Chronic lymphocytic leukemia (CLL) and the other low-grade non-Hodgkin lymphomas are among the most common lymphoid malignancies. Recent studies suggest that more than 4% of the general population ...over age 40 harbor a population of clonal B cells with the phenotype of either CLL or another B-cell malignancy, a condition now designated monoclonal B-cell lymphocytosis (MBL). Although all cases of CLL appear to be preceded by MBL, the majority of individuals with MBL will not develop a hematologic malignancy. The biologic characteristics and clinical implications of MBL appear to differ based on whether it is identified during the diagnostic evaluation of lymphocytosis or incidentally discovered through screening of individuals with normal lymphocyte counts as part of research studies using highly sensitive detection methods. In this paper, we provide a state of the art review on the prevalence, nomenclature, biology, natural history and clinical management of MBL.
Monoclonal B-cell lymphocytosis (MBL) is a preclinical hematologic syndrome characterized by small accumulations of CD5(+) B lymphocytes. Most MBL share phenotypic characteristics with chronic ...lymphocytic leukemia (CLL). Although some MBL progress to CLL, most MBL have apparently limited potential for progression to CLL, particularly those MBL with normal absolute B-cell counts ('low-count' MBL). Most CLL are monoclonal and it is not known whether MBL are monoclonal or oligoclonal; this is important because it is unclear whether MBL represent indolent CLL or represent a distinct premalignant precursor before the development of CLL. We used flow cytometry analysis and sorting to determine immunophenotypic characteristics, clonality and molecular features of MBL from familial CLL kindreds. Single-cell analysis indicated four of six low-count MBL consisted of two or more unrelated clones; the other two MBL were monoclonal. 87% of low-count MBL clones had mutated immunoglobulin genes, and no immunoglobulin heavy-chain rearrangements of V(H) family 1 were observed. Some MBL were diversified, clonally related populations with evidence of antigen drive. We conclude that although low-count MBL share many phenotypic characteristics with CLL, many MBL are oligoclonal. This supports a model for step-wise development of MBL into CLL.
Chronic lymphocytic leukemia (CLL) can be immunosuppressive in humans and mice, and CLL cells share multiple phenotypic markers with regulatory B cells that are competent to produce interleukin ...(IL)-10 (B10 cells). To identify functional links between CLL cells and regulatory B10 cells, the phenotypes and abilities of leukemia cells from 93 patients with overt CLL to express IL-10 were assessed. CD5(+) CLL cells purified from 90% of the patients were IL-10-competent and secreted IL-10 following appropriate ex vivo stimulation. Serum IL-10 levels were also significantly elevated in CLL patients. IL-10-competent cell frequencies were higher among CLLs with IgV(H) mutations, and correlated positively with TCL1 expression. In the TCL1-transgenic (TCL1-Tg) mouse model of CLL, IL-10-competent B cells with the cell surface phenotype of B10 cells expanded significantly with age, preceding the development of overt, CLL-like leukemia. Malignant CLL cells in TCL1-Tg mice also shared immunoregulatory functions with mouse and human B10 cells. Serum IL-10 levels varied in TCL1-Tg mice, but in vivo low-dose lipopolysaccharide treatment induced IL-10 expression in CLL cells and high levels of serum IL-10. Thus, malignant IL-10-competent CLL cells exhibit regulatory functions comparable to normal B10 cells that may contribute to the immunosuppression observed in patients and TCL1-Tg mice.
Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to ...chronic lymphocytic leukemia (CLL), and 'CLL-like' MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5(+)CD20(dim)sIg(dim)), 11 atypical MBL (CD5(+)CD20(+)sIg(+)) and 7 CD5(neg) MBL (CD5(neg)CD20(+)sIg(neg)). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 ...(rs10484561, combined P = 1.12 × 10−29 and rs7755224, combined P = 2.00 × 10−19; r2 = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 × 10−9).
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL ...susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P=1.22×10(-14)), 18q21.33 (BCL2, P=7.76×10(-11)), 11p15.5 (C11orf21, P=2.15×10(-10)), 4q25 (LEF1, P=4.24×10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P=2.50×10(-9)), 9p21.3 (CDKN2B-AS1, P=1.27×10(-8)), 18q21.32 (PMAIP1, P=2.51×10(-8)), 15q15.1 (BMF, P=2.71×10(-10)) and 2p22.2 (QPCT, P=1.68×10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P=2.08×10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
Background: Immuno-oncology therapies have shown durable clinical responses in a subset of patients with mTNBC. Combination therapy with checkpoint inhibition and chemotherapy is under ...investigation; preliminary research showed improved objective response rate (ORR) with combination therapy versus chemotherapy alone.1 Durvalumab is a selective, high-affinity, engineered, human monoclonal antibody that blocks programmed cell death-ligand 1 (PD-L1) binding to programmed cell death 1 (PD-1) and CD80 allowing T cells to recognize and kill tumor cells. This study is designed to assess the efficacy and safety of durvalumab + paclitaxel as 1L treatment in patients with mTNBC. Additionally, this study will also evaluate potential novel triplet treatment regimens of durvalumab + paclitaxel in combination with immune-modulating agents, selumetinib (ARRY-142886; AZD6244, an inhibitor of mitogen activated protein kinase/extracellular signal regulated kinase MAPK/ERK), danvatirsen (AZD9150, an antisense oligonucleotide designed to down-regulate expression of signal transducer and activator of transcription 3 protein), oleclumab (MEDI9447, an anti-CD73 monoclonal antibody), and capivasertib (AZD5363, a highly selective, oral, small molecule AKT inhibitor) that may provide further benefit to patients with mTNBC.
Methods: BEGONIA is a phase Ib/II, open-label, multicenter, platform study (EudraCT No: 2018-000764-29) consisting of 2 parts: Part 1 is a phase Ib study planned to be conducted in approximately 100 patients (20 per arm) to assess the safety and tolerability of durvalumab (1500 mg intravenous IV, q4w) + paclitaxel (90 mg/m2 IV, 4 week cycle, 3 weeks once weekly days 1, 8, 15, 1 week off) (arm 1); and durvalumab + paclitaxel in combination with selumetinib (arm 2), danvatirsen (arm 3), oleclumab (arm 4) and capivasertib (arm 5) until disease progression. Dosing of the immune-modulating agents will be based on the previously defined recommended phase 2 doses of the component doublets (where available) in combination with durvalumab + paclitaxel using a rolling 6-patient design to evaluate for toxicity. Part 2 is a phase II study planned to be conducted in approximately 150 to 225 patients to evaluate efficacy of up to 2 best triplet combination arms based on their safety and efficacy outcomes in Part 1. The primary objective of Part 1 is safety and of Part 2 is efficacy (primary endpoint: progression free survival PFS); additionally, efficacy will be assessed in both parts, including overall survival, ORR, PFS, and duration of response (RECIST 1.1). Immunotherapy naïve adult patients (≥18 years) with locally assessed and confirmed TNBC, ECOG PS 0 or 1, stage IV breast adenocarcinoma and no prior systemic treatment for metastatic disease will be enrolled.
1Adams et al., J Clin Oncol 2016;34(Suppl):abstr 1009
Citation Format: Schmid P, Nunes AT, Lall R, D'Cruz C, Grinsted L, Lanasa MC. BEGONIA: Phase Ib/II open-label, platform study of safety and efficacy of durvalumab, paclitaxel and other novel oncology therapy agents as first-line (1L) therapy in patients with metastatic triple negative breast cancer (mTNBC) abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-01-01.
Summary
A recent meta‐analysis of three genome‐wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. ...To verify and further explore the association of these variants with other non‐Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P = 0·01; rs210142: P = 6·8 × 10−3). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.
B-cell chronic lymphocytic leukemia (CLL) is characterized by slow accumulation of malignant cells, which are supported in the microenvironment by cell-cell interactions and soluble cytokines such as ...tumor necrosis factor (TNF). We evaluated the effect of the small molecule TNF inhibitor LMP-420 on primary CLL cells. The mean concentration of LMP-420 required to induce 50% cytotoxicity (ED50) at 72 h was 245 n. LMP-420-induced time- and dose-dependent apoptosis, as shown by annexin V staining, caspase activation and DNA fragmentation. These changes were associated with decreased expression of anti-apoptotic proteins Mcl-1, Bcl-xL and Bcl-2. CLL cells from patients with poor prognostic indicators showed LMP-420 sensitivity equal to that for cells from patients with favorable characteristics. In addition, LMP-420 potentiated the cytotoxic effect of fludarabine and inhibited in vitro proliferation of stimulated CLL cells. Gene expression profiling indicated that the mechanism of action of LMP-420 may involve suppression of nuclear factor-kappaB and immune response pathways in CLL cells. LMP-420 had minimal effects on normal peripheral blood mononuclear cell, B- and T-cell function, and hematopoietic colony formation. Our data suggest that LMP-420 may be a useful treatment for CLL with negligible hematologic toxicities.
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