Elevated Rates of Monoclonal Gammopathy in High-Risk Chronic Lymphocytic Leukemia Pedigrees

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1449-1449
Author(s):  
Nicola J Camp ◽  
Rosalie G Waller ◽  
Cassandra Garner ◽  
Guido J Tricot ◽  
Michael Tomasson ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Monoclonal Gammopathy ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Clinical State ◽  
Light Chains ◽  
Solid Cancer ◽  
Monoclonal Gammopathies

Abstract High-risk pedigrees can be a powerful design for disease gene discovery. Understanding tumor spectrum in high-risk pedigrees optimizes power for discovery, allows meaningful assessment of segregation and determination of familial risk. Many studies have observed that different hematological malignancies co-aggregate in families. In particular, we previously performed genealogical cluster analysis in the Utah Population Database and identified significant co-aggregation between chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We have also determined that the frequency of the pre-clinical state, monoclonal B-cell lymphocytosis (MBL), is elevated in high-risk CLL pedigrees. Here, we explore evidence for monoclonal gammopathies in high-risk CLL pedigrees using serum immunoglobulin (Ig) biomarkers. Monoclonal gammopathies are characterized by a clonal expansion of plasma cells that secrete a monoclonal Ig. We used two serum biomarker tests to indicate the existence of clonal Ig proteins: Freelite™ and Hevylite™ immunoassays. These were performed on 498 frozen serum samples: 163 population controls; 97 MM/MGUS cases; 114 CLL cases (91 sporadic CLL and 23 from high-risk pedigrees); and 124 relatives in CLL pedigrees. Freelite detects and quantitates free light chains (κ and λ). Hevylite detects and quantitates specific immunoglobulins (IgA, IgG or IgM) bound to specific light chains. We determined monoclonality if either assay indicated an abnormal κ/λ ratio (specifically in conjunction with increased total Ig-type for Hevylite).The majority of monoclonality identified (92%) included restricted free lights chains. Those involving monoclonal Ig heavy chains only were all positively confirmed by standard serum protein and/or immunofixation electrophoresis. We observed a background of monoclonal gammopathy in our control samples (5/163, frequency =0.031), consistent with the advanced age of this comparison set (average 67y). As expected, monoclonal gammopathy was evident in the MM/MGUS cases (38/97, frequency=0.392, p=3.5×10-14), which increased to frequency=0.732, for abnormal κ/λ ratio considered without requiring increase of the specific Ig-type for Hevylite. The absence of complete identification is likely due to our samples being from prevalent cases at different treatment stages, in addition to non-secretory disease. The CLL cases (sporadic or pedigree) exhibited very similar rates of suggested monoclonal gammopathy (together 43/114, frequency=0.377, p=6.5×10-14). Pedigree relatives also exhibited evidence of clonal Ig proteins (9/124, frequency=0.073). The frequency across all relatives was not statistically different than the control set; however, the relatives were substantially younger than controls (minimum age 20y). When relatives were restricted to those over 49y (with average 67y), the frequency increased to 0.095 and became statistically increased compared to controls (p=0.028). The 9 relatives with monoclonality were: 1 non-Hodgkin lymphoma NOS, 1 MBL case, 2 solid cancer cases, and 5 relatives with no known cancer diagnoses. In conclusion, using sensitive Ig biomarkers we find that individuals in high-risk CLL pedigrees are at a greater risk of monoclonal gammopathy than the general population. This observation is consistent with previous clustering results indicating co-aggregation and a possible genetic etiologic overlap between CLL and MM. Furthermore, these Ig quantitative measures offer detailed phenotypes for all pedigree members, creating more informative pedigrees, increasing the power for gene identification. These measures offer an avenue for exploiting similarities across B-cell malignancies and have the potential to improve our ability to identify at-risk individuals. Disclosures No relevant conflicts of interest to declare.

scholarly journals Association between clonogenic cell growth and clinical risk group in B- cell chronic lymphocytic leukemia

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 142-149 ◽  
Author(s):  
R Dadmarz ◽  
SN Rabinowe ◽  
SA Cannistra ◽  
JW Andersen ◽  
AS Freedman ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Cell Growth ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Risk Groups ◽  
Lymphocytic Leukemia ◽  
Cloning Efficiency ◽  
Activated T Cells ◽  
Clonogenic Cells

Abstract Chronic lymphocytic leukemia of B-cell origin (B-CLL) is a disease with a variable clinical course, despite the fact that the neoplastic cells in this disorder are homogeneous with respect to morphology, immunophenotype, and cell cycle stage. To further investigate the heterogeneity observed in the clinical behavior of B-CLL, we determined the phenotype and growth requirements of clonogenic cells from 28 patients with B-CLL from low-, intermediate-, and high-risk groups as defined by the Rai staging system. Using methyl-cellulose as a semi- solid media with feeder cells and/or growth factors, colonies were observed with one or more of the culture conditions tested in 25 of 28 CLLs. Phenotypic analysis of colonies demonstrated that the clonogenic cells uniformly expressed la, CD19, CD20, CD5, and the identical light chain as the original CLL cell cultured. However, heterogeneity was observed in clonogenic B-CLL cell growth among the three different CLL risk groups. Clonogenic cells from patients with low-risk CLL required either irradiated unstimulated T cells, with or without conditioned media (CM) or irradiated activated T cells alone for colony formation. Both the number of colonies (227 +/- 15) as well as the number of cells per colony (220 +/- 82) were large, with a mean cloning efficiency of 0.39%. In contrast, clonogenic cells from patients with intermediate- and high-risk CLL required the combination of both irradiated activated T cells and CM. As compared with the low-risk CLLs, both the number and size of the colonies formed by the intermediate- (74 +/- 17, 70 +/- 39) and high- (83 +/- 28, 40 +/- 14) risk groups were significantly lower (P less than .0001). Similarly, the mean cloning efficiency was significantly reduced to 0.15% and 0.14%, respectively. None of the recombinant cytokines (interleukin 1 [IL-1] to IL-7, tumor necrosis factor, alpha and gamma-interferon, B-cell growth factor, and granulocyte macrophage colony-stimulating factor) alone or in combination with each other could entirely replace the stimulatory effect of the activated T cells. These data suggest that clinical progression of B-CLL is associated with a loss of clonogenic potential in the circulating pool of neoplastic cells, which require as yet undefined factors provided by activated T cells and CM.

Characteristics and Outcome of B-Cell Chronic Lymphocytic Leukemia in HCV-Positive Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4986-4986
Author(s):  
Stefano Molica ◽  
Rosanna Mirabelli ◽  
Demetrio Misuraca ◽  
Caterina Battaglia
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Monoclonal Gammopathy ◽  
Absolute Lymphocyte Count ◽  
Serum Levels ◽  
Autoimmune Disorders ◽  
Lymphocytic Leukemia ◽  
Severe Infections ◽  
Hodgkin's Lymphomas ◽  
Cell Chronic Lymphocytic Leukemia

Abstract HCV-associated B-cell non-Hodgkin’s lymphomas (NHL) show distinctive clinico-pathological features such as older age, liver damage, presence of monoclonal gammopathy, increased incidence of autoimmune disorders, extranodal localizations and restricted histological subtypes. As far as B-cell chronic lymphocytic leukemia (CLL) is concerned, information dealing with either characteristics or outcome of HCV-associated CLL are limited. With this background we compared clinico-hematological features and outcome of 34 HCV-positive patients diagnosed at our institution as having immunologically typical B-cell CLL (i.e., CD5+/CD23+/CD79b-/SmIg dim) with 161 unselected CLL HCV-negative patients followed-up in the last 10 years. The two groups were alike with respect to main clinico-hematological features such as age (P=0.780), sex (P=0.650), absolute lymphocyte count (P=0.788), platelet count (P=0.362), haemoglobin level (P=0.704), β2-microglobulin (P=0.192), Binet stage distribution (P=0.224) and lymphocyte doubling time (LDT)(P= 0.620). As expected either ALT or AST serum levels at the time of CLL diagnosis were significantly higher in HCV-positive patients in comparison to HCV-negative ones (P<0.0001 for both). In contrast, no difference was found in the incidence of monoclonal gammopathy between HCV-positive and HCV-negative patients (10.3% versus 7.7%; P=0.708). The same applied for autoimmune disorders which were homogeneously distributed in the two subgroups (P=0.711) and accounted, more frequently, for autoimmune emolytic anemia (AEA)(HCV-negative subgroup, 5.5%; HCV-positive subgroup, 9.0%). The proportion of severe infections registered did not reflect the HCV-status (HCV-negative subgroup, 9.6%; HCV-positive subgroup 6.4%; P= 0.510). Also second tumours were equally distributed among HCV-positive and HCV-negative subgroups (10% versus 6.8%; P=0.655). Survival curves projected at 10 years did not show any statistical in terms overall survival (Hazard Risk, 0.690; 95% CI: 0.216–1.304; P=0.167). Finally, the short term hepatic toxicity of chemotherapy did not increase among HCV-positive patients (P=0.671). In conclusion, HCV-positive patients with B-cell CLL do not differ from other patients both for presentation and clinical outcome. The need to activate specific protocols of antiviral therapy appears less urgent in comparison to NHL, however, younger CLL patients HCV-positive who are eligible for therapies at higher immunosuppressive potential (i.e., chemo-immunotherapy) should be taken in special consideration.

Rituximab Consolidation and Maintenance Immunotherapy Improve Outcome in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2035-2035 ◽  
Author(s):  
Giovanni Del Poeta ◽  
Maria Ilaria Del Principe ◽  
Luca Maurillo ◽  
Francesco Buccisano ◽  
Gianfranco Catalano ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Maintenance Therapy ◽  
B Cell ◽  
Response Duration ◽  
Lymphocytic Leukemia ◽  
Induction Treatment ◽  
Hematologic Toxicity ◽  
Grade 3 ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Monoclonal antibodies in combination with chemotherapy allowed us to obtain more responses and longer response duration in B-cell chronic lymphocytic leukemia (B-CLL), reducing disease burden to levels detectable only by flow cytometry. Moreover, it has been reported that low-dose rituximab decreases CD20 antigen loss via shaving and promotes enhanced targeting in CLL (Williams, 2006). We performed a phase II study that added rituximab to fludarabine (Flu) as therapy for symptomatic, untreated CLL. Remission status was assessed by a multiparametric flow cytometric method based on the detection of CD19+CD5+CD79b– residual B-CLL lymphocytes. VH mutational status, CD38, ZAP-70 and cytogenetics were obtained in all pts before treatment. We defined as “high risk” pts having at least two of the following markers: unmutated IgVH, CD38>30%, ZAP-70>20%, intermediate/unfavorable cytogenetics (trisomy 12 or del11q or del17p). Eighty-two CLL pts, median age 61 years, received six monthly courses of Flu (25 mg/m2 for 5 days) and four weekly doses of rituximab (375 mg/m2) starting after completion of Flu therapy. According to modified Rai stages, 8 pts had a low stage, 70 an intermediate stage and 4 a high stage. Based on NCI criteria, 66/82 (80%) pts achieved a complete remission (CR), 12/82 (15%) a partial remission (PR) and 4/82 (5%) no response or progression. Hematologic toxicity included mainly neutropenia (grade 3 and/or 4 in 42 pts) and thrombocytopenia (grade 3 and/or 4 in 4 pts). Thirty-five pts in clinical CR or PR, either with CD5+CD19+CD79b– bone marrow (BM) cells >1% (MRD+, n=20 pts) or MRD negative but presenting CD5+CD19+ peripheral blood lymphocytes (PBL) >1000/microl (n=15 pts) within 1 year after completion of the induction treatment, underwent consolidation/maintenance therapy with four monthly cycles of rituximab at 375 mg/m2 followed by twelve monthly doses of rituximab at 150 mg/m2. The median follow-up duration was 46 months. Noteworthy, all B-CLL pts experienced a long progression-free survival (PFS) from the end of induction treatment (68% at 5 years). Nevertheless, CLL pts that underwent consolidation and maintenance therapy (n=35) showed a significant longer response duration (85% at 5 years, Figure). On the other hand, BM and PBL persistently MRD negative (>1 year) pts (n=29) showed a response duration similar to that of the consolidated pts (87% at 5 years). A significant shorter PFS was observed within CD38+ pts (39% vs 78% at 5 years, P=0.002), unmutated pts (45% vs 94% at 2.5 years, P=0.001) and ZAP-70+ pts (36% vs 88% at 6 years; P=0.00002). Notably, within the “high risk” subset (n=30), considering only MRD+ pts in CR or PR (n=20), MRD+ consolidated pts (n=11) showed a significant longer response duration (64% vs 13% at 2 years, P=0.006) in comparison with MRD+ unconsolidated pts (n=9). In conclusion, consolidation/maintenance therapy with rituximab prolongs significantly the response duration in B-CLL, improving also the outcome of the “high risk” subset. Figure Figure

Extensive Intraclonal Diversification in a Subgroup of Chronic Lymphocytic Leukemia Patients with Stereotyped IGHV4-34/IGKV2-30 B cell Receptors: Implications for Ongoing Interactions with Antigen.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2337-2337
Author(s):  
Lesley-Ann Sutton ◽  
Efterpi Kostareli ◽  
Anastasia Hadzidimitriou ◽  
Nikos Darzentas ◽  
Athanasios Tsaftaris ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
B Cell Receptors ◽  
Valuable Insight ◽  
Cell Receptors ◽  
Mutational Status ◽  
The Impact

Abstract Abstract 2337 Poster Board II-314 Several studies indicate that the development of chronic lymphocytic leukemia (CLL) may be influenced by antigen (Ag) recognition through the clonotypic B cell receptors (BCRs). However, it is still unclear whether Ag involvement is restricted to the malignant transformation phase or whether the putative Ag(s) may continuously trigger the CLL clone. Valuable insight into these issues may be gleaned from the study of intraclonal diversification (ID) within the immunoglobulin (IG) genes through ongoing somatic hypermutation (SHM). Definitive data regarding ID within IG genes in CLL remains limited and conflicting. In the present study we systematically explored the presence of ID within IG genes of CLL, not only at cohort level but also in subgroups defined by BCR stereotypy and IG gene mutational status. We thus conducted a large-scale subcloning study of both IG heavy and light variable genes, in a total of 1496 and 1008 subcloned sequences from 71 and 56 CLL cases, respectively. The analysis was intentionally biased to cases expressing IGHV4-34/IGKV2-30 IGs (subset #4) and IGHV3-21/IGLV3-21 IGs (subset #2) that exhibit distinctive, subset-biased SHM patterns. PCR reactions were run using the high-fidelity Accuprime Pfx polymerase and at least 14 colonies/case were analyzed. All “non-ubiquitous” sequence changes from the germline were evaluated and recorded as follows: (i) unconfirmed mutation (UCM) - a mutation observed in only one subcloned sequence from the same sample (ii) confirmed mutation (CM) - a mutation observed more than once among subcloned sequences from the same sample. Analysis of heavy chain sequences revealed that 40% (28/71) of cases carried intraclonally diversified IGHV-D-J genes with CMs amongst subclones, whilst 32% (23/71) of cases carried only UCMs. The remaining 28% (20/71) of cases carried sets of identical IGHV-D-J subcloned sequences. Although most cases showed no or low levels of ID, an intense and, likely, functionally driven ID was evident in selected cases, especially those belonging to subset #4. The distinct ID in subset #4 was statistically significant when compared to all other groups defined by IGHV gene usage and mutation status, BCR stereotypy or heavy chain isotype. Subsequent analysis of the clonotypic light chains revealed that the impact of ID was generally low, with the outstanding exception again relating to subset #4. In fact, of 22 IGKV-J rearrangements exhibiting CMs, 11 (50%) utilized the IGKV2-30 gene and notably 10/11 (91%) of these were expressed by subset #4 cases. In such cases, the expressed IGKV2-30 gene was affected by an active and precisely targeted ID, analogous to their partner IGHV4-34 gene. These findings suggest that the SHM mechanism may continuously operate in certain subsets of CLL patients, particularly those cases expressing stereotyped IGHV4-34/IGKV2-30 BCRs typical of subset #4. In such cases, the observed ID patterns attest to the very precise targeting of the SHM process and may be considered as evidence for a “stereotyped response” to an active, ongoing interaction with Ag(s). Disclosures: No relevant conflicts of interest to declare.

CCR4:CCL17 Interaction Influences TLR-9 Mediated Cell Survival and Proliferation In Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3593-3593
Author(s):  
Sonal C. Temburni ◽  
Ryon M. Andersen ◽  
Luke Janson ◽  
Xiao-Jie Yan ◽  
Barbara Sherry ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Dose Range ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Novel Therapy

Abstract Abstract 3593 Unlike other hematologic disorders, chronic lymphocytic leukemia(CLL) exhibits remarkable heterogeneity in the rates of disease progression among cases. CLL cells survive by receiving signals from the microenvironment via various receptors: B-cell antigen receptor (BCR), Toll-like receptors (TLRs) and cytokine and chemokine receptors. We previously reported that CLL clones with somatically mutated IGHVs and high (≥30%) percentage of CD38 expressing cells have the highest percentage of CCR4-expressing cells. To further explore the functional contribution of the CCR4:CCL17 axis in CLL, we studied CCL17-induced chemotactic behavior in 16 CLL cases. In transwell cultures we observed a bimodal migratory response to CCL17 at 2 doses in a dose range of 0.78– 25ng/ml, in ~60% of cases; the remaining cases showed maximal migration at a single dose (1.56 or 3.12ng/ml). A comparison of phenotypes of the migrated and non-migrated cell populations was undertaken in 10 cases, analyzing CXCR3, CXCR4, CCR4 and CCR7 that are involved in homing of cells to sites favoring growth, and CD31, CD38 and CD69, activation related molecules. The migrated cells consistently showed significantly higher percentages and densities of CD38 expression than the non-migrated cells suggesting a role for CD38 in the CCR4-mediated downstream pathway. CCR4 ligand, CCL17, is constitutively expressed in the thymus and is produced by dendritic cells, endothelial cells, keratinocytes and fibroblasts, whereas CCL22 is produced by tumor cells and the tumor microenvironment. Serum levels of both these ligands in untreated patients were quantified by ELISA. CCL17 levels ranged between 45-1, 229 pg/ml in U-CLL cases (n=23) and between 43-1, 418 pg/ml in M-CLL cases (n=30). CCL22 levels ranged between 121-5, 497 pg/ml in U-CLL cases (n=23) and 409-5, 502 pg/ml in M-CLL cases (n=30). The percentages of CCR4- expressing B cells directly correlated with percentages of T cells expressing CCR4 in individual cases, whereas they inversely correlated with both, serum levels of CCL17 (p< 0.01) and CCL22 (p< 0.05). CCL17 produced by DCs in peripheral organs may exert an accessory role in BCR- and TLR-9-mediated immune responses in B cells. We therefore tested if CCL17 supported BCR- and TLR-mediated proliferative responses in a cohort of 31 (16 U-CLL and 15M-CLL) CLL cases. CCL17 augmented BCR-mediated B-cell proliferation in 9/16 (56%) U-CLL cases, but only in 3/15 (20%) M-CLL cases. On the other hand, CCL17 showed an additive effect in promoting TLR-9-mediated cell proliferation in 13/15 (87%) M-CLL cases at a dose of 2ng/nl (approximating that detected in serum); it also augmented TLR-9 mediated B cell proliferation in 6/16 U-CLL cases but at a 5-fold or higher dose (10-25 ng/ml). In a subset of this cohort (8 cases) CCL17-induced modulation of molecules involved in the apoptotic process was studied. We found upregulation of anti-apoptotic proteins Mcl-1 and Bcl2 and down-regulation of pro-apoptotic molecules Bim, PUMA, and Bid in 5 of these cases. The pro-survival effects of CCL17 were partially abrogated by the blocking anti-CCR4 mAb (1G1). Taken together, these findings suggest that CCL17 plays a role in modulating TLR-9-mediated signaling and migration in CLL. Therefore, inhibition of CCR4:CCL17 interaction in vivo represents a novel therapy by preventing migration of CLL cells towards an environment that promotes their survival. Disclosures: No relevant conflicts of interest to declare.

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.

Tyro3, Axl Ve Mer (TAM) Receptors On Surfaces of Mononuclear Cells in Patients with B-Cell Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4588-4588
Author(s):  
Dilvin Guney ◽  
Aysin Tulunay ◽  
Funda Pepedil ◽  
Isik Kaygusuz ◽  
Cafer Adiguzel ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Gradient Centrifugation ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Ligand Molecule ◽  
Tam Receptors ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abstract 4588 Background: Tyro 3 (Sky), Axl, and Mer receptors are members of the family of tyrosine kinases and Gas6 is their ligand molecule. In some types of cancer, upregulation of Axl/Gas6 indicated a worse prognosis, but an opposite situation was observed in renal “cell” carcinoma. This contradiction may suggest that Axl/Gas6 pathway varies depending on the type of cancer. The objective of this study is to investigate TAM receptors on surfaces of mononuclear cells in patients with B-Cell chronic lymphocytic leukemia (B-Cell-CLL). Material & Methods: B-Cell-CLL patients (grade 0–1, according to the classification of RAI), who were not on a drug treatment, were recruited in this study (n= 20; 9 female, 11 male). Their ages were 44 to 74 (mean: 63), and the control group consisted of 13 healthy volunteers (5 female, 8 male), whose age range is 20–89 (mean: 36). Mononuclear cells were isolated by density gradient centrifugation, and then surface TAM receptors were detected by flow cytometry. Mononuclear cell were stained with the primary antibodies against Tyro3, Axl and Mer. Results: The percentage of the surface TAM receptors on mononuclear cells from the patient group (25–75% interquartile range): Tyro 3= 25.50 (4.2– 45.62); Axl= 17/55 (5.57– 36.32), and Mer= 19.90 (1.92– 37.55). In the control group the following values were obtained: Tyro 3= 2.60 (1.35–3.25); Axl= 0.9 (0.4–2.6), and Mer= 2.50 (0.35–3.65). The percentage of three of them was significantly higher in the B-Cell-CLL group than those in the control group (P<0.01). Conclusion: In conclusion, this preliminary study showed that TAM receptors on surfaces of mononuclear cells are higher in patients with B-Cell-CLL patients than the control group. Gas6/TAM signaling may play a potential role in the pathogenesis of B Cell-CLL. Further studies are required to elucidate the actual role of Gas6/TAM signaling in B-Cell-CLL. Gas6/TAM signaling might be a new strategic goal for the treatment of B-Cell-CLL. Disclosures: No relevant conflicts of interest to declare.

Role Of Lyn Kinase In The Pathogenesis Of Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 668-668
Author(s):  
Phuong-Hien Nguyen ◽  
Nina Reinart ◽  
Michael Hallek
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Myeloid Cells ◽  
Lymphocytic Leukemia ◽  
Negative Regulator ◽  
Lymphoid Tissues ◽  
Malignant Cells ◽  
Deficient Mice

Abstract The Src family kinase Lyn is predominantly expressed in B cells and plays a central role in initiating B cell receptor (BCR) signaling. Lyn is associated with BCR complexes and is renowned for its role in B cell activation and proliferation. Active Lyn contributes to positive regulation of signalling through tyrosine phosphorylation of components of the BCR. Intriguingly, Lyn was also shown as a negative regulator of BCR signal transduction. Lyn plays an essential role in negative regulation of signalling through its unique ability to phosphorylate immunoreceptor tyrosine based inhibition motifs (ITIM) in inhibitory cell surface receptors. ITIM phosphorylation induces the recruitment of inhibitory phosphatases such as SHP-1/2 and SHIP-1, which attenuate BCR signalling. Lyn-deficient mice have reduced number of B cells and increased numbers of myeloid progenitors. It was reported that expression and activity of Lyn in human chronic lymphocytic leukemia (CLL) is elevated compared to healthy B cells. Besides, higher levels of Lyn are associated with a shorter treatment-free survival of CLL patients. This rises up a hypothesis about Lyn’s significant role in B cell tumorigenesis, malignant transformation of B cells, and the balance between myeloid cells and B lymphocytes. We generated Eµ-TCL1 transgenic LYN-deficient mice (TCL1+/wtLYN-/-) and monitored them in order to identify the population of malignant B cells and to characterize the development of malignant cells in these mice in comparison with Eµ-TCL1 transgenic mice (TCL1+/wtLYNwt/wt). In comparison to TCL1+/wtLYNwt/wt mice, TCL1+/wtLYN-/- mice show a significantly reduced number of malignant B cells in the peripheral blood, as well as a reduced leukocyte count. Besides, TCL1+/wtLYN-/- mice have significantly decreased infiltration of malignant B cells in lymphoid tissues such as spleen, liver, lymph node and bone marrow. This result is also resembled in a hepato-splenomegaly in the TCL1+/wtLYNwt/wt mice. These mice develop severe splenomegaly and hepatomegaly due to infiltration of malignant cells, while TCL1+/wtLYN-/- mice do not develop hepatomegaly. The non-transgenic LYN-/- control mice develop splenomegaly due to infiltration of myeloid cells. Although TCL1+/wtLYN-/- mice have hindered development of TCL1-induced CLL, preliminary data suggest it is not only due to LYN-deficiency in B cell compartment of these mice. Indeed, B cell of TCL1+/wtLYN-/- mice show enhanced proliferation and better survival ex vivo compared to TCL1+/wtLYNwt/wt mice. Notably, TCL1+/wtLYN-/- mice developed a skewed microenvironment which might contribute to CLL down regulation. LYN-/- microenvironment, particularly in aged mice, does not support engraftment of TCL1-induced leukemic B cell as well as LYNwt/wt mice in our transplantation model. These results point to a complex regulation of Lyn signalling in CLL involving not only leukemic cells but also cells of the micromillieu, that needs further investigation. Disclosures: No relevant conflicts of interest to declare.

Prognostic Factors and Outcomes in Allogeneic Hematopoietic Stem Cell Transplant Vs. Non-Transplant Chronic Lymphocytic Leukemia (CLL) Patients: A Comparative Analysis with the Leukemia/BMT Program of British Columbia (BC) and the BC Provincial CLL Database

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2549-2549 ◽  
Author(s):  
Sebastian J. Swic ◽  
Alexander G. T. MacPhail ◽  
Chinmay B. Dalal ◽  
Steven J.T. Huang ◽  
Alina S. Gerrie ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Hematopoietic Stem Cell ◽  
Conflicts Of Interest ◽  
Early Recognition ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Long Term Outcome

Abstract Background: Chronic Lymphocytic Leukemia (CLL) patients (pts) have significant (sig) heterogeneity; survival ranges from decades to <5 years (yrs). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is promising treatment (tx) for high-risk pts. Ideally, predictive (pred) tools would allow clinicians to recognize such pts early, permitting transplant performance to maximize benefit and minimize procedure associated risk. Factors with significant (sig) pred capacity are not, however, entirely clarified. Moreover, limited studies compare CLL pts who have/have not received HSCT in terms of differences (diff) in characteristics (char) at diagnosis (dx), population (pop) composition and outcomes. This study evaluates pred factors for outcomes post allo-HSCT, and compares dx char between (bn) tx CLL pts who did /did not receive HSCT by evaluating a large pop-based CLL cohort (n= 1044) from the BC Provincial CLL Database (BCPCD). Methods: 102 CLL pts (71M, 31F) had consecutive allo-HSCT (01-91 to 03-13, L/BMT Program of BC). Median (med) age (range) at dx:HSCT was 50 (26-65):57 (32-68) yrs; med interval dx to HSCT 5.8 yrs (0.5 to 29). Most pts (78, 76%) received non-ablative therapy; (n=61 [60%] reduced-intensity fludarabine /busulfan [flu/bu] based [RIC], n=17 [17%] non-myeloablative flu-cyclophosphamide based [NMA]); 24 pts had myeloablative (MA) conditioning (CON). Donor status was 50% unrelated (UD) (51UD:51RD); 73M, 28 F. Results: With median (med) follow up (FU) (range) post allo-HSCT of 2 yrs (0.5-18); post dx of 9 yrs (1-38), 67 (50%) pts survive. 70 (69%) achieved CR post-HSCT a med of 187 (28-1274) days (d). 27 had CLL PROG a med of 339 (25-4367) d; 18 of 27 (67%) survive a med of 3 (0.5-18) yrs post HSCT. Factors pred OS post HSCT (KM p=; UVA HR=) (p<0.05) were: pre-HSCT FISH deletion 17p (del 17p) (0.005; 2.9), Dohner rank (0.02), HSCT specific comorbidity index (CoI) >3 vs. 0-2 (0.04; 2.5), HLA mismatched (MM) donor (0.03;2.3), pre-HSCT tx with alemtuzumab (alem) (0.005;3.0), CON (MA vs NMA or RIC) (0.046; 3.0), acute (A) graft vs host disease (GVHD) grade (g) 3-4 vs 0-2. (<0.001; 4.5), dn chim <90% (0.001; 5.2), abn FISH not clear post-HSCT (0.009; 2.6), yr of HSCT (pre- vs post-2010) (0.03; 3.13) and lack of CR post HSCT (<0.001; 10.5).The following sig pred for (OR; p=): >90% dn chim: no B symptoms at dx (2.5; 0.004), CON (RIC vs. NMA, (2.6; 0.006); clear FISH abn post-HSCT: CR post-HSCT (4.6; 0.004); CR post-HSCT: B symptoms at dx (0.4; 0.02), <=1 FISH abn (1.7; 0.045), rituximab (R) pre-HSCT (2.5; 0.001), clear FISH abn (2.5; 0.01), flu sensitivity (S) pre-HSCT (1.8; 0.03), S to last tx pre-HSCT (1.7; 0.03), CON (MA vs. RIC or NMA) (3.2; <0.001); PROG: Richter’s transformation ( Rich trans) pre-HSCT (3.5; 0.008), graft failure (3.3; 0.008), CoI >3 vs. 0-2 (6.9; 0.006), no R pre-HSCT (6.7; 0.01), CON (MA vs. NMA or RIC), (0.2; 0.03); NRM: pre-HSCT alem (2.7; 0.03), CoI >3 vs. 0-2 (2.7; 0.049), HLA MM (2.8; 0.01), CON (MA vs. rest) (3.0; 0.007), AGVHD g 3-4 vs. 0-2 (5.9; <0.001), FISH abn not clear (2.6; 0.04), and no CR (6.5; <0.001). Comparison bn allo-HSCT and BCPCD CLL pts showed sig diff at dx for Dohner FISH rank: more del 17p (23% vs.11%) and 11q (23% vs. 9%) in allo-HSCT pts (n=84 with pre-HSCT FISH); less +12 (13% vs. 17%), del 13q (24% vs.41%) or normal (22% vs 18%), p<0.001 than non-HSCT pts (n=952); Age at dx (med, range) was lower in HSCT (50, 26-65) vs non (62, 25-96), p<0.001; lymphocyte (lymph) count higher (14, 1-300 vs.11, 1-662, p=0.03), tx-free survival (TFS) from dx to 1st tx shorter at 0.75 (0-9.3) vs. 2.86 (0-20.6) yrs. Rich trans was more frequent in HSCT pts (8%) vs. non (3%), p=0.015.OS was sig better for HSCT pts (n=103) (med 17.6, SE 4.5, CI 95% 8.8-26) compared to non (n=494) (med 14.4, SE 1.1, CI 95% 12.1-16.6) (p=0.03). Conclusion: CLL allo-HSCT pts have sig diff than non including higher lymph at dx, shorter time to 1st tx, and higher risk FISH abn. 17p del remains high-risk with allo-HSCT. Pre-HSCT R increased post HSCT CR. Strategies to optimize post-HSCT CR and dn chim are important; these milestones are crucial to best outcome. PROG post-HSCT does not confer worse OS; rescue strategies are successful and deserve further study. Comparison of this large allo HSCT and pop-based BPCDB cohort indicate improved OS for allo-HSCT tx CLL pts vs. other, with a survival plateau. This data indicates early recognition of high-risk CLL patients for HSCT is likely to yield best long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document