How to approach CLL in clinical practice

Hallek, Michael; Fürstenau, Moritz

doi:10.1002/hon.2583

Cited by 8 publications

(7 citation statements)

References 43 publications

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“…Likewise, such a prognostic model could be useful to design clinical trials for patients with high-risk, early-stage CLL, an issue that has gained momentum because of the availability of effective small molecules with manageable toxicity. 51,52 The development of the IPS-E followed an extensively used approach for the generation of prognostic scores in hematology. 18,[53][54][55][56] However, the risk for biases related to the timing of scheduled evaluations and premature censoring cannot be discarded.…”

Section: Discussionmentioning

confidence: 99%

International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

Condoluci

Bergamo

Langerbeins

et al. 2020

Blood

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106

113

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Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

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Section: Discussionmentioning

confidence: 99%

International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

Condoluci

Bergamo

Langerbeins

et al. 2020

Blood

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106

113

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“…Chronic Lymphocytic Leukemia (CLL) is the most common leukemia among adults in the Western World and it is characterized by the relentless accumulation of mature monoclonal B lymphocytes with a specific immunophenotype, positive for CD19 and CD5, along with CD23 (1). CLL is considered a dynamic and heterogeneous disease, where leukemic cells traffic and home in the peripheral blood (PB), bone marrow (BM) and secondary lymphoid tissues, such as lymph nodes (LNs) and spleen (SP) (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

3D Bioprinting Allows the Establishment of Long-Term 3D Culture Model for Chronic Lymphocytic Leukemia Cells

et al. 2021

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Chronic Lymphocytic Leukemia (CLL) represents the most common leukemia in the western world and remains incurable. Leukemic cells organize and interact in the lymphoid tissues, however what actually occurs in these sites has not been fully elucidated yet. Studying primary CLL cells in vitro is very challenging due to their short survival in culture and also to the fact that traditional two-dimensional in vitro models lack cellular and spatial complexity present in vivo. Based on these considerations, we exploited for the first time three-dimensional (3D) bioprinting to advance in vitro models for CLL. This technology allowed us to print CLL cells (both primary cells and cell lines) mixed with the appropriate, deeply characterized, hydrogel to generate a scaffold containing the cells, thus avoiding the direct cell seeding onto a precast 3D scaffold and paving the way to more complex models. Using this system, we were able to efficiently 3D bioprint leukemic cells and improve their viability in vitro that could be maintained up to 28 days. We monitored over time CLL cells viability, phenotype and gene expression, thus establishing a reproducible long-term 3D culture model for leukemia. Through RNA sequencing (RNAseq) analysis, we observed a consistent difference in gene expression profile between 2D and 3D samples, indicating a different behavior of the cells in the two different culture settings. In particular, we identified pathways upregulated in 3D, at both day 7 and 14, associated with immunoglobulins production, pro-inflammatory molecules expression, activation of cytokines/chemokines and cell-cell adhesion pathways, paralleled by a decreased production of proteins involved in DNA replication and cell division, suggesting a strong adaptation of the cells in the 3D culture. Thanks to this innovative approach, we developed a new tool that may help to better mimic the physiological 3D in vivo settings of leukemic cells as well as of immune cells in broader terms. This will allow for a more reliable study of the molecular and cellular interactions occurring in normal and neoplastic conditions in vivo, and could also be exploited for clinical purposes to test individual responses to different drugs.

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“…S druge strane, u studiji baziranoj na starijoj populaciji (≥ 60 godina), terapijske linije su podeljene na tri grupe: monoterapiju ibrutinibom, kombinaciju ibrutinib-rituksimab (IR) i standard prve linije za starije bolesnike, bendamustin-rituksimab (BR). Rezultati su pokazali superiorniji PFS (ali ne i OS) za monoterapiju ibrutinibom i IR u poređenju sa BR, osim za podgrupu bolesnika sa nemutiranim IGHV genom (27). Najčešći neželjeni efekti primene ibrutiniba su gradusa 1/2: dijareja, infekcije gornjeg respiratornog trakta i zamor.…”

Section: Inhibitori Brutonove Tirozin Kinazeunclassified

Prognosis and new therapeutic approaches in chronic lymphocytic leukemia treatment

Otašević¹,

Mihaljević²

2019

Medicinski podmladak

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Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, comprising about 30% of all leukemias in Europe and United States. Also, it represents one of the most active hematological disease regarding clinical trials. Nearly 80% of CLL patients have some chromosomal aberration, with following being emphasized due to its frequency and importance: 13q14 deletion (del13q14), 11q22-q23 deletion (del11q), chromosome 12 trisomy, 17p deletion (del17p) or/and tumor suppressor gene TP53 mutation. The use of new therapeutic agents in CLL treatment has markedly improved survival and quality of life of CLL patients. Ibrutinib, Bruton's kinase inhibitor (BTK), is approved for first line therapy for CLL patients with del17p or TP53 mutation, as well for relapsed/refractory CLL patients (R/R CLL). The use of venetoclax, antiapoptotic protein bcl-2 inhibitor, is indicated for R/R CLL patients who are resistant to ibrutinib or for whose ibrutinib is contraindicated (use of anticoagulant therapy; increased bleeding risk). Phosphoinositide 3-kinase (PI3K), idelalisib (in combination with rituximab) and duvelisib (monotherapy), are approved for treatment of R/R CLL patients. The PI3K inhibitors are rarely used in treatment of R/R CLL patients before ibrutinib or venetoclax, primarily because of unfavourable safety profile of these drugs. New therapeutic agents are providing CLL patients longer overall survival and progression free survival, especially for CLL patients with adverse prognostic factors.

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How to approach CLL in clinical practice

Cited by 8 publications

References 43 publications

International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia

3D Bioprinting Allows the Establishment of Long-Term 3D Culture Model for Chronic Lymphocytic Leukemia Cells

Prognosis and new therapeutic approaches in chronic lymphocytic leukemia treatment

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