Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL.

The randomized Haemato Oncology Foundation for Adults in The Netherlands 68 phase 3 trial compared front-line chemotherapy with chemotherapy plus the CD52 monoclonal antibody alemtuzumab for high-risk chronic lymphocytic leukemia, defined as at least 1 of the following: unmutated immunoglobulin heavy chain genes, deletion 17p or 11q, or trisomy 12. Fit patients were randomized to receive either 6 28-day cycles of oral FC chemotherapy (days 1 through 3: fludarabine 40 mg/m(2) per day and cyclophosphamide 250 mg/m(2) per day: n = 139) or FC plus subcutaneous alemtuzumab 30 mg day 1 (FCA, n = 133). FCA prolonged the primary end point, progression-free survival (3-year progression-free survival 53 vs 37%, P = .

Combination of two anti-CD5 monoclonal antibodies synergistically induces complement-dependent cytotoxicity of chronic lymphocytic leukaemia cells.

The treatment of chronic lymphocytic leukaemia (CLL) has been improved by introduction of monoclonal antibodies (mAbs) that exert their effect through secondary effector mechanisms. CLL cells are characterized by expression of CD5 and CD23 along with CD19 and CD20, hence anti-CD5 Abs that engage secondary effector functions represent an attractive opportunity for CLL treatment. Here, a repertoire of mAbs against human CD5 was generated and tested for ability to induce complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) both as single mAbs and combinations of two mAbs against non-overlapping epitopes on human CD5.

Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies.

Plasma alemtuzumab levels in patients with chronic lymphocytic leukemia treated with alemtuzumab combined with chemotherapy reflect the efficacy of the treatment: a hypothesis.

In the HOVON68 trial comparing subcutaneous low-dose alemtuzumab (LD-A) used together with fludarabine (F) and cyclophosphamide (C) with FC alone in high-risk chronic lymphocytic leukemia (CLL), LD-AFC resulted in significantly more clinical and molecular responses than FC, but also in more opportunistic infections. In a subgroup analysis of alemtuzumab trough levels during treatment by a sensitive enzyme-linked immunosorbent assay (ELISA) method, detectable levels were found in 4/6 complete and 0/3 partial responders. A relationship between alemtuzumab plasma levels, response and duration of lymphocytopenia was evident.

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies.

Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm.

Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia.

Background: High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution.

Design And Methods: We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays.

LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia.

Background: The expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these different RNA-based markers.

Design And Methods: Using real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome.

Quality of life in patients with diffuse large B-cell lymphoma treated with dose-dense chemotherapy is only affected temporarily.

(R)-CHOP-14 has substantially improved outcome in DLBCL, but may have increased morbidity and reduced quality of life (QoL). Our aim was to evaluate QoL during (R)-CHOP-14-based chemotherapy. Twenty-six patients participated (small single-center study).

TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia.

TP53 mutations in the absence of 17p-deletion correlate with rapid disease progression and poor survival in chronic lymphocytic leukemia (CLL). Herein, we determined the TP53 mutation frequency in 268 newly diagnosed CLL patients from a population-based material. Overall, we detected TP53 mutations in 3.

Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors.

Background: Numerous subsets of patients with chronic lymphocytic leukemia display similar immunoglobulin gene usage with almost identical complementarity determining region 3 sequences. Among IGHV4-34 cases, two such subsets with "stereotyped" B-cell receptors were recently identified, i.e.

Verification that common variation at 2q37.1, 6p25.3, 11q24.1, 15q23, and 19q13.32 influences chronic lymphocytic leukaemia risk.

A recent genome wide association study of chronic lymphocytic leukaemia (CLL) provided evidence that common variation at 2q13 (rs17483466), 2q37.1 (rs13397985), 6p25.3 (rs872071), 11q24.

High-density screening reveals a different spectrum of genomic aberrations in chronic lymphocytic leukemia patients with 'stereotyped' IGHV3-21 and IGHV4-34 B-cell receptors.

Background: The existence of multiple subsets of chronic lymphocytic leukemia expressing 'stereotyped' B-cell receptors implies the involvement of antigen(s) in leukemogenesis. Studies also indicate that 'stereotypy' may influence the clinical course of patients with chronic lymphocytic leukemia, for example, in subsets with stereotyped IGHV3-21 and IGHV4-34 B-cell receptors; however, little is known regarding the genomic profile of patients in these subsets.

Design And Methods: We applied 250K single nucleotide polymorphism-arrays to study copy-number aberrations and copy-number neutral loss-of-heterozygosity in patients with stereotyped IGHV3-21 (subset #2, n=29), stereotyped IGHV4-34 (subset #4, n=17; subset #16, n=8) and non-subset #2 IGHV3-21 (n=13) and non-subset #4/16 IGHV4-34 (n=34) patients.

Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk.

To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.

Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia.

The 309T>G polymorphism in the promoter region of the MDM2 gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment.

Propionic acid secreted from propionibacteria induces NKG2D ligand expression on human-activated T lymphocytes and cancer cells.

We found that propionic acid secreted from propionibacteria induces expression of the NKG2D ligands MICA/B on activated T lymphocytes and different cancer cells, without affecting MICA/B expression on resting peripheral blood cells. Growth supernatant from propionibacteria or propionate alone could directly stimulate functional MICA/B surface expression and MICA promoter activity by a mechanism dependent on intracellular calcium. Deletion and point mutations further demonstrated that a GC-box motif around -110 from the MICA transcription start site is essential for propionate-mediated MICA promoter activity.

[Multi-facetted clinical presentation of thrombotic thrombocytopenic purpura].

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathic disease. TTP is due to reduced activity of the von Willebrand factor which cleaves ADAMTS13. The disease is characterized by thrombocytopenia (<20 billion/l) intravascular Coombs-negative haemolysis and schistocytes in blood smears.

Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia--a comparative study of four differently designed, high resolution microarray platforms.

Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent), and two SNP arrays (250K, Affymetrix and 317K, Illumina). Cross-platform comparison revealed 29 concordantly detected CNAs, including known recurrent alterations, which confirmed that all platforms are powerful tools when screening for large aberrations.

Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: a randomized phase II study from the Nordic Lymphoma Group.

The purpose of this phase II randomized trial was to evaluate the effect and safety of interferon-alpha2a (IFN) in combination with extended dosing rituximab in patients with symptomatic, advanced indolent lymphoma responding to a standard single course of rituximab. Totally 123 patients were treated with rituximab 375 mg/m2 once weekly for 4 weeks leading to 14 complete response (CR; 11%), 56 partial response (PR; 46%), and 13 minor responses (MR; 11%). Patients achieving either PR or MR were randomized to four more infusions of rituximab alone (n = 36) or in combination with five weeks of IFN (n = 33), with an overall response rate (CR + PR) of 78% and 94%, respectively.

Feasibility, efficacy and safety of CHOP-14 in elderly patients with very high-risk diffuse large B-cell lymphoma.

Objectives: The dose-dense CHOP-14 regimen is efficient and safe in elderly patients with diffuse large B-cell lymphoma (DLBCL). However, no clinical data regarding very high-risk patients [age >75 yr and/or performance status (PS) >3] are available. The objective of this study was to evaluate the feasibility, efficacy and safety of CHOP-14 in these patients not eligible for clinical trials.

Kaposi sarcoma-associated herpes virus targets the lymphotactin receptor with both a broad spectrum antagonist vCCL2 and a highly selective and potent agonist vCCL3.

Large DNA viruses such as herpesvirus and poxvirus encode proteins that target and exploit the chemokine system of their host. These proteins have the potential to block or change the orchestrated recruitment of leukocytes to sites of viral infection. The genome of Kaposi sarcoma-associated herpes virus (KSHV) encodes three chemokine-like proteins named vCCL1, vCCL2, and vCCL3.

CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia.

We recently identified a disease-specific gene CLLU1 in chronic lymphocytic leukemia (CLL) and also demonstrated that high CLLU1 expression levels predict poor clinical outcome. To validate this finding, we measured CLLU1 mRNA expression levels by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in 175 patients with CLL. Analyses of IgV(H) mutational status, ZAP-70 expression, CD38 expression, and chromosomal aberrations were also performed.

CLLU1 expression levels predict time to initiation of therapy and overall survival in chronic lymphocytic leukemia.

Objectives: Chronic lymphocytic leukemia (CLL) is an incurable disease with a highly variable clinical course. IgV(H) mutational status, chromosomal aberrations, CD38 expression and ZAP-70 expression are prognostic markers in CLL, however, they are not exclusively confined to this disease. We recently identified a novel CLL-specific gene (CLL upregulated gene1, CLLU1) that is exclusively upregulated in CLL cells.