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.

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

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.

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.

scholarly journals Chronic lymphocytic leukemia cells induce defective LFA-1–directed T-cell motility by altering Rho GTPase signaling that is reversible with lenalidomide

Blood ◽  
2013 ◽  
Vol 121 (14) ◽  
pp. 2704-2714 ◽  
Author(s):  
Alan G. Ramsay ◽  
Rachel Evans ◽  
Shahryar Kiaii ◽  
Lena Svensson ◽  
Nancy Hogg ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Motility ◽  
Rho Gtpase ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Key Points ◽  
Gtpase Activation ◽  
Activation Signaling

Key Points CLL cells induce defects in T-cell LFA-1–mediated migration by altering Rho GTPase activation signaling, downregulating RhoA and Rac1, and upregulating Cdc42. Lenalidomide repairs these T-cell defects by restoring normal Rho GTPase activation signaling.

scholarly journals Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia

Blood ◽  
2014 ◽  
Vol 124 (3) ◽  
pp. 453-462 ◽  
Author(s):  
Mohini Rajasagi ◽  
Sachet A. Shukla ◽  
Edward F. Fritsch ◽  
Derin B. Keskin ◽  
David DeLuca ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dna Sequencing ◽  
Lymphocytic Leukemia ◽  
Class I ◽  
Massively Parallel ◽  
Central Tolerance ◽  
Key Points ◽  
Tumor Specificity ◽  
Massively Parallel Dna Sequencing ◽  
Systematic Identification

Key Points Tumor neoantigens are a promising class of immunogens based on exquisite tumor specificity and the lack of central tolerance against them. Massively parallel DNA sequencing with class I prediction enables systematic identification of tumor neoepitopes (including from CLL).

scholarly journals CLL dedifferentiation to clonally related myeloid cells

2020 ◽  
Vol 4 (24) ◽  
pp. 6169-6174
Author(s):  
Qianze Dong ◽  
Yan Xiu ◽  
Aaron Bossler ◽  
Sergei Syrbu ◽  
Hongming Wang ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Progenitor Cells ◽  
Myeloid Cells ◽  
Lymphocytic Leukemia ◽  
Key Points ◽  
Myeloid Leukemias ◽  
Acute Myeloid

Key Points Common progenitor cells exist in clonally related concomitant chronic lymphocytic leukemia and acute myeloid leukemias. CLL cells dedifferentiated to clonally related myeloid cells posttransplantation.

scholarly journals Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia

Blood ◽  
2018 ◽  
Vol 132 (2) ◽  
pp. 170-178 ◽  
Author(s):  
Md Kamrul Hasan ◽  
Jian Yu ◽  
George F. Widhopf ◽  
Laura Z. Rassenti ◽  
Liguang Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Key Points

Key Points Wnt5a enhances activation of Rac1/2 by inducing ROR1 to interact with DOCK2. ROR1-DOCK2 interaction contributes to Wnt5a-enhanced CLL cell proliferation.

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