scholarly journals An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 894 ◽  
Author(s):  
Jared A. Cohen ◽  
Riccardo Bomben ◽  
Federico Pozzo ◽  
Erika Tissino ◽  
Andrea Härzschel ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Predictive Biomarkers ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Region Gene ◽  
Novel Biomarkers

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.

Usage of IGHV4-39 with Stereotypic B Cell Receptor Is An Independent Risk Factor of Chronic Lymphocytic Leukemia Transformation to Richter Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 778-778
Author(s):  
Davide Rossi ◽  
Valeria Spina ◽  
Michaela Cerri ◽  
Clara Deambrogi ◽  
Lorenzo De Paoli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Control Analysis ◽  
Ighv Gene ◽  
Gene Usage

Abstract Richter’s syndrome (RS) represents the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma, mainly occurring as diffuse large B-cell lymphoma (DLBCL). The biology of CLL transformation to RS is poorly understood and knowledge on risk factors of RS development is scant. We tested whether IGHV gene usage and stereotypic B cell receptor (BCR) at CLL diagnosis have an impact on RS transformation. The first step of the study consisted of a case-control analysis comparing IGHV gene usage and prevalence of stereotypic HCDR3 in RS (n=69; all DLBCL) versus a control group (n=715) of CLL that had not transformed to RS. The second step consisted of an actuarial assessment of the impact of IGHV gene usage and stereotypic HCDR3 at CLL diagnosis, on the risk of subsequent transformation to RS in a cohort of 754 CLL, of which 39 had transformed to RS. Comparison of IGHV usage in unmutated RS versus unmutated control CLL documented that IGHV4-39 was the sole gene preferentially utilized (6/48, 12.5% vs 5/277, 1.8%, respectively, p=.002) by RS. Prevalence of stereotypic HCDR3 was significantly higher in RS compared to non-transformed CLL when considering all cases (RS: 50.7% vs non-transformed CLL: 22.2%; p<.000001), unmutated cases only (RS: 58.3% vs non-transformed CLL: 35.7%; p=.003), and mutated cases only (RS: 33.3% vs non-transformed CLL: 13.7%; p=.022). Compared to non-transformed CLL, RS preferentially utilized BCR belonging to a subset characterized by rearrangement of unmutated IGHV4-39/IGHD6-13/IGHJ5 genes (2/159, 1.2% vs 5/35, 14.3%, respectively; p=.002). All cases with stereotypic IGHV4-39 carried +12 as the sole FISH abnormality. After a median follow-up of 41.1 months, 39/754 CLL had transformed to RS. Univariate analysis documented: shorter time to transformation in CLL utilizing IGHV4-39 (5-year risk: 35.4%) compared to CLL utilizing other IGHV genes (5-year risk: 5.6%) (p<.000001); higher risk of RS in CLL utilizing stereotypic HCDR3 (5-year risk: 14.2%) compared to CLL without stereotypic HCDR3 (5-year risk: 3.9%) (p<.00001). CLL with stereotypic HCDR3 and IGHV homology 98% showed a significantly higher risk of transformation (5-year risk: 18.4%) compared to CLL with IGHV homology 98% but without stereotypic HCDR3 (5-year risk: 6.8%) (p=.006). Also, stereotypic HCDR3 identified a CLL subgroup that, despite presenting with IGHV homology <98%, showed an increased risk of RS (p=.040). This observation indicates that stereotypic HCDR3 is not a surrogate of IGHV homology for RS prediction. We then tested the independent predictive value for RS transformation of IGHV4-39 usage and of stereotypic HCDR3. Multivariate analysis selected IGHV4-39 usage (HR: 4.25; p=.002) and stereotypic HCDR3 at CLL diagnosis (HR: 3.08; p=.002) as independent predictors of RS transformation. The observation that all RS utilizing IGHV4-39 carried stereotypic HCDR3 prompted investigation of the interaction between IGHV4-39 usage and stereotypic HCDR3 in the model. Multivariate analysis selected the interaction between IGHV4-39 usage and stereotypic HCDR3 at CLL diagnosis as the strongest independent predictor of RS transformation (HR: 5.13; p=.001). The relevance of the interaction between IGHV4-39 and stereotypic HCDR3 was confirmed by bivariate log rank analysis. Accordingly, CLL utilizing both IGHV4-39 and stereotypic HCDR3 were identified as the disease category with highest risk of transformation (5-year risk: 68.7%). Transformation to RS and progression to symptomatic disease according to NCI Working Group guidelines are distinct events in CLL. Accordingly, neither IGHV4-39 usage nor stereotypic HCDR3 affected the risk of CLL progression occurring without transformation to RS. IGHV4-39 usage and stereotypic HCDR3 may be appropriate biological markers for RS prediction since: these markers predict RS in a fashion that is independent of other clinical and biological features; given the widespread use of IGHV sequencing for CLL prognostication, information on IGHV4-39 and stereotypic HCDR3 may be obtained at CLL diagnosis without additional testing; and importantly all CLL with concomitant IGHV4-39 usage and stereotypic HCDR3 ultimately transform to RS. A close monitoring and a careful biopsy policy may be of help for early recognition of RS transformation in patients carrying IGHV4-39 usage and stereotypic HCDR3.

Evidence for Autostimulatory Mechanisms in Chronic Lymphocytic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2880-2880
Author(s):  
Martin Trepel ◽  
Fabian Muller ◽  
Mareike Frick ◽  
Janina Rahlff ◽  
Claudia Wehr ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phage Display ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Specific Binding ◽  
Variable Region ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Fab Fragment

Abstract Abstract 2880 Background: The development and / or course of chronic lymphocytic leukemia (CLL) may be driven by the recognition of antigens through the B cell receptor (BCR). While it has been recognized that the diversity of epitope recognition may be astonishingly confined in CLL, knowledge on antigens recognized by CLL BCRs is still limited. Here, we identified and characterized an epitope recognized by a defined CLL BCR which may broaden our view on potential mechanisms of antigenic drive in CLL. Methods: The B- cell receptor of a random CLL-patient was cloned and expressed as Fab fragment in E.coli. Random phage display reptile litanies we skeletal on the immobilized Fab and landed peptides were tested for specific binding. Specific clones we sequenced and sequences were analyzed for homology to known proteins. Recognition of candidate proteins was verified in brooding assays or recombinant proteins. Results: Screening random phage display peptide libraries, we identified a CLL BCR epitope mimic that displayed a high degree of homology to a conserved peptide string in the variable region of immunoglobulin heavy and light chains. CLL BCR binding to this epitope as well as binding to full length heavy and light immunoglobulin chains was verified by binding assays and a protein array screening. Interestingly, the CLL BCR also interacted with itself, as the identified epitope was also present in its own primary amino acid sequence. Conclusions: These findings suggest the possibility of self-recognition of BCRs within the CLL cell membrane or BCR interactions between neighboring CLL cells. This may potentially result in autostimulation of the leukemic cell independent of “exogenous” antigens and may account for self-sufficient signaling of some CLL-BCRs in driving disease progression. As the peptide mimicking this immunoglobulin epitope is known to be recognized by BCRs of other CLL cases in addition to the index case investigated here, such autostimulatory mechanisms may be relevant to a large number of CLL patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Autoantibody-associated cross-reactive idiotypes expressed at high frequency in chronic lymphocytic leukemia relative to B-cell lymphomas of follicular center cell origin

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 422-428 ◽  
Author(s):  
TJ Kipps ◽  
BA Robbins ◽  
P Kuster ◽  
DA Carson
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Light Chain ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Kappa Light Chain ◽  
Region Gene ◽  
Variable Regions ◽  
Hodgkin's Lymphomas ◽  
Center Cell

Using murine monoclonal antibodies (MoAbs) specific for immunoglobulin (Ig) cross-reactive idiotypes (CRI), we performed immunohistochemical analyses on frozen tissue sections and cytocentrifuge preparations of Ig-expressing malignant cells from patients with chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin's lymphomas (NHL) of follicular center cell origin. Twenty percent (4/20) of the Ig kappa light chain- expressing CLL cells reacted with 17.109, a MoAb against a major CRI on human IgM autoantibodies that is encoded by a conserved Ig variable- region gene (V gene) of the V kappa IIIb sub-subgroup. Another MoAb specific for V kappa IIIb framework determinant(s) reacted exclusively with all the 17.109-reactive CLL cells. Only one of 20 kappa light- chain-expressing CLL cells reacted with 6B6.6, a monoclonal antibody specific for a CRI commonly found on rheumatoid factor (RF) paraproteins with light-chain variable regions of the V kappa IIIa sub- subgroup. Finally, greater than 20% (8/34) of all CLL reacted with G6, a MoAb specific for an Ig heavy chain-associated CRI present on several RF paraproteins. In contrast, these CRIs were expressed at significantly lower frequencies in NHL of follicular center cell origin. Only one of 30 NHL expressing kappa light chains reacted with the 17.109 MoAb. Also, in contrast to the concordance between the 17.109-CRI and V kappa IIIb framework determinant(s) in CLL, two lymphomas in addition to the 17.109-reactive lymphoma were recognized by the anti-V kappa IIIb framework MoAb. None of the NHL reacted with either the 6B6.6 or the G6 MoAbs. These results are the first to demonstrate that CLL and NHL differ with respect to the expression of autoantibody-associated CRIs. The data support the notion that NHL of follicular center cell origin differs from CLL in its utilization and/or somatic mutation of Ig variable-region genes. The physiological and immunotherapeutic implications of these findings are discussed.

scholarly journals Precision Medicine Management of Chronic Lymphocytic Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 642 ◽  
Author(s):  
Riccardo Moia ◽  
Andrea Patriarca ◽  
Mattia Schipani ◽  
Valentina Ferri ◽  
Chiara Favini ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Precision Medicine ◽  
Treatment Algorithm ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Biological Drugs ◽  
Durable Response

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.

Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4609-4614 ◽  
Author(s):  
Liguang Chen ◽  
George Widhopf ◽  
Lang Huynh ◽  
Laura Rassenti ◽  
Kanti R. Rai ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Tyrosine Phosphorylation ◽  
Variable Region ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cytosolic Proteins ◽  
V Genes

We examined isolated leukemia B cells of patients with chronic lymphocytic leukemia (CLL) for expression of zeta-associated protein 70 (ZAP-70). CLL B cells that have nonmutated immunoglobulin variable region genes (V genes) expressed levels of ZAP-70 protein that were comparable to those expressed by normal blood T cells. In contrast, CLL B cells that had mutated immunoglobulin variable V genes, or that had low-level expression of CD38, generally did not express detectable amounts of ZAP-70 protein. Leukemia cells from identical twins with CLL were found discordant for expression of ZAP-70, suggesting that B-cell expression of ZAP-70 is not genetically predetermined. Ligation of the B-cell receptor (BCR) complex on CLL cells that expressed ZAP-70 induced significantly greater tyrosine phosphorylation of cytosolic proteins, including p72Syk, than did similar stimulation of CLL cells that did not express ZAP-70. Also, exceptional cases of CLL cells that expressed mutated immunoglobulin V genes and ZAP-70 also experienced higher levels tyrosine phosphorylation of such cytosolic proteins following BCR ligation. Following BCR ligation, ZAP-70 underwent tyrosine phosphorylation and became associated with surface immunoglobulin and CD79b, arguing for the involvement of ZAP-70 in BCR signaling. These data indicate that expression of ZAP-70 is associated with enhanced signal transduction via the BCR complex, which may contribute to the more aggressive clinical course associated with CLL cells that express nonmutated immunoglobulin receptors.

Cerebral aspergillosis in a patient on ibrutinib therapy—A predisposition not to overlook

2018 ◽  
Vol 25 (6) ◽  
pp. 1486-1490 ◽  
Author(s):  
Muhammad Salman Faisal ◽  
Hira Shaikh ◽  
Ahmed Khattab ◽  
Mary Albrethsen ◽  
Salman Fazal
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Rare Complication ◽  
B Cell Lymphoma ◽  
Complete Recovery ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Receptor Signaling

Ibrutinib has revolutionized the treatment of B-cell malignancies since its approval for chronic lymphocytic leukemia. It is also used in mantle cell lymphoma, diffuse large B-cell lymphoma, Waldenstrom’s macroglobulinemia, among others. It is a Bruton’s tyrosine kinase inhibitor that acts on B-cell receptor signaling pathway and predisposes to various infections due to its effects on neutrophils, monocytes and T cells. We present a case of cerebral invasive aspergillosis in a patient being treated with ibrutinib for relapsed chronic lymphocytic leukemia. It was hard to associate the condition to ibrutinib versus the chronic lymphocytic leukemia. The patient was successfully treated with a combination of voriconazole and micafungin, resulting in complete recovery and no residual deficits. This highlights the importance of recognizing the rare complication in those on ibrutinib and initiating the treatment immediately with appropriate antifungal agents to improve prognosis of this potentially fatal condition.

scholarly journals Targeting Bruton’s Tyrosine Kinase in CLL

2021 ◽  
Vol 12 ◽  
Author(s):  
Inhye E. Ahn ◽  
Jennifer R. Brown
Keyword(s):  
B Cell ◽  
Covalent Binding ◽  
Variable Region ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
B Cell Lymphomas ◽  
Region Gene ◽  
Resistant Disease ◽  
B Cell Receptor Signaling ◽  
Combination Regimens

Targeting the B-cell receptor signaling pathway through BTK inhibition proved to be effective for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Covalent BTK inhibitors (BTKis) led to an unprecedented improvement in outcome in CLL, in particular for high-risk subgroups with TP53 aberration and unmutated immunoglobulin heavy-chain variable-region gene (IGHV). Ibrutinib and acalabrutinib are approved by the US Food and Drug Administration for the treatment of CLL and other B-cell lymphomas, and zanubrutinib, for patients with mantle cell lymphoma. Distinct target selectivity of individual BTKis confer differences in target-mediated as well as off-target adverse effects. Disease progression on covalent BTKis, driven by histologic transformation or selective expansion of BTK and PLCG2 mutated CLL clones, remains a major challenge in the field. Fixed duration combination regimens and reversible BTKis with non-covalent binding chemistry hold promise for the prevention and treatment of BTKi-resistant disease.

scholarly journals Clinical Implications of Novel Genomic Discoveries in Chronic Lymphocytic Leukemia

2017 ◽  
Vol 35 (9) ◽  
pp. 984-993 ◽  
Author(s):  
Gregory Lazarian ◽  
Romain Guièze ◽  
Catherine J. Wu
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
New Era ◽  
Sequencing Technologies ◽  
B Cell Malignancy ◽  
Future Drug ◽  
Indolent Disease

Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy with a remarkably heterogeneous course, ranging from indolent disease with no need for immediate therapy to rapidly progressive disease associated with therapeutic resistance. The recent US Food and Drug Administration approvals of novel targeted therapies such as inhibitors of B-cell receptor signaling and B-cell lymphoma 2 have opened up new opportunities in the clinical management of patients with CLL and heralded a new era in the clinical treatment of this disease. In parallel, the implementation of novel sequencing technologies has provided new insights into CLL complexity, identifying a growing list of putative drivers that underlie inter- and intratumor heterogeneities in CLL affecting disease progression and resistance. The identification of these novel genomic features that can indicate future drug resistance or guide therapeutic management is now becoming a major goal in CLL so that patients can best benefit from the increasingly diverse available therapies, as discussed herein.

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