Gene Mutations and Treatment Outcome in the Context of Chlorambucil (Clb) without or with the Addition of Rituximab (R) or Obinutuzumab (GA-101, G) - Results of an Extensive Analysis of the Phase III Study CLL11 of the German CLL Study Group

Estenfelder, Sven; Tausch, Eugen; Robrecht, Sandra; Bahlo, Jasmin; Goede, Valentin; Ritgen, Matthias; Dongen, Jacques J.M. van; Langerak, Anton W.; Fingerle‐Rowson, Günter; Kneba, Michael; Fischer, Kirsten; Hallek, Michael; Döhner, Hartmut; Stilgenbauer, Stephan

doi:10.1182/blood.v128.22.3227.3227

Cited by 20 publications

(25 citation statements)

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“…More recently, Estenfelder et al described the predictive power of the NOTCH1 gene mutation in 689 patients enrolled in the CLL11 protocol. In this study, obinutuzumab in addition to chlorambucil improved PFS compared with what was observed in patients treated with rituximab and chlorambucil in the subgroups with mutated NOTCH1 ( 95 ). The application of all these findings to clinical practice is not yet fully defined, as these data need confirmation in independent cohorts before being applied in routine practice.…”

Section: Prognostic and Predictive Impact Of Notch1 mentioning

confidence: 49%

NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

et al. 2018

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Chronic lymphocytic leukemia (CLL) is an incurable B-cell neoplasm characterized by highly variable clinical outcomes. In recent years, genomic and molecular studies revealed a remarkable heterogeneity in CLL, which mirrored the clinical diversity of this disease. These studies profoundly enhanced our understanding of leukemia cell biology and led to the identification of new biomarkers with potential prognostic and therapeutic significance. Accumulating evidence indicates a key role of deregulated NOTCH1 signaling and NOTCH1 mutations in CLL. This review highlights recent discoveries that improve our understanding of the pathophysiological NOTCH1 signaling in CLL and the clinical impact of NOTCH1 mutations in retrospective and prospective trials. In addition, we discuss the rationale for a therapeutic strategy aiming at inhibiting NOTCH1 signaling in CLL, along with an overview on the currently available NOTCH1-directed approaches.

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Section: Prognostic and Predictive Impact Of Notch1 mentioning

confidence: 49%

NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

et al. 2018

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“…Unmutated IGHV, mutated TP53 and del(17p) remained independent negative prognostic factors also for patients treated with obinutuzumab-chlorambucil, whereas mutated NOTCH1 was not predictive of lack of benefit for the addition of obinutuzumab to chlorambucil therapy. 37…”

Section: Established Treatmentsmentioning

confidence: 99%

From Biology to Therapy: The CLL Success Story

et al. 2019

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Chemoimmunotherapy has been the standard of care for patients with chronic lymphocytic leukemia (CLL) over the last decade. Advances in monoclonal antibody technology have resulted in the development of newer generations of anti-CD20 antibodies with improved therapeutic effectiveness. In parallel, our knowledge about the distinctive biological characteristics of CLL has progressively deepened and has revealed the importance of B-cell receptor (BCR) signaling and upregulated antiapoptotic proteins for survival and expansion of malignant cell clones. This knowledge provided the basis for development of novel targeted agents that revolutionized treatment of CLL. Ibrutinib and idelalisib inhibit the Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) delta, respectively, thus interfering with supportive signals coming from the microenvironment via the BCR. These drugs induce egress of CLL cells from secondary lymphoid organs and remarkably improve clinical outcomes, especially for patients with unmutated immunoglobulin heavy-chain genes or with p53 abnormalities that do not benefit from classical treatment schemes. Latest clinical trial results have established ibrutinib with or without anti-CD20 antibodies as the preferred first-line treatment for most CLL patients, which will reduce the use of chemoimmunotherapy in the imminent future. Further advances are achieved with venetoclax, a BH3-mimetic that specifically inhibits the antiapoptotic B-cell lymphoma 2 protein and thus causes rapid apoptosis of CLL cells, which translates into deep and prolonged clinical responses including high rates of minimal residual disease negativity. This review summarizes recent advances in the development of targeted CLL therapies, including new combination schemes, novel BTK and PI3K inhibitors, spleen tyrosine kinase inhibitors, immunomodulatory drugs, and cellular immunotherapy.

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“…These biological findings possibly reflect a deregulated epigenetic loop associated with the impaired function of histone deacetylases (HDAC) that is induced by NOTCH1 mutations and is partially restored by treatment with HDAC inhibitors [35]. The novel anti-CD20 antibody obinutuzumab, provided with a higher efficacy compared to rituximab, has been shown to overcome the refractoriness to anti-CD20 therapy in CLL carrying mutations of NOTCH1 [36]. NOTCH1 mutations frequently co-occur with trisomy 12, a genetic lesion found in approximately 15% of CLL patients at the time of diagnosis [22].…”

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

confidence: 99%

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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Gene Mutations and Treatment Outcome in the Context of Chlorambucil (Clb) without or with the Addition of Rituximab (R) or Obinutuzumab (GA-101, G) - Results of an Extensive Analysis of the Phase III Study CLL11 of the German CLL Study Group

Cited by 20 publications

References 0 publications

NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

NOTCH1 Aberrations in Chronic Lymphocytic Leukemia

From Biology to Therapy: The CLL Success Story

Precision Medicine Management of Chronic Lymphocytic Leukemia

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