Chronic Lymphocytic Leukemia (CLL)
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Information for Health Professionals / Researchers (7 links)

Latest Research Publications

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

Visco C, Moretta F, Falisi E, et al.
Double productive immunoglobulin sequence rearrangements in patients with chronic lymphocytic leukemia.
Am J Hematol. 2013; 88(4):277-82 [PubMed]
The immunoglobulin heavy chain variable (IGHV) gene mutational status represents a major prognostic marker in chronic lymphocytic leukemia (CLL). Usually, the prognostic implications of IGHV gene analysis can be reliably ascertained but, occasionally, double productive rearrangements have been detected. Clinical presentation and biological features of such cases are unknown. Sixty patients with morphologically and phenotypically monoclonal CLL but double productive IGHV rearrangements were retrospectively identified by mRNA analysis from three Hematology Institutions. Clinical and biological features and survival of these 60 patients were compared with a control group of patients with CLL and single IGHV rearrangement. A prospective registry was used to assess the epidemiology of double productive IGHV among incidental patients with CLL. Using standard criteria to define IGHV-mutated (M) or unmutated (U) cases, 39 of the 60 patients (65%) with double productive IGHV rearrangement had concordant status (23 MM, 16 UU), while 21 (35%) had discordant IGHV status. As compared with M patients, the MM ones had lower CD38 expression, more favorable cytogenetics and more indolent clinical behavior. Cases with UU had similar characteristics of U patients. Discordant cases presented with adverse prognostic features and had an aggressive clinical behavior requiring early treatment, similar to U patients. The prevalence of double IGHV was 3.1%. Patients with CLL with double concordant mutational status (MM or UU) have a clinical course similar to that of the corresponding single IGHV status, while those exhibiting discordant status represent a high risk population. This may help correct stratification within clinical trials.


Visco C, Finotto S, Pomponi F, et al.
The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high-risk patients with chronic lymphocytic leukemia.
Am J Hematol. 2013; 88(4):289-93 [PubMed]
Treatment of patients with B-cell chronic lymphocytic leukemia (CLL) relapsed/refractory (R/R) to conventional treatments is particularly challenging. The combination of bendamustine and cytarabine has demonstrated distinct and synergistic mechanisms of action in preclinical studies on cell lines and primary tumor cells of several B-cell lymphomas, including 17p deleted or TP53 mutated CLL. The efficacy of rituximab (375 mg/m(2) , Day 1), plus bendamustine (70 mg/m(2) , days 1-2), and cytarabine (800 mg/m(2) , Day 1-3; R-BAC), every 28 days for up to four courses, was evaluated in a pilot trial enrolling 13 patients with very selected high-risk R/R CLL. All patients (median age 60 years, range 53-74) had symptomatic Binet stage B or C active disease requiring treatment, were characterized by adverse cytogenetics (17p deletion, 11q deletion, or both), unmutated immunoglobulin heavy-chain variable region, and were heavily pretreated (1-5, median three previous lines). Overall, R-BAC was well tolerated with limited non-hematological toxicity. Major toxicities were transient Grade 3/4 neutropenia and thrombocytopenia in 84% and 85% of patients, respectively. Overall response rate (OR) was 84%, including complete and partial response in 38% and 46% of patients, respectively. Patients with 17p deletion had an OR of 78%. After a median follow-up of 17 months, median progression-free survival was 16 months while median overall survival (OS) was not reached (1-year OS: 75 ± 13%). R-BAC is an active regimen in R/R heavily pretreated high-risk patients with CLL, representing an option for the treatment of patients that are usually refractory to standard therapy.


Zenz T
Exhausting T cells in CLL.
Blood. 2013; 121(9):1485-6 [PubMed]
In this issue of Blood, Riches and colleagues provide an in-depth characterization of T cells and particularly CD8+ T cells from patients with chronic lymphocytic leukemia (CLL). They demonstrate that CD8+ T cells exhibit defects in proliferation, cytotoxicity, and increased expression of inhibitory receptors and thus exhibit features of T-cell exhaustion.


Maeshima AM, Taniguchi H, Fukuhara S, et al.
Follow-up data of 10 patients with B-cell non-Hodgkin lymphoma with a CD20-negative phenotypic change after rituximab-containing therapy.
Am J Surg Pathol. 2013; 37(4):563-70 [PubMed]
Recently, a CD20-negative phenotypic change in CD20-positive B-cell non-Hodgkin lymphoma (B-NHL) after rituximab therapy was described. We report the follow-up data of 10 B-NHL patients showing this change after rituximab therapy. Ten patients (4 men and 6 women; median age, 57 y) with B-NHL who were initially CD20 positive and became CD20 negative after rituximab therapy were analyzed. Clinicopathologic features, including clinical course, CD20 expression, and histopathology, were examined. CD20 expression in lymphoma cells was evaluated using immunohistochemistry and/or flow cytometry. Histopathologically, diagnosis at initial presentation was follicular lymphoma (FL) in 7 patients; diffuse large B-cell lymphoma in 1; and chronic lymphocytic leukemia in 2. Six patients (60%, 3 FL, 1 diffuse large B-cell lymphoma, and 2 chronic lymphocytic leukemia patients) showed continuous CD20 negativity until 24 months after the phenotypic change. Three patients (30%) with FL regained CD20 expression within 1 to 7 months after detection of the CD20 change. Two patients (20%) with FL, including 1 who regained CD20 expression, showed heterogenous CD20 expression with a CD20-negative low-grade component and a CD20-positive large cell component. The overall response rate to therapy before the CD20-negative change was 70%. We reported the follow-up data of 10 B-NHL patients with a CD20-negative phenotypic change associated with rituximab-containing therapy. The most common histologic phenotypes were continuous CD20 negativity, recovery of CD20 expression within 7 months, and heterogenous CD20 expression. As the changes in morphology and CD20 expression after rituximab therapy vary widely, careful follow-up and rebiopsy are recommended.


Rafiq S, Butchar JP, Cheney C, et al.
Comparative assessment of clinically utilized CD20-directed antibodies in chronic lymphocytic leukemia cells reveals divergent NK cell, monocyte, and macrophage properties.
J Immunol. 2013; 190(6):2702-11 [PubMed] Article available free on PMC after 15/03/2014
CD20 is a widely validated, B cell-specific target for therapy in B cell malignancies. Rituximab is an anti-CD20 Ab that prolongs survival of chronic lymphocytic leukemia (CLL) patients when combined with chemotherapy. Ofatumumab and GA101 (obinutuzumab) are CD20-directed Abs currently being developed as alternative agents to rituximab in CLL based upon different properties of enhanced direct cell death, NK cell-mediated Ab-dependent cellular cytotoxicity, or complement-dependent cytotoxicity. Despite widespread study, ofatumumab and GA101 have not been compared with each other, nor studied for their interactions with monocytes and macrophages which are critical for the efficacy of anti-CD20 Abs in murine models. In CLL cells, we show that direct cell death and complement-dependent cytotoxicity are greatest with GA101 and ofatumumab, respectively. GA101 promotes enhanced NK cell activation and Ab-dependent cellular cytotoxicity at high Ab concentrations. Ofatumumab elicits superior Ab-dependent cellular phagocytosis with monocyte-derived macrophages. GA101 demonstrated reduced activation of monocytes with diminished pERK, TNF-α release, and FcγRIIa recruitment to lipid rafts. These data demonstrate that GA101 and ofatumumab are both superior to rituximab against CLL cells via different mechanisms of potential tumor elimination. These findings bear relevance to potential combination strategies with each of these anti-CD20 Abs in the treatment of CLL.


Landau DA, Carter SL, Stojanov P, et al.
Evolution and impact of subclonal mutations in chronic lymphocytic leukemia.
Cell. 2013; 152(4):714-26 [PubMed] Article available free on PMC after 14/02/2014
Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.


Jain P, O'Brien S
Richter's transformation in chronic lymphocytic leukemia.
Oncology (Williston Park). 2012; 26(12):1146-52 [PubMed]
Richter's transformation, or Richter's syndrome, is an uncommon clinicopathological condition observed in about 5% to 10% of patients with chronic lymphocytic leukemia (CLL). "Richter's transformation" refers to the development of aggressive lymphoma during the course of CLL. Diffuse large B-cell lymphoma occurs in the majority of cases of Richter's transformation. Clinically, patients with Richter's transformation present with an aggressive disease course with rapidly enlarging lymph nodes, hepatosplenomegaly, and elevated serum lactate dehydrogenase levels. Specific risk factors for the development of Richter's transformation in a patient with CLL have yet to be identified; however, TP53 disruption, c-MYCabnormalities, unmutated immunoglobulin heavy chain (IGHV) < 2%, non-del13q cytogenetics, CD38 gene polymorphisms, stereotypy, and VH4-39 gene usage may predispose to Richter's transformation. The prognosis is generally poor, with a median survival of about 10 months. Development of rituximab (Rituxan)-containing intensive chemotherapy regimens and chemo-immunotherapy regimens (eg, R-HyperCVAD [rituximab plus hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone] or OFAR [oxaliplatin (Eloxatin), fludarabine, and ara-C]) have improved response rates but have not clearly affected long-term outcomes. Allogeneic stem-cell transplantation may offer a chance for prolonged survival.


Velusamy T, Palanisamy N, Kalyana-Sundaram S, et al.
Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia.
Proc Natl Acad Sci U S A. 2013; 110(8):3035-40 [PubMed] Article available free on PMC after 19/08/2013
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. Two of seven index cases (28%) harbored the reciprocal RNA chimeras in our initial screening. Using quantitative real-time PCR (q real-time PCR), YPEL5/PPP1CB and PPP1CB/YPEL5 fusion transcripts were detected in 97 of 103 CLL samples (95%) but not in paired normal samples, benign lymphocytes, or various unrelated cancers. Whole-genome sequencing and Southern blotting demonstrated no evidence for a genomic fusion between YPEL5 and PPP1CB. YPEL5/PPP1CB chimera, when introduced into mammalian cells, expressed a truncated PPP1CB protein that demonstrated diminished phosphatase activity. PPP1CB silencing resulted in enhanced proliferation and colony formation of MEC1 and JVM3 cells, implying a role in the pathogenesis of mature B-cell leukemia. These studies uncover a potential role for recurrent RNA chimeras involving phosphatases in the pathogenesis of a common form of leukemia.


Russo M, Spagnuolo C, Volpe S, et al.
ABT-737 resistance in B-cells isolated from chronic lymphocytic leukemia patients and leukemia cell lines is overcome by the pleiotropic kinase inhibitor quercetin through Mcl-1 down-regulation.
Biochem Pharmacol. 2013; 85(7):927-36 [PubMed]
Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in adult population and despite numerous studies, it is considered an incurable disease. Since CLL is characterized by overexpression of pro-survival Bcl-2 family members, treatments with their antagonists, such as ABT-737, represent a promising new therapeutic strategy. ABT-737 is a BH3 mimetic agent which binds Bcl-2, Bcl-XL and Bcl-w with high affinity, while weakly interacts with Mcl-1 and Bfl-1. Previous studies demonstrated that quercetin, a flavonoid naturally present in food and beverages, was able to sensitize B-cells isolated from CLL patients to apoptosis when associated with death ligands or fludarabine, through a mechanism involving Mcl-1 down-regulation. Here, we report that the association between ABT-737 and quercetin synergistically induces apoptosis in B-cells and in five leukemic cell lines (Combination Index <1). Peripheral blood mononuclear cell from healthy donors were not affected by quercetin treatment. The molecular pathways triggered by quercetin have been investigated in HPB-ALL cells, characterized by the highest resistance to both ABT-737 and quercetin when applied as single molecules, but highly sensitivity to the co-treatment. In this cell line, quercetin down-regulated Mcl-1 through the inhibition of PI3K/Akt signaling pathway, leading to Mcl-1 instability. The same mechanism was confirmed in B-cells. These results may open new clinical perspectives based on a translational approach in CLL therapy.


Emmett C, Kane G
Necrotising fasciitis caused by P aeruginosa in a male patient with chronic lymphocytic leukaemia.
BMJ Case Rep. 2013; 2013 [PubMed]
A 53-year-old man with chronic lymphocytic leukaemia and multiple comorbidities presented with a 2-day history of increasing pain and swelling in his left leg following a minor trauma, associated with signs of systemic sepsis and worsening multiorgan failure. The clinical picture was consistent with necrotising fasciitis and he was taken to the theatre for an above-knee amputation. Blood and tissue cultures grew Pseudomonas aeruginosa only, which is very rare as a monomicrobial infection, with relatively few cases being reported in the literature. The combination of aggressive timely surgical intervention, broad-spectrum antibiotics and treatment on the intensive care unit yielded a successful outcome from this acute episode.


Solomon BM, Rabe KG, Slager SL, et al.
Overall and cancer-specific survival of patients with breast, colon, kidney, and lung cancers with and without chronic lymphocytic leukemia: a SEER population-based study.
J Clin Oncol. 2013; 31(7):930-7 [PubMed]
PURPOSE: Chronic lymphocytic leukemia (CLL) is associated with an increased risk of developing second cancers. However, it is unknown whether CLL alters the disease course of these cancers once they occur.
PATIENTS AND METHODS: All patients with cancers of the breast (n = 579,164), colorectum (n = 412,366), prostate (n = 631,616), lung (n = 489,053), kidney (n = 95,795), pancreas (n = 82,116), and ovary (n = 61,937) reported to the SEER program from 1990 to 2007 were identified. Overall survival (OS; death resulting from any cause) and cancer-specific survival were examined, comparing patients with and without pre-existing CLL. Cancer-specific survival was evaluated for each tumor type in a site-specific manner (eg, death resulting from breast cancer in a patient with breast cancer).
RESULTS: Patients with cancers of the breast (hazard ratio [HR], 1.70; P < .001), colorectum (HR, 1.65; P < .001), kidney (HR, 1.54; P < .001), prostate (HR, 1.92; P < .001), or lung (HR, 1.19; P < .001) had inferior OS if they had a pre-existing diagnosis of CLL after adjusting for age, sex, race, and disease stage. These results for OS remained significant for patients with cancers of the breast, colorectum, and prostate after excluding or censoring CLL-related deaths. Cancer-specific survival was also inferior for patients with cancers of the breast (HR, 1.41; P = .005) and colorectum (HR, 1.46; P < .001) who had pre-existing CLL after adjusting for age, sex, race, and disease stage.
CONCLUSION: Inferior OS and cancer-specific survival was observed for several common cancers in patients with pre-existing CLL. Additional studies are needed to determine the optimal management of these malignancies in patients with CLL and whether more aggressive screening or alternative approaches to adjuvant therapy are needed.


Kaucká M, Plevová K, Pavlová S, et al.
The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte migration.
Cancer Res. 2013; 73(5):1491-501 [PubMed]
The planar cell polarity (PCP) pathway is a conserved pathway that regulates cell migration and polarity in various contexts. Here we show that key PCP pathway components such as Vangl2, Celsr1, Prickle1, FZD3, FZD7, Dvl2, Dvl3, and casein kinase 1 (CK1)-ε are upregulated in B lymphocytes of patients with chronic lymphocytic leukemia (CLL). Elevated levels of PCP proteins accumulate in advanced stages of the disease. Here, we show that PCP pathway is required for the migration and transendothelial invasion of CLL cells and that patients with high expression of PCP genes, FZD3, FZD7, and PRICKLE1, have a less favorable clinical prognosis. Our findings establish that the PCP pathway acts as an important regulator of CLL cell migration and invasion. PCP proteins represent an important class of molecules regulating pathogenic interaction of CLL cells with their microenvironment.


Tavolaro S, Peragine N, Chiaretti S, et al.
IgD cross-linking induces gene expression profiling changes and enhances apoptosis in chronic lymphocytic leukemia cells.
Leuk Res. 2013; 37(4):455-62 [PubMed]
Gene profile and functional changes upon IgD cross-linking were evaluated in chronic lymphocytic leukemia (CLL). Microarrays highlighted responsiveness to IgD in all cases, independently of clinico-biological characteristics. Stimulated samples exhibited the down-regulation of transcripts of B-cell receptor signaling and cell-adhesion at 24h and the up-modulation of differentiation and apoptosis genes at 48 h. A significant increase in apoptosis upon ligation was also documented. Furthermore, comparison between IgD and IgM stimulation displayed a differential transcriptional/functional response. In conclusion, CLL respond to IgD displaying expression changes and cell-death enhancement, indicating the apoptosis induction via-IgD as an alternative approach for CLL management.


Stephens DM, Byrd JC
Chronic lymphocytic leukemia with del(17p13.1): a distinct clinical subtype requiring novel treatment approaches.
Oncology (Williston Park). 2012; 26(11):1044-54 [PubMed]
Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease with significant variation in clinical presentation, time to disease progression, survival, and aggressiveness of clinical course. A subgroup of patients who have been repeatedly identified as having a poor response to therapy are those with del(17p13.1)--identified by either interphase cytogenetics or other comparable strategies. Although there has been much progress over the past few years in the development of new therapeutic targets for CLL patients, this subgroup has continued to lag behind others. Because of the poor response or significant therapy-related toxicity experienced by patients with del(17p13.1)--and the small number of these patients included in clinical trials--current guidelines are unable to provide suggestions for the care of newly diagnosed, symptomatic but untreated patients (as well as relapsed patients) in this subgroup on account of the modest amount of evidence. However, novel agents are on the horizon that appear to be significantly more effective in this patient population, and these will likely shape the standard of care for these patients in the future.


Skorkina MY, Fedorova MZ, Muravyov AV, Sladkova EA
The use of nanomechanic sensor for studies of morphofunctional properties of lymphocytes from healthy donors and patients with chronic lymphoblastic leukemia.
Bull Exp Biol Med. 2012; 154(1):163-6 [PubMed]
Tapping mode-atomic force microscopy and force spectroscopy were used for studies of the topography of the cell surface and elastic properties of lymphocytes from healthy donors and patients with chronic lymphoblastic leukemia. It was demonstrated that the decrease in lymphocytes stiffness in patients with chronic lymphoblastic leukemia by 51.4% (p<0.05) was accompanied by spatial modification of the cell surface, in particular, increase in the number of globular protrusions and depressions by 247 and 122%, respectively (p<0.05), in comparison with normal lymphocytes.


Lutzny G, Kocher T, Schmidt-Supprian M, et al.
Protein kinase c-β-dependent activation of NF-κB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo.
Cancer Cell. 2013; 23(1):77-92 [PubMed] Article available free on PMC after 19/08/2013
Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here, we describe a survival signaling pathway activated in stromal cells by contact to B cells from patients with chronic lymphocytic leukemia (CLL). The expression of protein kinase C (PKC)-βII and the subsequent activation of NF-κB in bone marrow stromal cells are prerequisites to support the survival of malignant B cells. PKC-β knockout mice are insusceptible to CLL transplantations, underscoring the in vivo significance of the PKC-βII-NF-κB signaling pathway in the tumor microenvironment. Upregulated stromal PKC-βII in biopsies from patients with CLL, acute lymphoblastic leukemia, and mantle cell lymphoma suggests that this pathway may commonly be activated in a variety of hematological malignancies.


Greaves M
Clonal expansion in B-CLL: fungal drivers or self-service?
J Exp Med. 2013; 210(1):1-3 [PubMed] Article available free on PMC after 14/07/2013
Relatively few cancers arise in mature, differentiated cells. The propensity of mature B cells to transform has been linked to their longevity and proliferative potential, and stimulation of the B cell receptor (BCR) by cognate antigen may promote the transformation process. A study in this issue (Hoogeboom et al.) lends support to this notion, showing that cancer cells from a subset of patients with chronic lymphocytic leukemia (CLL) express a BCR specific for a sugar expressed by commensal yeast species. Another study, in contrast, suggests that B-CLL cells uniquely acquire the ability to signal in the complete absence of ligand.


Véronèse L, Tournilhac O, Combes P, et al.
Contribution of MLPA to routine diagnostic testing of recurrent genomic aberrations in chronic lymphocytic leukemia.
Cancer Genet. 2013 Jan-Feb; 206(1-2):19-25 [PubMed]
To better define the place of multiplex ligation-dependent probe amplification (MLPA) in routine cytogenetic diagnosis in chronic lymphocytic leukemia (CLL), we compared MLPA and fluorescence in situ hybridization (iFISH) data obtained in 77 CLL patients. Although MLPA detected most recurrent copy number genomic aberrations (90.9%), false-negative results were found in cases with small-size abnormal clones and false-positive MLPA findings resulting from point mutations (TP53) or an apparent lack of probe specificity (chromosome 19) were observed. Thus, MLPA may be a useful complementary but not alternative approach for iFISH testing of genomic aberration in CLL.


Le Clech L, Ianotto JC, Quintin-Roue I, Tempescul A
Severe CMV complication following maintenance therapy with rituximab.
BMJ Case Rep. 2013; 2013 [PubMed]
Cytomegalovirus (CMV) encephalitis is a rare infection that immunodeficient patients, mainly where HIV-positive, may suffer from. Several cases were described when complications with the treatment with monoclonal antibodies, like rituximab, for malignant lymphomas. We will describe here the case of a patient, who has developed CMV gastritis, then CMV encephalitis after the treatment of a CLL with a chemotherapy and maintenance therapy with rituximab.


Hoogeboom R, van Kessel KP, Hochstenbach F, et al.
A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi.
J Exp Med. 2013; 210(1):59-70 [PubMed] Article available free on PMC after 14/07/2013
B cell chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is a clonal expansion of CD5(+)CD19(+) B lymphocytes. Two types of CLLs are being distinguished as carrying either unmutated or somatically mutated immunoglobulins (Igs), which are associated with unfavorable and favorable prognoses, respectively. More than 30% of CLLs can be grouped based on their expression of stereotypic B cell receptors (BCRs), strongly suggesting that distinctive antigens are involved in the development of CLL. Unmutated CLLs, carrying Ig heavy chain variable (IGHV) genes in germline configuration, express low-affinity, poly-, and self-reactive BCRs. However, the antigenic specificity of CLLs with mutated IGHV-genes (M-CLL) remained elusive. In this study, we describe a new subset of M-CLL, expressing stereotypic BCRs highly specific for β-(1,6)-glucan, a major antigenic determinant of yeasts and filamentous fungi. β-(1,6)-glucan binding depended on both the stereotypic Ig heavy and light chains, as well as on a distinct amino acid in the IGHV-CDR3. Reversion of IGHV mutations to germline configuration reduced the affinity for β-(1,6)-glucan, indicating that these BCRs are indeed affinity-selected for their cognate antigen. Moreover, CLL cells expressing these stereotypic receptors proliferate in response to β-(1,6)-glucan. This study establishes a class of common pathogens as functional ligands for a subset of somatically mutated human B cell lymphomas.


Richardson SE, Khan I, Rawstron A, et al.
Risk-stratified adoptive cellular therapy following allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukaemia.
Br J Haematol. 2013; 160(5):640-8 [PubMed]
Following reduced intensity-conditioned allogeneic stem cell transplantation (RIC allo-SCT) for chronic lymphocytic leukaemia (CLL), there is an inverse relationship between relapse and extensive chronic graft-versus-host disease (GVHD). We evaluated outcomes in 50 consecutive patients with CLL using the approach of alemtuzumab-based RIC allo-SCT and pre-emptive donor lymphocyte infusions (DLI) for mixed chimerism or minimal residual disease (MRD), with the intention of reducing the risk of GVHD. Forty two patients had high-risk disease, including 30% with 17p deletion (17p-). Of patients who were not in complete remission (CR) entering transplant, 83% subsequently achieved MRD-negative CR. Both MRD detection and uncorrected mixed chimerism were associated with greater risks of treatment failure. Nine of sixteen patients receiving DLI for persistent or relapsed disease subsequently attained MRD-negative CR. With a median follow-up of 4.3 years, 4-year current progression-free survival was 65% and overall survival was 75% (60% and 61% in respectively, patients with 17p-). DLI was associated with a 29% cumulative incidence of severe GVHD and mortality of 6.4%. At last follow-up, 83% of patients in CR were off all immunosuppressive treatment. In conclusion, the directed delivery of allogeneic cellular therapy has the potential to induce durable remissions in high-risk CLL without incurring excessive GVHD.


Spina F, Rezzonico F, Farina L, Corradini P
Long-term molecular remission with lenalidomide treatment of relapsed chronic lymphocytic leukemia.
Eur J Haematol. 2013; 90(4):340-4 [PubMed]
Lenalidomide is effective against relapsed chronic lymphocytic leukemia (CLL). We report the first case of long-term molecular remission with continuous lenalidomide treatment in a young patient with CLL relapsed to multiple treatments. Minimal residual disease was assessed by nested polymerase chain reaction on bone marrow samples with patient-specific primers. A 20-yr-old patient with standard-risk CLL was treated with lenalidomide after multiple relapses and achieved a 4 yr long complete molecular response with minimal toxicities. Published biologic data support that lenalidomide induces an immune-mediated control of CLL, and our case suggests that long-term treatment with lenalidomide is effective at a molecular level in patients with relapsed CLL.


Hubmann R, Hilgarth M, Schnabl S, et al.
Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells.
Br J Haematol. 2013; 160(5):618-29 [PubMed]
Chronic lymphocytic leukaemia (CLL) cells express constitutively activated NOTCH2 in a protein kinase C (PKC)- dependent manner. The transcriptional activity of NOTCH2 correlates not only with the expression of its target gene FCER2 (CD23) but is also functionally linked with CLL cell viability. In the majority of CLL cases, DNA-bound NOTCH2 complexes are less sensitive to the γ-secretase inhibitor (GSI) DAPT. Therefore, we searched for compounds that interfere with NOTCH2 signalling at the transcription factor level. Using electrophoretic mobility shift assays (EMSA), we identified the Aspergillum-derived secondary metabolite gliotoxin as a potent NOTCH2 transactivation inhibitor. Gliotoxin completely blocked the formation of DNA-bound NOTCH2 complexes in CLL cells independent of their sensitivity to DAPT. The inhibition of NOTCH2 signalling by gliotoxin was associated with down regulation of CD23 (FCER) expression and induction of apoptosis. Short time exposure of CLL cells indicated that the early apoptotic effect of gliotoxin is independent of proteasome regulated nuclear factor κB activity, and is associated with up regulation of NOTCH3 and NR4A1 expression. Gliotoxin could overcome the supportive effect of primary bone marrow stromal cells in an ex vivo CLL microenvironment model. In conclusion, we identified gliotoxin as a potent NOTCH2 inhibitor with a promising therapeutic potential in CLL.


Badoux XC, Keating MJ, Wen S, et al.
Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia.
J Clin Oncol. 2013; 31(5):584-91 [PubMed]
PURPOSE: Lenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL.
PATIENTS AND METHODS: Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m(2) intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically.
RESULTS: The overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study.
CONCLUSION: The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation.


Jadidi-Niaragh F, Ghalamfarsa G, Memarian A, et al.
Downregulation of IL-17-producing T cells is associated with regulatory T cell expansion and disease progression in chronic lymphocytic leukemia.
Tumour Biol. 2013; 34(2):929-40 [PubMed]
Little is known about the immunobiology of interleukin-17 (IL-17)-producing T cells and regulatory T cells (Treg) in chronic lymphocytic leukemia (CLL). In this study, the frequencies of Th17, Tc17, and CD39(+) Treg cells were enumerated in peripheral T cells isolated from 40 CLL patients and 15 normal subjects by flow cytometry. Our results showed a lower frequency of Th17 and Tc17 cells in progressive (0.99 ± 0.12 % of total CD3(+)CD4(+) cells; 0.44 ± 0.09 % of total CD8(+) cells) compared to indolent patients (1.57 ± 0.24 %, p = 0.042; 0.82 ± 0.2 %, p = 0.09) and normal subjects (1.78 ± 0.2 %, p = 0.003; 0.71 ± 0.09 %, p = 0.04). Decrease in IL-17-producing T cells was associated with CD39(+) Treg cells expansion. Variation of IL-17-producing cells and Treg cells in indolent and progressive patients was neither associated to the expression levels of Th1- and Th2-specific transcription factors T-bet and GATA-3 nor to the frequencies of IFN-γ and IL-4-producing CD4(+) T cells in a selected number of samples. Additionally, suppressive potential of CD4(+) Treg was similar in CLL patients and normal subjects. Our data indicate that progression of CLL is associated with downregulation of IL-17-producing T cells and expansion of Treg cells, implying contribution of these subsets of T cells in the progression of CLL.


Burger JA, Montserrat E
Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling.
Blood. 2013; 121(9):1501-9 [PubMed]
Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and BCR signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after the clinical activity of kinase inhibitors that target BCR signaling (spleen tyrosine kinase, Bruton tyrosine kinase, PI3Kδ inhibitors) was established. Besides antiproliferative activity, these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along with a transient surge in lymphocytosis, before inducing objective remissions. Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCR-signaling inhibitors resembles redistribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution and similarities between old and new drugs affecting these processes. In addition, we outline how these discoveries are changing our understanding of CLL biology and therapy.


Laprevotte E, Ysebaert L, Klein C, et al.
Endogenous IL-8 acts as a CD16 co-activator for natural killer-mediated anti-CD20 B cell depletion in chronic lymphocytic leukemia.
Leuk Res. 2013; 37(4):440-6 [PubMed]
Rituximab (RTX, anti-CD20 antibody) combined with chemotherapy is currently standard treatment for chronic lymphocytic leukemia (CLL). Serum level of IL-8 is a prognostic factor for CLL that correlates with disease stage. We investigated whether endogenous IL-8 affects RTX or Obinutuzumab (GA101) B-leukemic depletion mediated by natural killers (NK). Using whole peripheral blood lymphocytes from untreated CLL patients, RTX, but most significantly GA101, were effective in B-cell depletion and NK activation. IL-8 inhibition completely inhibited B-cell depletion by RTX and reduced GA101-induced B-cell depletion. Altogether results underline IL-8 as an endogenous NK co-activator and confirm GA101 therapeutic potential for CLL treatment.


Riches JC, Davies JK, McClanahan F, et al.
T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production.
Blood. 2013; 121(9):1612-21 [PubMed] Article available free on PMC after 28/02/2014
T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8+ and CD4+ T cells from CLL patients had increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1+BLIMP1HI subset. These molecules were most highly expressed in the expanded population of effector T cells in CLL. CLL CD8+ T cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-γ and TNFα and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of cytomegalovirus (CMV)–specific cells, although CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, although CLL CD8+ T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. These findings also exclude CMV as the sole cause of T-cell defects in CLL.


Rossi D, Rasi S, Spina V, et al.
Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia.
Blood. 2013; 121(8):1403-12 [PubMed] Article available free on PMC after 21/02/2014
The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a training-validation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring +12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared with FISH karyotype (P < .0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1, and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions.


Herishanu Y, Kay S, Dezorella N, et al.
Divergence in CD19-mediated signaling unfolds intraclonal diversity in chronic lymphocytic leukemia, which correlates with disease progression.
J Immunol. 2013; 190(2):784-93 [PubMed]
Emerging data on intraclonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. In this study, we report intraclonal diversity resolved by responses to CD19 engagement in CLL cells, which can be classified into CD19-responsive (CD19-R) and -nonresponive subpopulations. Engagement of CD19 by anti-CD19 Ab rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA, exhibited distinct morphological features, and were preferentially abolished in rituximab-treated patients. Both subpopulations reacted to sIgM stimulation in a similar manner and exhibited similar levels of Akt and Erk phosphorylation, pointing to functional signaling divergence within the BCR. CD19 unresponsiveness was partially reversible, where nonresponding CD19 cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19-signaling attenuating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow-derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with >15.25% of the CD19-R cell fraction had a shorter median time to treatment compared with patients with <15.25% of CD19-R cell fraction. In conclusion, divergence in CD19-mediated signaling unfolds both interpatient and intraclonal diversity in CLL. This signaling diversity is associated with physiological implications, including the location of the cells, their responses to anti-CLL therapeutics, and disease progression.


This page last updated: 22nd May 2013
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