Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group

Hoechstetter, Manuela; Busch, Raymonde; Eichhorst, Barbara; Bühler, Andreas; Winkler, Dirk; Bahlo, Jasmin; Robrecht, Sandra; Eckart, Michael J.; Vehling-Kaiser, Ursula; Jacobs, Georg; Jäger, Ulrich; Hurtz, Hans Jürgen; Hopfinger, Georg; Hartmann, Frank; Fuss, Harald; Abenhardt, Wolfgang; Blau, Ilona; Freier, W.; Müller, Lothar; Goebeler, Marie-Elisabeth; Wendtner, Clemens; Fischer, Kirsten; Herling, Carmen D.; Starck, Michael; Bentz, Martin; Emmerich, Bertold; Döhner, Hartmut; Stilgenbauer, Stephan; Hallek, Michael

doi:10.1038/s41375-020-0727-y

Cited by 34 publications

(38 citation statements)

References 35 publications

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“… 29 reported that Mut/Del CLL patients had a TTFT shorter than that of the Mut/noDel patients. Moreover, Hoechstetter et al 30 showed that del(17p) is the highest weighted factor of the six considered in a multivariate analysis to predict TTFT and OS in Binet stage A CLL, although it requires the cooperation of additional factors to determine progression.…”

Section: Discussionmentioning

confidence: 99%

Time to first treatment and P53 dysfunction in chronic lymphocytic leukaemia: results of the O-CLL1 study in early stage patients

Monti

Lionetti

Luca

et al. 2020

Sci Rep

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Chronic lymphocytic leukaemia (CLL) is characterised by a heterogeneous clinical course. Such heterogeneity is associated with a number of markers, including TP53 gene inactivation. While TP53 gene alterations determine resistance to chemotherapy, it is not clear whether they can influence early disease progression. To clarify this issue, TP53 mutations and deletions of the corresponding locus [del(17p)] were evaluated in 469 cases from the O-CLL1 observational study that recruited a cohort of clinically and molecularly characterised Binet stage A patients. Twenty-four cases harboured somatic TP53 mutations [accompanied by del(17p) in 9 cases], 2 patients had del(17p) only, and 5 patients had TP53 germ-line variants. While del(17p) with or without TP53 mutations was capable of significantly predicting the time to first treatment, a reliable measure of disease progression, TP53 mutations were not. This was true for cases with high or low variant allele frequency. The lack of predictive ability was independent of the functional features of the mutant P53 protein in terms of transactivation and dominant negative potential. TP53 mutations alone were more frequent in patients with mutated IGHV genes, whereas del(17p) was associated with the presence of adverse prognostic factors, including CD38 positivity, unmutated-IGHV gene status, and NOTCH1 mutations.

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Section: Discussionmentioning

confidence: 99%

Time to first treatment and P53 dysfunction in chronic lymphocytic leukaemia: results of the O-CLL1 study in early stage patients

Monti

Lionetti

Luca

et al. 2020

Sci Rep

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“…S-β2M level and s-TK level were reported as independent predictors of progression-free survival (PFS) of CLL more than 20 years ago [11]. S-β2M was widely used to improve risk stratification and retained independent prognostic value in several multiparameter scores [12][13][14][15][16][17][18][19][20][21]. Elevated s-TK level, which relates to shorter LDT and IGHV unmutated status, indicates the high risk of CLL patients and predicts disease progression [22].…”

Section: Serum Markersmentioning

confidence: 99%

“…For patients with early stage, Manuela A. Hoechstetter et al raised a prognostic model (CLL1-PM) for newly diagnosed CLL patients in Binet A stage by a multicenter, prospective CLL1 trial of the German CLL study group [21]. Del17p, unmutated IGHV, del11q, s-β2M > 3.5 mg/ dL, LDT < 12 months and age > 60 years were identified as 6 independent factors and associated with OS and TTFT.…”

Section: Risk Staging Systems In Cllmentioning

confidence: 99%

Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

2020

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Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia with high heterogeneity in the western world. Thus, investigators identified a number of prognostic biomarkers and scoring systems to guide treatment decisions and validated them in the context of immunochemotherapy. A better understanding of prognostic biomarkers, including serum markers, flow cytometry outcomes, IGHV mutation status, microRNAs, chromosome aberrations and gene mutations, have contributed to prognosis in CLL. Del17p/ TP53 mutation, NOTCH1 mutation, CD49d, IGHV mutation status, complex karyotypes and microRNAs were reported to be of predictive values to guide clinical decisions. Based on the biomarkers above, classic prognostic models, such as the Rai and Binet staging systems, MDACC nomogram, GCLLSG model and CLL-IPI, were developed to improve risk stratification and tailor treatment intensity. Considering the presence of novel agents, many investigators validated the conventional prognostic biomarkers in the setting of novel agents and only TP53 mutation status/del 17p and CD49d expression were reported to be of prognostic value. Whether other prognostic indicators and models can be used in the context of novel agents, further studies are required.

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“…Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western societies, characterized by clonal expansion of mature CD5 + /CD19 + expressing B lymphocytes with significant genetic and clinical heterogeneity [1]. The majority of CLL patients are diagnosed at an early stage with low tumor volume and moderate disease activity [2]. While a small percentage of CLL cases will never progress from this indolent disease phase, most patients will maintain a watchful waiting period until worsening cytopenias or disease symptoms emerge, upon which treatment begins.…”

Section: Introductionmentioning

confidence: 99%

Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

et al. 2021

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Background Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood. Methods We performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor). Results We report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL. Conclusions These findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.

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Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group

Cited by 34 publications

References 35 publications

Time to first treatment and P53 dysfunction in chronic lymphocytic leukaemia: results of the O-CLL1 study in early stage patients

Time to first treatment and P53 dysfunction in chronic lymphocytic leukaemia: results of the O-CLL1 study in early stage patients

Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

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