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Chronic Lymphocytic Leukemia (CLL)

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Richter's Syndrome

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Robak T, Stilgenbauer S, Tedeschi A
Front-line treatment of CLL in the era of novel agents.
Cancer Treat Rev. 2017; 53:70-78 [PubMed] Related Publications
Although chemoimmunotherapy prolongs survival and as such, is the standard of care for treatment-naïve patients, its effectiveness may be reduced by associated toxicity and dose reductions. In addition, it has been associated with the development of myelosuppression and secondary neoplasms; treatments are hence needed which offer greater survival and lowered toxicity. A range of new targeted agents, ibrutinib, idelalisib and venetoclax, have demonstrated such a balance in a second-line setting, offering CLL patients durable remissions and a modest toxicity profile. Ibrutinib has since been given first-line approval, and with news of second-generation targeted agents on the horizon, high-level discussions have taken place concerning their use in elderly or unfit patients; with potential use in younger patients in a first-line setting. This article reviews the potential first-line therapeutic options for treating CLL and their clinical potential and examines whether first-line chemotherapy has a place in the age of targeted agents.

Campregher PV, Petroni RC, Muto NH, et al.
A Novel Assay for the Identification of NOTCH1 PEST Domain Mutations in Chronic Lymphocytic Leukemia.
Biomed Res Int. 2016; 2016:4247908 [PubMed] Free Access to Full Article Related Publications
Aims. To develop a fast and robust DNA-based assay to detect insertions and deletions mutations in exon 34 that encodes the PEST domain of NOTCH1 in order to evaluate patients with chronic lymphocytic leukemia (CLL). Methods. We designed a multiplexed allele-specific polymerase chain reaction (PCR) combined with a fragment analysis assay to detect specifically the mutation c.7544_7545delCT and possibly other insertions and deletions in exon 34 of NOTCH1. Results. We evaluated our assay in peripheral blood samples from two cohorts of patients with CLL. The frequency of NOTCH1 mutations was 8.4% in the first cohort of 71 unselected CLL patients. We then evaluated a second cohort of 26 CLL patients with known cytogenetic abnormalities that were enriched for patients with trisomy 12. NOTCH1 mutations were detected in 43.7% of the patients with trisomy 12. Conclusions. We have developed a fast and robust assay combining allele-specific PCR and fragment analysis able to detect NOTCH1 PEST domain insertions and deletions.

McCaw L, Shi Y, Wang G, et al.
Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells.
EBioMedicine. 2017; 15:24-35 [PubMed] Free Access to Full Article Related Publications
Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6±10.4months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the "watch-and-wait" phase of management.

Al-Sawaf O, Fischer K, Herling CD, et al.
Alemtuzumab consolidation in chronic lymphocytic leukaemia: a phase I/II multicentre trial.
Eur J Haematol. 2017; 98(3):254-262 [PubMed] Related Publications
OBJECTIVE: Despite high rates of long-lasting remissions in patients with chronic lymphocytic leukaemia (CLL) treated with chemoimmunotherapy, none of the current therapeutic approaches is curative with the exception of allogeneic transplantation. One strategy to extend progression-free survival and long-term survival might be the establishment of consolidation therapies.
METHODS: In this trial, patients with complete or partial second remission after fludarabine-based treatment received consolidation therapy with alemtuzumab. The aim of this phase I/II trial was to determine the maximal tolerable dose (MTD) of alemtuzumab consolidation and to evaluate safety and efficacy in patients who responded to second-line fludarabine-based treatment. Thirteen patients in complete (CR) or partial remission (PR) received alemtuzumab dose escalation starting with 10 mg intravenously (iv) once weekly for 8 wk and increasing in 10-mg intervals per dose level.
RESULTS: The main dose-limiting toxicities (DLTs) were infectious complications, and the MTD was determined at 10 mg. After alemtuzumab consolidation, seven of 13 patients (53%) were in CR, and four of these patients (30.7%) achieved minimal residual disease (MRD) negativity (<1 × 10E-4). At a median follow-up of 71.5 months, four patients were progression-free, with a median progression-free survival (PFS) of 28.5 months after the end of second-line treatment.
CONCLUSION: The results provide a safe and efficient schedule with weekly intravenous application of 10 mg of alemtuzumab as a consolidation regime in patients with CLL.

Haerzschel A, Catusse J, Hutterer E, et al.
BCR and chemokine responses upon anti-IgM and anti-IgD stimulation in chronic lymphocytic leukaemia.
Ann Hematol. 2016; 95(12):1979-1988 [PubMed] Free Access to Full Article Related Publications
Dysregulation of B cell receptor (BCR) signalling is a hallmark of chronic lymphocytic leukaemia (CLL) pathology, and targeting BCR pathway kinases has brought great therapeutic advances. Activation of the BCR in lymphoid organs has been associated with CLL cell proliferation and survival, leading to progressive disease. While these responses are mediated predominantly by IgM, the role of IgD is less clear. Seeking to uncover downstream consequences of individual and combined stimulation of the two BCR isotypes, we found an amplification of IgD expression and IgD-mediated calcium signalling by previous stimulation of IgM in CLL. Furthermore, no heterologous downmodulation of the isotypes, as observed in healthy donors, was present. Only marginal downregulation of the expression of various chemokine receptors by α-IgM and α-IgD stimulation was found as compared to normal B cells. Consistently, calcium responses of CLL cells to different chemokines were only weakly affected by preceding BCR activation. In contrast, migration towards the two homeostatic chemokines CXCL12 and CCL21 was differentially regulated by IgM and IgD. While IgM activation reduced migration of CLL cells towards CXCL12, but not CCL21, IgD activation predominantly impacted on CCL21 but not CXCL12-mediated chemotaxis. This indicates that the preference for one chemokine over the other may depend on the functional presence of the two isotypes in CLL. Inhibitors against the kinases Syk, Lyn, and Btk antagonised both BCR- and chemokine-induced calcium signals.

Morrison EJ, Flynn JM, Jones J, et al.
Individual differences in physical symptom burden and psychological responses in individuals with chronic lymphocytic leukemia.
Ann Hematol. 2016; 95(12):1989-1997 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is an incurable illness, with some patients requiring no treatment until disease progression. Burden from physical symptoms has been associated with depression, anxiety, and stress in cancer patients. Additionally, patient factors, i.e., individual differences, have been associated with worse psychological outcomes. There are few psychological studies of CLL, with no examination of individual differences. A cross-sectional design studied the covariation of symptom burden with depressive and anxiety symptoms and cancer-specific stress, and tested patients' individual differences as predictors and as moderators. CLL patients (N = 112) receiving active surveillance participated. They were Caucasian (100 %) and predominately male (55 %) with a mean age of 61; most (62.5 %) had stage 0 disease. A composite measure of physical symptom burden (CLL symptoms, fatigue, pain, impaired functional status) was tested as a predictor of psychological responses. Individual differences in psychiatric history and social support were tested as moderators. Using multiple linear regression, greater symptom burden covaried with higher levels of depressive and anxiety symptoms and cancer stress (ps < .05). Those with a psychiatric history, low social support, and low relationship satisfaction with one's partner reported greater symptom burden and more psychological symptoms and stress (ps < .05). Findings suggest that CLL patients in surveillance with a psychiatric history and/or low social support are at risk for greater distress when coping with high symptom burden. These new data clarify the experience of CLL surveillance and identify characteristics of patients with heightened risk for symptom burden, stress, and anxiety or depressive symptoms.

Kron F, Kutsch N, Kostenko A, et al.
Economic evaluation of chronic lymphocytic leukemia from a hospital management perspective.
Eur J Haematol. 2017; 98(2):169-176 [PubMed] Related Publications
OBJECTIVES: Treatment of chronic lymphocytic leukemia (CLL) is currently undergoing dramatic changes. We analyzed economic risks in hospitalized patients with CLL from a management perspective.
METHODS: One hundred and twelve patients with CLL hospitalized in 2013 and 2014 at the University Hospital of Cologne were analyzed. To assess profit margins (PMs) per case, diagnosis-related group (DRG) reimbursement data were merged with an internal cost accounting scheme depending on age, prognostic factors, and DRG key performance indicators.
RESULTS: In 112 patients, 284 cases coded by 19 different DRG with strongly fluctuating cost revenue ratios were found with an overall negative PM of €137 147. The DRG R61H was identified as the one most commonly coded (174 cases, 61.3%) with a deficit per case of €814. Subanalysis demonstrated that the payments were not cost covering due to excessive length of stay and staff costs. Significant differences in PM per case concerning age, length of stay and number of operation and procedure key (OPS) codes (P < 0.05) were found.
CONCLUSION: In our research-driven tertiary care hospital, inpatient treatment of patients with CLL is not cost covering. This analysis demonstrates the need for novel care/reimbursement structures in CLL. From a hospital management perspective, cost revenue controlling is crucial to avoid major economic risks.

Khan AS, Hojjat-Farsangi M, Daneshmanesh AH, et al.
Dishevelled proteins are significantly upregulated in chronic lymphocytic leukaemia.
Tumour Biol. 2016; 37(9):11947-11957 [PubMed] Related Publications
Dishevelled (DVL) proteins are components of the Wnt signalling pathways, and increased expression is associated with various malignancies. Information on DVLs in chronic lymphatic leukaemia (CLL) is limited. The aim of the present study was to investigate the role of DVLs in CLL cells and association with Wnt pathways downstream of ROR1. DVL1, 2 and 3 were exclusively expressed in CLL cells as compared to normal peripheral blood mononuclear cells (PBMCs). The expression of DVL1 and DVL3 proteins was significantly more pronounced in progressive than in non-progressive disease (p < 0.01), whereas the level of DVL2 was significantly higher in non-progressive as compared to progressive disease (p < 0.001). Treatment of CLL cells with anti-ROR1 specific monoclonal antibodies induced dephosphorylation of ROR1 as well as of tyrosine and serine residues of both DVL2 and DVL3. However, gene silencing of DVLs in the CLL cell line (EHEB) did not induce detectable apoptosis. Non-progressive CLL patients had a different protein activity pattern with regard to Wnt signalling pathway proteins as GSK-3β, β-catenin and AKT as compared to progressive disease. The DVL2 protein may play a role in the activation of signalling pathways in CLL during early stages of the disease, while DVL1 and 3 may have a role in later phases of the leukaemia.

Filip AA, Grenda A, Popek S, et al.
Expression of circulating miRNAs associated with lymphocyte differentiation and activation in CLL-another piece in the puzzle.
Ann Hematol. 2017; 96(1):33-50 [PubMed] Free Access to Full Article Related Publications
Expression of microRNAs is altered in cancer. Circulating miRNA level assessed in body fluids commonly reflects their expression in tumor cells. In leukemias, however, both leukemic and nonleukemic cells compose circulating miRNA expression profile of peripheral blood. The latter contribution to extracellular miRNA pool may result in specific microenvironmental signaling, which promotes proliferation and survival. In our study, we used qT-PCR to assay peripheral blood serum of 22 chronic lymphocytic leukemia (CLL) patients for the expression of 84 miRNAs associated with activation and differentiation of B and T lymphocytes. Results were analyzed regarding the most important prognostic factors. We have found that the general expression of examined miRNAs in CLL patients was lower as compared to healthy volunteers. Only miR-34a-5p, miR31-5p, miR-155-5p, miR-150-5p, miR-15a-3p, and miR-29a-3p were expressed on a higher level. Alterations of expression observed in CLL patients involved miRNAs associated both with B and T lymphocyte differentiation and activation. The most important discriminating factors for all functional miRNA groups were trisomy 12, CD38 expression, B2M level, WBC, and NOTCH1 gene mutation. Correlation of expression of miRNAs related to T lymphocytes with prognostic factors proves their supportive function in a leukemic microenvironment. Further studies utilizing a larger test group of patients may warrant the identification of circulating miRNAs that are key players in intercellular interactions and should be considered in the design of microenvironment-targeted therapies.

Minervini CF, Cumbo C, Orsini P, et al.
TP53 gene mutation analysis in chronic lymphocytic leukemia by nanopore MinION sequencing.
Diagn Pathol. 2016; 11(1):96 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The assessment of TP53 mutational status is becoming a routine clinical practice for chronic lymphocytic leukemia patients (CLL). A broad spectrum of molecular techniques has been employed so far, including both direct Sanger sequencing and next generation sequencing. Oxford Nanopore Technologies recently released the MinION an USB-interfaced sequencer. In this paper we report our experience, with the MinION technology for the detection of the TP53 gene mutation in CLL patients. Twelve CLL patients at diagnosis were included in this study. All except one patient showed the TP53 gene deletion in Fluorescence in situ hybridization experiments. Patients were investigated for TP53 mutation by Sanger and by MinION sequencing. Analysis by Sanger was performed according with the IARC protocol. Analysis by MinION was performed adopting a strategy based on long template PCR, read error correction, and post variant calling filtering.
RESULTS: Due to the high error rate of nanopore technology, sequence data were both used directly and before correction with two different in silico methods: ALEC and nanocorrect. A mean error rate of 15 % was detected before correction that was reduced to 4-5 % after correction. Analysis by Sanger sequencing was able to detect four patients mutated for TP53. MinION analysis detected one more mutated patient previously not detected from Sanger.
CONCLUSION: In our hands, the Nanopore technology shows correlation with Sanger sequencing but more sensitive, manageable and less expensive, and therefore has proven to be a useful tool for TP53 gene mutation detection.

González-Gascón Y Marín I, Martín AÁ, Hernández-Sanchez M, et al.
Hyperdiploidy as a rare event that accompanies poor prognosis markers in CLL.
Eur J Haematol. 2017; 98(2):142-148 [PubMed] Related Publications
The presence of chromosomal gains other than trisomy 12 in chronic lymphocytic leukaemia (CLL) is unusual. However, some patients may show gains on several chromosomes simultaneously suggesting a hyperdiploid karyotype.
OBJECTIVE: The objective of this study was to analyse by FISH the frequency and prognostic impact of hyperdiploidy in CLL.
METHOD: A review of 1359 consecutive cases diagnosed with CLL referred for FISH analysis to a unique institution was carried out. Hyperdiploidy was considered when a gain of at least three of the five FISH probes used was observed.
RESULTS: Seven cases (0.51%) with hyperdiploidy were found, confirming that it is a rare event in this disease. Although most patients presented with early Binet stages at diagnosis, six of seven (86%) shortly progressed. The median of time to the first therapy (TTFT) and overall survival (OS) for the patients with hyperdiploidy were short (1.4 months and 20 months, respectively). Moreover, comparing them with a control group of patients (non-hyperdiploid) with completed follow-up data, TTFT and OS of the patients with hyperdiploidy were significantly shorter than the control group.
CONCLUSION: The presence of hyperdiploidy is uncommon and probably associated with poor prognostic markers in CLL.

Korkmaz S, Kulakoglu S, Gorkem H, et al.
Coexistence of chronic lymphocytic leukemia and polycythemia vera: a case report and review of the literature.
Ann Saudi Med. 2016 Sep-Oct; 36(5):364-366 [PubMed] Related Publications
Polycythemia vera is a Philadelphia chromosome-negative myeloproliferative neoplasm. Chronic lymphocytic leukemia is a monoclonal expansion of a CD5+ CD19+ B lymphocytes. Chronic myeloproliferative neoplasms may coexist with indolent B-cell malignant lymphomas of various types. The association of chronic lymphocytic leukemia with polycythemia vera is a rare event with only a few cases of coexistence ever reported. We report a 56-year-old man in whom these two disorders were diagnosed concomitantly. Possible etiopathogenic relationships between both disorders are discussed in this case report.

Sachanas S, Pangalis GA, Karouzakis P, et al.
Malakoplakia of the Urinary Bladder in a Patient with Chronic Lymphocytic Leukemia Under Ibrutinib Therapy: A Case Report.
Anticancer Res. 2016; 36(9):4759-62 [PubMed] Related Publications
Malakoplakia, a rare granulomatous disease of infectious etiology, is commonly observed in immunocompromised patients. Chronic lymphocytic leukemia (CLL) is characterized by profound immune dysregulation resulting in significant infection-related morbidity and mortality, and several drugs used in CLL treatment have a severe immunosuppressive effect. Ibrutinib, has become a new standard-of-care in patients with CLL, especially for those harboring unfavorable genetic characteristics such as 17 p deletion, with however, unknown long-term immunological consequences. Here we report a case of a patient with CLL with 17 p deletion diagnosed with malakoplakia of the urinary bladder under ibrutinib therapy who developed severe hypogammaglobulinemia during treatment administration. Presumably, ibrutinib might contribute to the development of malakoplakia on the grounds of induced immunosuppression. This case report highlights the need for regular assessment of immunogammaglobulin adequacy during treatment with ibrutinib, considering that it should be given on a permanent basis.

Schmidt-Wolf IG, Plass C, Byrd JC, et al.
Assessment of Promoter Methylation Identifies PTCH as a Putative Tumor-suppressor Gene in Human CLL.
Anticancer Res. 2016; 36(9):4515-9 [PubMed] Related Publications
BACKGROUND: Chronic lymphocytic leukemia (CLL) is characterized by a clonal accumulation of neoplastic lymphocytes, indicating disruption of apoptosis.
PATIENTS AND METHODS: Differential methylation hybridization analysis was performed to identify novel target genes silenced by CpG island methylation in patients with CLL.
RESULTS: Patched (PTCH), a tumor-suppressor gene, was found to be frequently methylated in CLL samples compared to samples derived from healthy individuals. De novo methylation of a CpG island region located upstream of PTCH exon 1 was confirmed by pyrosequencing in 17/37 (46%) of peripheral blood mononuclear cells of patients with CLL, but in none isolated from seven healthy individuals. No association was found between PTCH hypermethylation and currently used prognostic CLL factors.
CONCLUSION: Our investigation suggests that epigenetic silencing of PTCH is a mechanism contributing to CLL tumorigenesis.

Nguyen-Khac F, Borie C, Callet-Bauchu E, et al.
Cytogenetics in the management of chronic lymphocytic leukemia: an update by the Groupe francophone de cytogénétique hématologique (GFCH).
Ann Biol Clin (Paris). 2016; 74(5):561-567 [PubMed] Related Publications
Acquired recurrent cytogenetic abnormalities are frequent in chronic lymphocytic leukaemia (CLL). They can be associated with good or poor prognostic factors, and also with gene mutations. Chromosomal abnormalities could be clonal or sub-clonal. Assessing the TP53 status (deletion/mutation) is currently mandatory before treating patients. The search for 11q deletion (ATM gene) is also recommended. Finally, the prognostic value of other chromosomal abnormalities including complex karyotype is still debated.

Koutroumpakis E, Lobe M, McCarthy L, Mehdi S
Symptomatic Hypercalcemia in a Patient with B-cell Chronic Lymphocytic Leukemia - A Case Report and Review of the Literature.
In Vivo. 2016 09-10; 30(5):691-4 [PubMed] Related Publications
BACKGROUND: Hypercalcemia due to malignancy is well described in the literature and a common paraneoplastic finding in certain solid tumors. Hematologic malignancies, however, are less frequently associated with hypercalcemia with the exception of myelomas and T-cell lymphomas.
CASE REPORT: This case report describes a patient with B-cell chronic lymphocytic leukemia (B-CLL) who developed symptomatic hypercalcemia. None of the pathogenetic mechanisms of malignancy-associated hypercalcemia already described in the literature could explain the pathogenesis of hypercalcemia in our patient. Calcium levels were normalized after initial treatment and remained within normal limits following treatment of the underlying B-CLL. The follow-up period was 26 months. The normalization of calcium levels was closely associated with the drop in the absolute lymphocyte count.
CONCLUSION: Symptomatic hypercalcemia in B-CLL is exceedingly rare and only documented a few times in the literature. Hypercalcemia, in the present case, was not caused by any of the mechanisms already described in the literature and responded well to treatment of the underlying B-CLL.

Villegas Gracia R, Franco Alzate C, Rendón Henao J, et al.
Frequency of monoclonal B-cell lymphocytosis in relatives of patients with chronic lymphocytic leukemia.
Colomb Med (Cali). 2016; 47(2):81-6 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Monoclonal B-cell lymphocytosis is a symptom free condition characterized by the circulation of small clonal population of B lymphocytes in peripheral blood (less than 5x10(9)/L) expressing an immunophenotype similar to chronic lymphocytic leukemia. Different studies based on big hospital series have manifested a higher risk in subjects with monoclonal B-cell lymphocytosis to progress to a chronic lymphocytic leukemia. The behavior of this hematologic entity is unknown therefore its frequency in sporadic chronic lymphocytic leukemia patient relatives was determined.
METHODS: Transversal descriptive study, 8 color flow cytometry was performed using two of the tubes of the Euro Flow recommended panel, with modifications, for the diagnose of chronic lymphoproliferative disorders of B lymphocytes; besides, a fluorescence in situ hybridization was performed. univariate and bivariate analyses of the information were performed.
RESULTS: Monoclonal B-cell lymphocytosis frequency found in 51 analyzed relatives was 2%, it was a female participant, 59 years old, with a total leukocyte count of 7.7x10(9)/L and a B lymphocyte count of 0.124x10(9)/L; from these, 0.04x10(9)/L were clonal cells with restrictions of the kappa light chain. Rearrangements of the IGH gene (14q32) were found.
CONCLUSION: Monoclonal B-cell lymphocytosis was detected in one relative of a patient with sporadic chronic lymphocytic leukemia in a frequency similar to the one reported in general population.

Khan N, Afridi HI, Kazi TG, et al.
Correlation of Cadmium and Magnesium in the Blood and Serum Samples of Smokers and Non-Smokers Chronic Leukemia Patients.
Biol Trace Elem Res. 2017; 176(1):81-88 [PubMed] Related Publications
It was studied that cancer-causing processes are related with the disproportions of essential and toxic elements in body tissues and fluid. The purpose of the current study was to evaluate the levels of magnesium (Mg) and cadmium (Cd) in serum and blood samples of smokers and nonsmokers who have chronic myeloid (CML) and lymphocytic (CLL) leukemia, age ranged 31-50 years. For comparative study, age-matched smokers and nonsmoker males were chosen as controls/referents. The levels of elements in patient were analyzed before any treatment by atomic absorption spectrophotometer, after microwave assisted acid digestion. The validation of the method was done by using certified reference materials of serum and blood samples. The resulted data indicated that the adult male smokers and nonsmokers have two- to fourfold higher levels of Cd in the blood and sera samples as compared to the referents (p < 0.01), whereas two- to threefold lower levels of Mg was found in blood and serum samples of both types of leukemia patients as related to referent values. The resulted data indicates significant negative correlation among Mg and Cd in leukemia patients and smoker referents. Further studies are needed to clarify the role of these elements in pathogenesis of chronic leukemia.

Yu KK, Dasanu CA
Rapidly Fatal Dissemination of Merkel Cell Carcinoma in a Patient Treated with Alemtuzumab for Chronic Lymphocytic Leukemia.
Conn Med. 2016 Jun-Jul; 80(6):353-8 [PubMed] Related Publications
Alemtuzumab is FDA-approved for the treatment of chronic lymphocytic leukemia (CLL). Nonetheless, its use for this indication has fallen out of favor due to serious concerns for infectious complications and increased risks of second malignancies from the profound and lasting immunosuppression. We report here in a patient with a rapidly progressive metastatic Merkel cell carcinoma (MCC) who was previously treated with alemtuzumab and fludarabine for CLL. He developed profound lymphopenia and hypogammaglobulinemia. While the risk of MCC is increased in CLL, its rapid dissemination has not been previously reported with fludarabine alone. In light of the rapidly fatal outcome in our patient due to MCC, we advise caution with the use of alemtuzumab. In patients treated with alemtuzumab for nononcologic indications, aggressive surveillance for cutaneous malignancies should be implemented until its safety profile can be further characterized.

Rombout A, Verhasselt B, Philippé J
Lipoprotein lipase in chronic lymphocytic leukemia: function and prognostic implications.
Eur J Haematol. 2016; 97(5):409-415 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation of a clonal population of B cells in peripheral blood, bone marrow, and lymphoid organs. More than 10 years ago, lipoprotein lipase (LPL) mRNA was identified as being strongly expressed in patients experiencing a more aggressive phenotype, while CLL patients with an indolent disease course lack expression of this marker. Since then, several reports confirmed the capability of LPL to predict CLL disease evolution at the moment of diagnosis. In contrast, data on the functional implications of LPL in CLL are scarce. LPL exerts a central role in overall lipid metabolism and transport, but plays additional, non-catalytic roles as well. Which of those is more important in the pathogenesis of CLL remains largely unclear. Here, we review the current knowledge on the prognostic and biological relevance of LPL in CLL.

Dai Z, Feng C, Zhang W, et al.
Lack of association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms and lymphoid malignancy risk: evidence from a meta-analysis.
Ann Hematol. 2016; 95(10):1685-94 [PubMed] Related Publications
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphisms have been associated with susceptibility to lymphoid malignancies. However, results from the published single studies are inconsistent. Therefore, the present meta-analysis was conducted to get a more accurate estimation of the relationship between CTLA-4 gene polymorphisms and the lymphoid malignancy risk. We identified nine independent studies accounting for 3090 subjects up to January 30, 2016. Summary odds ratios (OR) and 95 % confidence intervals (CI) were used to evaluate the risk of lymphoid malignancies. Overall, no significant association was found between +49A/G (rs231775), -318C/T (rs5742909), and +6230A/G (rs3087243) CTLA-4 gene polymorphisms and lymphoid malignancies. Furthermore, ethnicity (Asian and Caucasian) and histopathology subgroup analyses (non-Hodgkin's lymphoma) also failed to detect an association between the studied polymorphisms and lymphoid malignancy risk. Our study shows that common CTLA-4 gene polymorphisms may not contribute to lymphoid malignancy susceptibility based on the current evidence.

El-Schich Z, Abdullah M, Shinde S, et al.
Different expression levels of glycans on leukemic cells-a novel screening method with molecularly imprinted polymers (MIP) targeting sialic acid.
Tumour Biol. 2016; 37(10):13763-13768 [PubMed] Free Access to Full Article Related Publications
Sialic acid (SA) is normally expressed on the cell membranes and is located at the terminal position of the sugar chains. SA plays an important role for regulation of the innate immunity, function as markers of the cells and can be recognized by a variety of receptors. Interestingly, the level of SA expression is increased on metastatic cancer cells. The availability of specific antibodies against SA is limited and, therefore, biomarker tools for detection of SA are lacking. We have recently presented a novel method for specific fluorescence labeling of SA molecular imprinted polymers (MIP). Here, we have performed an extended screening of SA expression by using SA-MIP and included four different chronic lymphocytic leukemia (CLL) cell lines, conveniently analyzed by flow cytometry and fluorescence microscopy. SA expression was detected in four cell lines at different levels, and the SA expression were verified with lectin-FITC. These results show that SA-MIP can be used as a plastic antibody for detection of SA using both flow cytometry and fluorescence microscopy. We suggest that SA-MIP can be used for screening of different tumor cells of various stages, including CLL cells.

Shahidi M, Mohsen Razavi S, Hayat P
Induction of endothelial cell proliferation and von Willebrand factor expression and secretion by leukemic plasma of patients with chronic lymphocytic leukemia before and after inhibition of NF-κB.
Blood Coagul Fibrinolysis. 2016; 27(6):711-6 [PubMed] Related Publications
Although certain evidence has indicated a role for angiogenesis in the pathophysiology of hematopoietic malignancies, its role in chronic lymphocytic leukemia (CLL) prognosis is yet to be defined. To our knowledge, the effects of CLL plasma on cell culture have not been addressed. Therefore, we investigated the effects of CLL plasma on cell cycle regulation and von Willebrand factor (vWF) secretion, and expression in human umbilical vein endothelial cell cultures (HUVECs). Since nuclear factor-kappa B (NF-κB) transcription factor has been a therapeutic target for treatment of cancer, we inhibited NF-κB using small interfering RNA to clarify if there is a role for this factor in probable effects. The cells were treated with the plasma of patients with CLL. Subsequently, cell cycle phase distribution, vWF secretion, expression, and storage were detected using ELISA, flow cytometry, and immunohistochemical staining. In addition, NF-κB was inhibited using small interfering RNA. Plasma treatment promoted cell cycle progression by decreasing the cell number in G1 phase, while increasing the cell number in S phase and G2M phase. A significant increase of vWF expression, secretion, and storage was found, associated with the vWF levels of patients' plasma. We found that induction of cell cycle promotion, but not vWF expression and secretion, was partially suppressed by this inhibition. We found that endothelial cell cycle and vWF expression and secretion affected by CLL plasma and NF-κB play a role in the former. These findings would be useful for understanding the prognostic importance of plasma angiogenic factor levels in CLL.

Jasek M, Bojarska-Junak A, Wagner M, et al.
Association of variants in BAFF (rs9514828 and rs1041569) and BAFF-R (rs61756766) genes with the risk of chronic lymphocytic leukemia.
Tumour Biol. 2016; 37(10):13617-13626 [PubMed] Free Access to Full Article Related Publications
The B-cell activator factor (BAFF)/BAFF receptor (BAFF-R) axis seems to play an important role in the development and progression of chronic lymphocytic leukemia (CLL). Here, we investigated the association of eight single nucleotide polymorphisms (SNPs) in the BAFF (TNFSF13B) and BAFF-R (TNFRSF13C) genes with risk of sporadic CLL in a group of 439 CLL patients and 477 controls. We also examined the correlation between selected SNPs and CLL clinical parameters as well as BAFF plasma levels and intracellular BAFF expression. Our results point to a possible association between the rs9514828 (CT vs. CC + TT; OR = 0.74; CI 95 % = 0.57; 0.97; p = 0.022) and rs1041569 (AT vs. AA + TT; OR = 0.72; CI 95 % = 0.54; 0.95; p = 0.021) of BAFF gene and rs61756766 (CC vs. CT; OR = 2.03; CI 95 % = 1.03; 3.99; p = 0.03) of BAFF-R gene and CLL risk. Additionally, we observed that homozygotes rs1041569 AA and TT had a slightly higher risk (HR = 1.12) for the need of treatment in comparison to AT heterozygotes. In conclusion, our results indicate that SNPs in BAFF and BAFF-R genes may be considered as potential CLL risk factors.

Friman V, Winqvist O, Blimark C, et al.
Secondary immunodeficiency in lymphoproliferative malignancies.
Hematol Oncol. 2016; 34(3):121-32 [PubMed] Related Publications
Secondary immunodeficiencies occur as a consequence of various diseases, including hematological malignancies, and the use of pharmacological therapies, such as immunosuppressive, anti-inflammatory, and biological drugs. Infections are the main cause of morbidity and mortality in multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients. Recent advances in treatment have prolonged the duration of remission and the time between relapse phases in MM and CLL patients. However, managing multiple relapses and the use of salvage therapies can lead to cumulative immunosuppression and a higher risk of infections. The pathogenesis of immune deficiency secondary to lymphoproliferative malignancy is multifactorial including disease- and treatment-related factors. Supportive treatment, including early vaccination, anti-infective prophylaxis, and replacement immunoglobulin, plays a key role in preventing infections in MM and CLL. This article provides an overview of the basic immunology necessary to understand the pathogenesis of secondary immunodeficiency and the infectious complications in MM and CLL. We also discuss the evidence supporting the role of prophylactic replacement immunoglobulin treatment in patients with antibody failure secondary to MM and CLL and the indications for its use. Copyright © 2016 John Wiley & Sons, Ltd.

Varma G, Johnson TP, Advani RH
Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia and lymphoma.
Clin Adv Hematol Oncol. 2016; 14(7):543-54 [PubMed] Related Publications
The development of Bruton's tyrosine kinase (BTK) inhibitors and their introduction into clinical practice represent a major advance in the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Although ibrutinib is the only BTK inhibitor that has been approved by the US Food and Drug Administration, several others are under investigation. Ibrutinib is currently approved for use in relapsed/refractory CLL, CLL with 17p deletion (del[17p]), relapsed or refractory mantle cell lymphoma, and Waldenström macroglobulinemia. Although it is clear that ibrutinib has altered treatment paradigms and outcomes in these diseases, several questions remain regarding (1) its role in frontline vs salvage therapy; (2) its use as a single agent vs in combination with biologic agents, other small molecules, or traditional chemoimmunotherapy; (3) the optimal duration of treatment; and (4) the treatment of patients who cannot tolerate or have disease resistant to ibrutinib. Because sparse clinical data are available on other BTK inhibitors, it is unclear at present whether their clinical efficacy and toxicity will differ from those of ibrutinib.

Scarfò L, Ferreri AJ, Ghia P
Chronic lymphocytic leukaemia.
Crit Rev Oncol Hematol. 2016; 104:169-82 [PubMed] Related Publications
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among the adults in the Western World. CLL (and the corresponding nodal entity small lymphocytic lymphoma, SLL) is classified as a lymphoproliferative disorder characterised by the relentless accumulation of mature B-lymphocytes showing a peculiar immunophenotype in the peripheral blood, bone marrow, lymph nodes and spleen. CLL clinical course is very heterogeneous: the majority of patients follow an indolent clinical course with no or delayed treatment need and with a prolonged survival, while others experience aggressive disease requiring early treatment followed by frequent relapses. In the last decade, the improved understanding of CLL pathogenesis shed light on premalignant conditions (i.e., monoclonal B-cell lymphocytosis, MBL), defined new prognostic and predictive markers, improving patient stratification, but also broadened the therapeutic armamentarium with novel agents, targeting fundamental signaling pathways.

Liang L, Zhao M, Zhu YC, et al.
Efficacy of lenalidomide in relapsed/refractory chronic lymphocytic leukemia patient: a systematic review and meta-analysis.
Ann Hematol. 2016; 95(9):1473-82 [PubMed] Related Publications
Therapeutic results of relapsed/refractory chronic lymphocytic leukemia (CLL) are very disappointing at present. Lenalidomide has been proved to be effective for relapsed/refractory CLL as a single agent or in combination with various chemo-immunotherapeutic regimens. However, current clinical experience in its usage is still limited. Because of existing considerable variability in different studies, a systematic review and meta-analysis was conducted to describe overall response rate (ORR) of lenalidomide in patients with relapsed/refractory CLL. Pooled estimate of cumulative prevalence of total ORR was 42.23 % (95 % confidence interval [CI], 32.49-52.61 %), while pooled ORR in regimen with lenalidomide plus anti-CD20 monoclonal antibody (mAbs) and lenalidomide mono-therapy were 60.01 % (95 % CI, 53.86-65.86 %) and 24.38 % (95 % CI, 16.15-35.06 %), respectively. There was no significant difference between L + R (lenalidomide plus rituximab) group and L + O (lenalidomide plus ofatumumab) group, with pooled ORR of 66.38 % (95 % CI, 57.96-73.87 %) and 57.40 % (95 % CI, 46.46-67.65 %), respectively. When co-administrated with anti-CD20 mAbs, dosage of lenalidomide was not the key factor of ORR in combination therapy. Pooled ORR of patient with high-risk cytogenetic in L + anti-CD20 mAbs group was 56.74 % (95 % CI, 45.53-67.30 %). In comparison with patients without high-risk cytogenetic receiving the same treatment regimen, no significant difference was observed, with relative risk (RR) of 0.87 (95 % CI 0.68-1.11). Our finding demonstrated that lenalidomide plus anti-CD20 mAbs could be an efficient therapy regimen for relapsed/refractory CLL patients, especially for those with high-risk cytogenetic factor.

Lin X, Chen J, Huang H
Immunostimulation by cytosine-phosphate-guanine oligodeoxynucleotides in combination with IL-2 can improve the success rate of karyotype analysis in chronic lymphocytic leukaemia.
Br J Biomed Sci. 2016; 73(3):110-114 [PubMed] Related Publications
PURPOSE: To assess whether immunostimulatory cytosine-phosphate-guanine oligodeoxynucleotides (CpG-ODN) combined with interleukin-2 (IL-2) improves the number of mitotic metaphases and the detection rate of chromosomal abnormalities in chronic lymphocytic leukaemia (CLL).
MATERIALS AND METHODS: Bone marrow specimens were collected from 36 patients with CLL. CLL cells were cultured with CpG-ODN type DSP30 plus IL-2 for 72 h, following which R-banding analysis was conducted. Conventional culture without the immunostimulant served as the control group. The incidence of genetic abnormalities was measured by fluorescence in situ hybridisation (FISH) using a panel of five specific probes: D13S25 (13q14.3), RB1 (13q14), P53 (17p13), ATM (11q22.3) and CSP12 (trisomy 12, +12).
RESULTS: In the control group, chromosome analysis achieved a success rate of only 22.2, and 11.1% of abnormal karyotypes were detected. After immunostimulation with DSP30 plus IL-2, chromosome analysis achieved a success rate of up to 91.6, and 41.6% of abnormal karyotypes were detected. FISH analysis detected 77.7% of abnormalities. FISH combined with CpG-ODN DSP30 plus IL-2 improved the detection rate of chromosomal abnormalities in CLL to 83.3%.
CONCLUSION: CpG-ODN DSP30 combined with IL-2 is effective in improving the detection rate of chromosomal abnormalities in CLL cells. This combination with FISH analysis is conducive to increasing the detection rate of genetic abnormalities in CLL.

Barrientos JC
Idelalisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.
Future Oncol. 2016; 12(18):2077-94 [PubMed] Related Publications
Idelalisib is a first-in-class selective oral PI3Kδ inhibitor for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, a predominantly elderly population with high comorbidity. The drug promotes apoptosis in primary CLL cells ex vivo, independent of common prognostic markers and inhibits CLL cell homing, migration and adhesion to cells in the microenvironment. Idelalisib has shown efficacy with acceptable safety as monotherapy and combination therapy in relapsed/refractory CLL. Idelalisib has clinical activity in patients with CLL with del(17p). The development of other novel B-cell-targeted agents provides the opportunity to evaluate additional idelalisib treatment combinations for their potential to further improve outcomes in CLL/small lymphocytic lymphoma.

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