Chronic lymphocytic leukemia patients with highly stable and indolent disease show distinctive phenotypic and genotypic features

Blood ◽  
2003 ◽  
Vol 102 (3) ◽  
pp. 1035-1041 ◽  
Author(s):  
Anna Guarini ◽  
Gianluca Gaidano ◽  
Francesca Romana Mauro ◽  
Daniela Capello ◽  
Francesca Mancini ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Clinical Stage ◽  
Lymphocytic Leukemia ◽  
P53 Mutations ◽  
Distinctive Features ◽  
Indolent Disease ◽  
Aggressive Clinical Course ◽  
Cd38 Antigen ◽  
Autoimmune Phenomena

Abstract Different biologic features have been associated with a more or less aggressive clinical course in chronic lymphocytic leukemia (CLL). In the present study, 20 patients with highly stable CLL observed at a single institution over a period of 10 to 23 years and who never required treatment were extensively characterized. The aim was to identify a distinct and reproducible biologic profile associated with disease stability that may be used to recognize at presentation CLL patients who are likely to have a very benign clinical course and for whom treatment is not indicated. The results obtained indicate that numerous parameters are closely associated with disease stability: a typical CLL morphology and immunophenotype, the lack of expression of the CD38 antigen, the mutated immunoglobulin (Ig) heavy (H) chain variable (V) pattern, the absence of p53 mutations, a CD4/CD8 ratio more than 1, the lack of 17p and 11q deletions and of complex karyotypic aberrations, and the occurrence of the 13q14 deletion. No case displayed the VH3-21 gene, linked in mutated CLL with a poor outcome. In addition, the VH1-69 gene associated with unmutated CLL cases was never detected. These biologic features were coupled with an indolent clinical course characterized by an unmodified clinical stage over time, and by lack of autoimmune phenomena and of major infections requiring parental antibiotics. At a time when aggressive therapeutic strategies are always more frequently used in the management of CLL, the distinctive features of patients with long-lived stable disease should be prospectively identified at presentation.

B-Cell Receptor Recognition of Multiple Epitopes Correlates with An Aggressive Clinical Course of Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 56-56
Author(s):  
Mascha Binder ◽  
Antje Jackst ◽  
Barbara Léchenne ◽  
Fabian Mueller ◽  
Hendrik Veelken ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
Large Set ◽  
Epitope Recognition ◽  
Fab Fragments ◽  
Recognition Pattern ◽  
Aggressive Clinical Course ◽  
Mimicking Peptides

Abstract Abstract 56 INTRODUCTION: The malignant B-cells in chronic lymphocytic leukemia (CLL) express membrane immunoglobulins (B-cell receptors; BCR) which are specific for the leukemic clone of each individual patient. Emerging evidence suggests that the development and course of CLL may be driven by antigenic stimulation through the BCR. Here we set up a model system of epitope recognition in CLL to explore how diverse epitope recognition in CLL is and whether the epitope recognition pattern has clinical relevance. METHODS: BCRs from six randomly chosen CLL patients were cloned and recombinantly expressed as IgG1 Fab fragments. Combinatorial phage-displayed peptide libraries with five different insert designs were constructed and used for the selection of epitope-mimicking peptides on the Fab fragments. We tested the binding of phage displayed epitope mimics to the respective Fab fragment by ELISA as well as to the native BCR on the cells of CLL patients. Therefore, cell-bound phage displayed epitope mimics were separated from unbound phage by differential centrifugation and bound phage were quantified by bacterial infection. The binding of six ‘index‘ epitope mimics representative for each BCR was evaluated in a set of 100 unrelated CLL cell samples. Epitope recognition patterns of CLL BCRs were correlated with the clinical course of the disease by standard biostatistical analysis including Kaplan-Meier estimator, log-rank test, cox regression analysis and Chi-square test. RESULTS: We selected epitope-mimicking peptides from phage display libraries on six CLL BCRs from randomly chosen patients. The selected peptides bound to the recombinant BCRs as well as to the native BCRs on the respective CLL cells. To model epitope recognition in a larger cohort of CLL patients we chose six representative index epitope mimics and evaluated their binding in a large set of 100 unrelated CLL cases. Surprisingly, all CLL samples recognized one or several index epitopes. Some of the CLL samples showed marked polyreactivity whereas other samples were mono- or oligoreactive. We determined whether the degree of BCR polyreactivity correlates with the clinical course of the disease using time to first treatment (TTFT) as surrogate marker of disease progression. We found that CLL patients expressing BCRs reactive with each of the epitope mimics had a significantly worse clinical course than less reactive control patients (median TTFT 27 months versus 87 months). Moreover, CLL patients whose cells express BCRs reactive with five or more epitope mimics were also characterized by an aggressive clinical course as compared to patients reacting with less than five epitopes (median TTFT 24 months versus 97 months). These outcomes were unrelated to known prognostic markers such as BCR mutational status and high risk receptor configurations. CONCLUSIONS: We introduce a system for modelling and monitoring of BCR epitope reactivity in CLL. Our findings indicate that a polyreactive epitope recognition pattern may be a determinant of an aggressive clinical course in this disease. These findings further emphasize the functional and prognostic relevance of BCR epitope recognition patterns in CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Expression of the PIM2 gene is associated with more aggressive clinical course in patients with chronic lymphocytic leukemia

2018 ◽  
Vol 28 (3) ◽  
pp. 385-390
Author(s):  
Katarzyna Kapelko-Slowik ◽  
Jarosław Dybko ◽  
Krzysztof Grzymajło ◽  
Bożena Jaźwiec ◽  
Donata Urbaniak-Kujda ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
Aggressive Clinical Course

scholarly journals Incidental Richter transformation in chronic lymphocytic leukemia patients during temporary interruption of ibrutinib

2020 ◽  
Vol 4 (18) ◽  
pp. 4508-4511
Author(s):  
Paul J. Hampel ◽  
Hua-Jay J. Cherng ◽  
Timothy G. Call ◽  
Wei Ding ◽  
Mahsa Khanlari ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
Histologic Diagnosis ◽  
Key Points ◽  
Aggressive Clinical Course

Key Points An incidental histologic diagnosis of DLBCL was identified during temporary interruption of ibrutinib treatment in patients with CLL. In contrast to an aggressive clinical course typical of Richter transformation, these patients responded to reinitiation of ibrutinib alone.

Reappraising Immunoglobulin Repertoire Restrictions in Chronic Lymphocytic Leukemia: Focus on Major Stereotyped Subsets and Closely Related Satellites

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4376-4376 ◽  
Author(s):  
Andreas Agathangelidis ◽  
Anastasia Hadzidimitriou ◽  
Eva Minga ◽  
Lesley-Ann Sutton ◽  
Eleftheria Polychronidou ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
Sequence Motif ◽  
Cdr3 Length ◽  
Major Subset ◽  
Distinct Disease ◽  
Aggressive Clinical Course ◽  
Support Research

Abstract The existence of stereotyped B cell receptor immunoglobulins (BcR IG) in chronic lymphocytic leukemia (CLL) strongly implicated antigen selection in disease ontogeny. We have previously shown that the stereotyped fraction encompasses ~30% of all CLL and includes multiple subsets with distinct BcR IG configuration and variable size. Eventually, certain major subsets emerged as distinct clinical entities, exemplified by subset #2 (IGHV3-21/IGLV3-21, ~2.5-3% of all CLL, mixed somatic hypermutation (SHM) status) of a particularly aggressive clinical course, thus, sharply contrasting subset #4 (IGHV4-34/IGKV2-30, ~1% of all CLL, mutated IGHV genes, M-CLL), a prototype for indolent disease. Here, taking advantage of a multi-institutional cohort of 21,123 CLL IG rearrangements, almost three times the size of the largest previous study, and the availability of validated, purpose-built immunoinformatics methods, we reappraised BcR IG stereotypy especially focusing on major subsets and the degree of their sequence similarity to related minor subsets. Stereotypy discovery was performed with ARResT/Teiresias, while stereotypy assignment to existing subsets previously deemed as major was performed with ARResT/AssignSubsets (http://bat.infspire.org/arrest/). In the present study, a subset was characterized as major if representing > 0.2% of the cohort (i.e. at least 50 cases). Minor subsets closely related to major ones (termed satellite) were identified applying the following criteria: (i) usage of IGHV genes from the same phylogenetic clan; (ii) VH CDR3 length difference ranging from -2 to +2 compared to the respective major subset; (iii) shared VH CDR3 sequence motif; and, (iv) -2 to +2 difference in the offset of the VH CDR3 motif compared to the respective major subset. In total, 7378/21123 (34.9%) IG sequences were grouped into subsets with stereotyped VH CDR3, with the previously characterized 19 major subsets accounting collectively for 2594 sequences (12.3%) of the cohort: of these, 12 included cases with unmutated IGHV genes (U-CLL), 6 concerned M-CLL and 1 (subset #2) included cases with mixed SHM status. Four additional subsets exceeded 50 cases, and, thus, were also considered as 'major'. These results reinforce the notion that not all CLL will end up being stereotyped but rather that a plateau for stereotypy exists at ~1/3 of the cohort. Subset #2 was the largest subset (n=572, 2.7%), while subset #1 (IGHV clan I (IGHV1,5,7 subgroups)/IGKV1(D)-39) was the most frequent subset within U-CLL (n=515, 2.4%) and subset #4 the most common M-CLL subset (n=192, 0.9%), hence displaying remarkable consistency regarding their frequency in all cohorts published since the pioneering studies. Altogether, Teiresias and AssignSubsets gave concordant results for previously identified major subsets, illustrating the validity of our approach. Satellite subsets were sought for individually for each major subset. In general, few satellite subsets were identified, most of which concerned U-CLL major subsets. That notwithstanding, notable cases of satellite subsets were exemplified by major subset #1 and its satellite subset #99 from which it differed only in VH CDR3 length (13 aminoacids in subset #1 versus 14 in subset #99); interestingly, both subsets displayed equally aggressive clinical course. Another example concerned subset #8 (IGHV4-39/IGKV1(D)-39, U-CLL), an aggressive subset with very high risk for Richter's transformation, that, except for a one-aminoacid difference in VH CDR3 length, was otherwise identical to satellite subset #215, also displaying clinical aggressiveness. Overall, our results confirm that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease subgroups amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Most major subsets display unique sequence motifs, however satellite subsets exist, especially within U-CLL. Considering ever-increasing evidence that major stereotyped subsets may represent distinct disease subgroups, the existence of satellite subsets reveals a novel aspect of repertoire restriction and has implications for refined molecular classification of CLL. Disclosures Shanafelt: Genentech: Research Funding; GlaxoSmithkKine: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Cephalon: Research Funding; Hospira: Research Funding. Gaidano:Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Niemann:Janssen: Consultancy; Abbvie: Consultancy; Roche: Consultancy; Gilead: Consultancy. Langerak:F. Hofmann-LaRoche, Genentech: Research Funding; InVivoScribe Technologies: Patents & Royalties: Royalties are provided to European Network (EuroClonality). Jaeger:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kater:Celgene: Research Funding; Gilead: Research Funding; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding. Stilgenbauer:Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Rosenquist:Gilead Sciences: Speakers Bureau. Ghia:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding; Adaptive: Consultancy; Abbvie: Consultancy, Honoraria. Stamatopoulos:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding.

Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1524-1533 ◽  
Author(s):  
Fiona Murray ◽  
Nikos Darzentas ◽  
Anastasia Hadzidimitriou ◽  
Gerard Tobin ◽  
Myriam Boudjogra ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chronic Lymphocytic Leukemia ◽  
Heavy Chain ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Lymphocytic Leukemia ◽  
Chain Gene ◽  
Distinctive Features ◽  
Ighv Gene ◽  
Gene Usage

Abstract Somatic hypermutation (SHM) features in a series of 1967 immunoglobulin heavy chain gene (IGH) rearrangements obtained from patients with chronic lymphocytic leukemia (CLL) were examined and compared with IGH sequences from non-CLL B cells available in public databases. SHM analysis was performed for all 1290 CLL sequences in this cohort with less than 100% identity to germ line. At the cohort level, SHM patterns were typical of a canonical SHM process. However, important differences emerged from the analysis of certain subgroups of CLL sequences defined by: (1) IGHV gene usage, (2) presence of stereotyped heavy chain complementarity-determining region 3 (HCDR3) sequences, and (3) mutational load. Recurrent, “stereotyped” amino acid changes occurred across the entire IGHV region in CLL subsets carrying stereotyped HCDR3 sequences, especially those expressing the IGHV3-21 and IGHV4-34 genes. These mutations are underrepresented among non-CLL sequences and thus can be considered as CLL-biased. Furthermore, it was shown that even a low level of mutations may be functionally relevant, given that stereotyped amino acid changes can be found in subsets of minimally mutated cases. The precise targeting and distinctive features of somatic hypermutation (SHM) in selected subgroups of CLL patients provide further evidence for selection by specific antigenic element(s).

scholarly journals Prognostic significance of immunoglobulin phenotype in B cell chronic lymphocytic leukemia

Blood ◽  
1985 ◽  
Vol 65 (2) ◽  
pp. 340-344 ◽  
Author(s):  
L Baldini ◽  
R Mozzana ◽  
A Cortelezzi ◽  
A Neri ◽  
F Radaelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Clinical Prognosis ◽  
Delta Type ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Seventy-six consecutive untreated patients with B cell chronic lymphocytic leukemia (B-CLL) and classified according to Binet's staging system were studied at the clinical presentation. Several immunologic parameters (number of total and T circulating lymphocytes and their surface membrane immunoglobulin [Smlg] phenotypes and levels of serum Ig) were evaluated with the aim of identifying a biologic marker of prognostic relevance. In this series of persons, Binet staging confirmed its usefulness as a prognostic index (P less than .001). With regard to Smlg, they were mu-type in 41 cases (53.9%), mu- type plus delta-type in 29 cases (38.2%), alpha-type in one case, and not detectable in five cases. No correlations were found between clinical stage and immunoglobulin phenotype, although all but one patient in stage C showed mu-type Smlg alone. On analyzing the survival curves of our patients according to different Smlg phenotypes, we found that patients with only mu-type Smlg had a poorer prognosis (P less than .05) than those with mu-type plus delta-type; this difference was even more significant (P less than .01) in patients in stage A, whereas there were no statistical differences in those in stages B and C. Because the appearance of surface heavy chain of delta-type could be an expression of cell maturation, these results suggest that in B-CLL the presence of phenotypically more mature leukemic cells may correlate with better clinical prognosis, particularly in the early phase of the disease.

Abdominal Computed Tomography Predicts Progression in Patients With Rai Stage 0 Chronic Lymphocytic Leukemia

2007 ◽  
Vol 25 (12) ◽  
pp. 1576-1580 ◽  
Author(s):  
Ana Muntañola ◽  
Francesc Bosch ◽  
Pedro Arguis ◽  
Eduardo Arellano-Rodrigo ◽  
Carmen Ayuso ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Chronic Lymphocytic Leukemia ◽  
Early Stage ◽  
Strong Predictor ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Clinical Information ◽  
Lymphocytic Leukemia ◽  
Abdominal Ct ◽  
Work Up

Purpose Whether computed tomography (CT) should be routinely included in the diagnostic work-up in patients with chronic lymphocytic leukemia (CLL) has not yet been determined. The aim of this study was to analyze the prognostic significance of abdominal CT in patients with CLL in Rai clinical stage 0. Patients and Methods Abdominal CT was performed at diagnosis in 140 patients consecutively diagnosed with CLL in Rai stage 0 disease. Results An abnormal abdominal CT was found in 38 patients (27%). Abnormal CT correlated with increased bone marrow infiltration (P = .024), high lymphocyte count (P = .001), increased ZAP-70 expression (P = .003), and short lymphocyte doubling time (LDT; P = .007). Patients with abnormal CT progressed more frequently and had a shorter time to progression than those with normal CT (median, 3.5 years v not reached, respectively; P < .001) and required earlier treatment intervention. In a multivariate analysis, only high ZAP-70 expression (relative risk = 3.60) and an abnormal abdominal CT (RR = 2.71) correlated with disease progression. Conclusion In this series, an abnormal abdominal CT was a strong predictor of progression in patients with early-stage CLL. The inclusion of CT scans in the initial work-up of patients with early clinical stage on clinical grounds can, therefore, provide relevant clinical information.

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