Richter transformation in chronic lymphocytic leukemia (CLL)—a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials

Al‐Sawaf, Othman; Robrecht, Sandra; Bahlo, Jasmin; Fink, Anna‐Maria; Cramer, Paula; Tresckow, Julia von; Lange, Elisabeth; Kiehl, Michael; Dreyling, Martin; Ritgen, Matthias; Dürig, Jan; Tausch, Eugen; Schneider, Christof; Stilgenbauer, Stephan; Wendtner, C. M.; Fischer, Kirsten; Goede,; Hallek, Michael; Eichhorst, Barbara

doi:10.1038/s41375-020-0797-x

Cited by 61 publications

(62 citation statements)

References 46 publications

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“…B-CLL is twice as common in males than females; this fact was reflected exactly in our study as well with male to female ratio of 2:1 [15]. However, the median age at diagnosis in the current study was 62 years as compared to 72 years reported in western literature [11,16]. No statistically significant difference in Z-index was found with respect to the gender or age of the patients (Tables 1, 2).…”

Section: Discussionsupporting

confidence: 79%

Flow Cytometric Analysis of ZAP-70 Protein Expression for B-Cell Chronic Lymphocytic Leukemia Prognostication: Usefulness and Limitations

Shaikh

Ahmed

Sohail

et al. 2020

Cureus

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Objectives: The heterogenous clinical course in B-cell chronic lymphocytic leukemia (B-CLL) can be linked to several genetic and phenotypic characteristics of malignant B-cells. Prognostic analysis in B-CLL is routinely carried out to assist patient management; particularly to predict the time to initiate treatment. Increased ZAP-70 expression is a surrogate marker for unmutated immunoglobulin genes and inferior clinical outcomes which can be quantified to predict future outcomes in B-CLL patients. The study determined the ZAP-70 expression pattern using Z-index in Pakistani patients with B-CLL. Methods: A retrospective analysis of B-CLL cases diagnosed and confirmed on flow cytometry at Aga Khan University Hospital for the last six years which had also undergone ZAP-70 analysis were included. In all these cases, ZAP-70 expression was quantified by measuring mean fluorescence intensities (MFIs) of normal B-cells, T-cells, and CLL-cells (CD19 and CD5 double-positive population). ZAP-70 expression was divided into high, low, and negative categories based on Z-index calculation. Mann-Whitney U test was utilized to determine the significance of ZAP-70 variations in different age groups and genders. P-value <0.05 was considered significant. Results: A total of 120 patients of B-CLL had ZAP-70 analysis during the study period. The median age was 62 with an interquartile range of 35-87 and male to female ratio of 2:1. ZAP-70 expression was high in 18 (15%), low in 52 (43.3%) and negative in 50 (41.7%) cases. No significant difference in ZAP-70 expression with respect to the age or gender of the study population was identified using appropriate statistical calculations. Conclusions: This study showed only 15% of B-CLL cases showing high ZAP-70 expression, a surrogate biomarker for possible aggressive behavior which may necessitate therapeutic intervention and close surveillance.

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Section: Discussionsupporting

confidence: 79%

Flow Cytometric Analysis of ZAP-70 Protein Expression for B-Cell Chronic Lymphocytic Leukemia Prognostication: Usefulness and Limitations

Shaikh

Ahmed

Sohail

et al. 2020

Cureus

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“…Transformation of CLL into an aggressive lymphoma occurs in 2-10% of patients and in most of them (>90%) corresponds to a DLBCL, but Hodgkin lymphoma may also occur. 87 The DLBCL usually emerges as a linear evolution of the same CLL clone with only rare cases deriving from a branching divergent subclone. 88 CLL carrying stereotyped subset 8 (IGHV4-39), NOTCH1 or TP53 mutations and complex karyotypes are at higher risk of transformation after CIT.…”

Section: Pathogenic Mechanisms In the Evolution Of The Diseasementioning

confidence: 99%

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

et al. 2020

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Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma. All this knowledge has offered new perspectives that are being exploited therapeutically with novel target agents and management strategies. In this review we provide an overview of these novel advances and highlight questions and perspectives that need further progress to translate into the clinics the biological knowledge and improve the outcome of the patients.

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“…In this large cohort of 74,116 patients with CLL, 530 cases with RT were identified, with a 0.7% incidence of transformation [29]. The German CLL Study Group summarized their pooled analysis of 2975 patients included in the frontline treatment trials and an RT incidence of 3% was observed, 92% of which with DLBCL-RT [30]. In the era of novel agents, one raised concern was whether there was an increased rate of this rare and aggressive transformation among patients treated with Bruton tyrosine kinase inhibitors (BTKis) or BCL2 inhibitors (BCL2is).…”

Section: Trial Reference Treatment Del (17p) Incidence Of Richter Transformationmentioning

confidence: 99%

Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents

Tadmor

Levy

2021

Cancers

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Richter transformation (RT) is a poorly understood complication of chronic lymphocytic leukemia (CLL) with a dismal prognosis. It is associated with a switch in histopathology and biology, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or less frequently to Hodgkin’s variant of Richter transformation (HVRT). It occurs in 2–10% of CLL patients, with an incidence rate of 0.5–1% per year, and may develop in treatment-naïve patients, although it is more common following therapy. In recent years, there has been a deeper understanding of the molecular pathogenesis of RT that involves the inactivation of the TP53 tumor suppressor gene in 50–60% of cases and the activation of aberrations of NOTCH1 and MYC pathways in about 30% of cases. Compared to the preceding CLL, 80% of cases with DLBCL-RT and 30% of HVRT harbor the same IGHV-D-J rearrangements, indicating a clonal evolution of the disease, while the remaining cases represent de novo lymphomas that are clonally unrelated. Despite advances in understanding the molecular variations and the pathogenesis of the disease, there is still no significant improvement in patient outcomes. However, if no clinical trials were designed for patients with RT in the past, now there many studies for these patients that incorporate new drugs and novel combinations that are being explored. In this review, we summarize the new information accumulated on RT with special emphasis on results involving the novel therapy tested for this entity, which represents an unmet clinical need.

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Richter transformation in chronic lymphocytic leukemia (CLL)—a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials

Cited by 61 publications

References 46 publications

Flow Cytometric Analysis of ZAP-70 Protein Expression for B-Cell Chronic Lymphocytic Leukemia Prognostication: Usefulness and Limitations

Flow Cytometric Analysis of ZAP-70 Protein Expression for B-Cell Chronic Lymphocytic Leukemia Prognostication: Usefulness and Limitations

Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents

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