model development. The final PK‐PD model accurately described ALC dynamics for different patient profiles. It consisted in two compartments (tissues and blood circulation) with ibrutinib plasmatic concentration inducing two drug effects: stimulation of lymphocyte redistribution and death. Patients with hyperlymphocytosis had significantly higher tissues to circulation baseline lymphocyte count ratio, and lower death effect. Patients who progressed under ibrutinib had significantly lower baseline lymphocyte counts in tissues (2‐fold lower) and blood (3‐fold lower). The first PK‐PD model for ALC in patients with CLL under ibrutinib treatment was developed. This model suggests that estimated lymphocyte counts in tissues and blood could be used as an early predictor of response in patients with CLL.

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