Table of contents :

  • Epidemiology
  • Aetiology
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Differential diagnosis
  • Therapy 
  • Prognosis
  • Richter's syndrome
  • prolymphocytic leukemia (PLL)
  • Web resources

  • Epidemiology : CLL is the most frequent type of leukemia in the Western world and affects mainly elderly individuals, but about a third of patients are < 60 years of age at diagnosisref. 95% of all CLLs. Prevalence : 15:100,000. In USA 9730 new cases are expected in 2005.
    Aetiology : risk factors :

    Pathogenesis :

    IgVH unmutated B-CLL (U-CLL) (intraclonal variation < 95%) (50%)
    IgVH mutated B-CLL (M-CLL) (50%)
    intraclonal variation (ongoing SHM) absent or very low low
    morphology atypical according to the criteria of Matutes et alref as > 10% (but < 55%) prolymphocytes or > 15% cells with cleaved nuclei and/or lymphoplasmacytoid cells in the peripheral blood of patients whose predominant cell type was a small lymphocyte with coarsely clumped chromatin (dense cells (DC) / Rieder's cell or lymphocyte (a myeloblast whose nucleus with wide and deep indentations suggesting lobulation, which may represent asynchronism of nuclear and cytoplasmic maturation)) typical (Gumprecht shadow or basket cells (BC) are highly suggestiveref1, ref2)
    stage at diagnosis advanced (C) early (A, B)
    cell source pregerminal center naive B-cells germinal center exposed B-cells
    CD38 : a receptor that induces proliferation and increases survival of CLL cells. CD38 signals start upon interaction with the CD31 ligand expressed by stromal and nurse-like cells. CD38/CD31 contacts up-regulate CD100, a semaphorin involved in sustaining CLL growth. Evidence that nurselike cells express high levels of CD31 and plexin-B1, the high-affinity ligand for CD100, offers indirect confirmation for this model of receptor cross-talk. Elements of variation in the clinical course of CD38+ CLL patients include (1) potential intersection with ZAP-70, a kinase involved in the CD38 signaling pathway in T and NK cells, and (2) the effects of genetic polymorphisms of the receptors involved, at least of CD38 and CD31. Consequently, CD38 together with ZAP-70 appear to be the key elements of a coreceptor pathway that may sustain the signals mediated by the BcR and potentially by chemokines and their receptorsref. Regardless of the size of the CD38+ fraction within a CLL clone, CD38+ subclones are markedly enriched for expression of Ki-67, CD27, CD62L, CD69, ZAP-70, human telomerase reverse transcriptase, and telomerase activity. Although the percentage of cells (~2%) entering the cell cycle, as defined by Ki-67 expression, is small, the absolute number within a clone can be sizeable and is contained primarily within the CD38+ fraction. Despite these activation/proliferation differences, both CD38+ and CD38- fractions have similar telomere lengths suggesting that CD38 expression is dynamic and transientref high (> 30%) low (< 30%)
    ZAP70ref is a key mediator of TCR signaling and is structurally homologous to Syk, which plays an analogous role in BCR signaling. BCR-mediated activation of ZAP-70 is very inefficient in CLL and lymphoma B-cells and is negligible when compared to activation of Syk. Despite the inefficient catalytic activation, the ability of ZAP-70 to recruit downstream signaling molecules in response to antigen-receptor stimulation appeared relatively preserved. Moreover, ectopic expression of ZAP-70 was found to enhance and prolong activation of several key mediators of BCR signaling, such as the Syk, ERK and Akt kinases, and to decrease the rate of ligand-mediated BCR internalizationref high (> 20% or ZAP-70/Syk mRNA ratios > 0.25ref) in 86-88% of casesref1, ref2 low (< 20%) in 44% of cases
    chromosomal aberrations +12, del(11q), del(17p) normal or del(13q14) (which contains 2 small miRNA genes that are turned off in about 60% of CLL cases)
    miRNA signatureref reduced expression of miR-16 reduced expression of miR-16
    DNA microarray : the expression of 358 genes differed significantly between ZAP-70+CD38+ with ZAP-70-CD38- subgroups, including genes involved in BcR signaling, angiogenesis and lymphomagenesis. 3 of these genes, that is, IRTA4/FcRH2, angiopoietin 2 and Pim2 were selected for further validating studies in a cohort of 94 B-CLL patients. In healthy individuals, IRTA4/FcRH2 protein expression was associated with a CD19+CD27+ memory cell phenotype. Disease progression may be related to proangiogenic processes and strong Pim2 expressionref IRTA4/FcRH2 low, 2-fold higher ANGPT2 plasma concentrations, Pim2 overexpression IRTA4/FcRH2 high
    response to immunostimulatory CpG-oligodeoxynucleotides (CpG ODN), related to the magnitude of Akt signalingref proliferation   G1/S cell cycle arrest and apoptosis 
    therapy poor response good response
    survival average life expectancy of about 8 years and is universally fatal average survival of 25 years and most people with this form die of other causes rather than of CLL
    experimental animal model IgH and IgL rearrangements in TCL1 mice display minimal levels of somatic mutations and exhibit several molecular features found in the human disease. Like human B-CLL, TCL1 leukemic rearrangements from different mice can be very similar structurally and closely resemble autoantibodies and antibodies reactive with microbial antigens. Antigen-binding analyses confirm that selected TCL1 clones react with glycerophospholipid, lipoprotein, and polysaccharides that can be autoantigens and be expressed by microbes. This (auto)antigen-driven mouse model reliably captures the BCR characteristics of aggressive, treatment-resistant human B-CLLref ?
    B-CLL cell survival is dependent on the threshold of BCR stimulation induced by immobilized antibody, in contrast to soluble anti-m F(ab)'2 antibody, which leads to apoptosis. Measurement of metabolic activity and apoptotic response discriminated 2 subgroups. "Nonresponders" showed low metabolic activity and unmodified apoptotic response upon BCR stimulation. In contrast, "responders" exhibited increased metabolic activity and inhibition of spontaneous apoptosis. This survival advantage was associated to a BCR-dependent activation profile leading to induction of cyclin D2/CDK4 expression and G1 cell cycle progression. The ability to respond to BCR ligation correlated with an unfavorable clinical course and allowed to define an additional group of patients among IgVH-mutated cases exhibiting a risk of progression. Remarkably, Zap70 expression was neither mandatory nor sufficient to generate downstream survival signals and cyclin D2/cdk4 up-regulationref. Unmutated cases (U-CLL) have an increased ability to phosphorylate p72Syk in response to sIgM ligation, compared to mutated (M-CLL). Cases responding to sIgM ligation express higher levels of CD38, ZAP-70 and sIgM. However, CD38 does not influence signalling in vitro or associate with response in bimodal CD38-expressing cases. Similarly, ZAP-70 expression is not required for response in either U-CLL or M-CLL. Strikingly, partially or completely anergized sIgM responses from each subset can recover both sIgM expression and signal capacity spontaneously in vitro or following capping/endocytosis. This provides direct evidence for engagement of putative antigen in vivo. Signaling via sIgD differs markedly being almost universally positive in both U-CLL and M-CLL, with no association with CD38 or ZAP-70 expression. Downstream signalling pathways therefore appear intact in CLL, locating anergy to sIgM, mainly in M-CLL. Integration of differential isotype-specific effects mediated by (auto)antigen may determine tumor behaviorref.
    There is a bias in the use of certain VH, D, and JH genes among B-CLL cells. VH genes of ~ 50% of the IgM+ B-CLL cells and ~ 75% of the non-IgM+ B-CLL cells can exhibit somatic mutations according to the VH family expressed by the B-CLL cell (VH3 expressers displaying more mutation than VH1 and VH4 expressers). In addition, the extent of mutation can be sizeable with ~ 32% of the IgM+ cases and ~ 68% of the non-IgM+ cases differing by > 5% from the most similar germline gene. Approximately 20% of the mutated VH genes display replacement mutations in a pattern consistent with antigen selection. However, CDR3 characteristics (D and JH gene use and association and HCDR3 length, composition, and charge) suggest that selection for distinct BCR occurs in many more B-CLL cells. Many B-CLL cells have been previously stimulated, placing them in the "experienced" or "memory" CD5+ B cell subset. The frequent expression of the otherwise rare IgVH3-72 gene was demonstrated in highly stable B-CLLs. All IgVH3-72 B-CLLs revealed a homogeneous immunophenotypic profile, expressing all the markers associated with good prognosis, but not those representing the signature of bad prognosis B-CLLs, including ZAP-70ref
    Despite the malignant B cells typically express low-density membrane IgM or IgM/IgD, CSR is a frequent phenomenon in B-CLL, and a subset of the CLL lymphocytes progress to later stages of B cell differentiation. In most cases switching occurs to a1 and g3, but CLL transcripts corresponding to the other g chain isotypes are also detected. In one case both the productively and nonproductively rearranged allele are found to undergo H chain CSR. CLL g transcripts are also present in surface IgG+ sorted B cells, demonstrating that a small subset of the CLL cells express membrane IgG. In addition, transcripts encoding secretary g2 and g3 H chains are detected in some cases, which suggests that some serum IgG could be produced by the leukemic clone. Analysis of sorted PBL shows that CSR occurs in CLL cells that express the CD5 antigen. Finally, nucleotide sequence analysis showed that the m, a, and g CLL transcripts are identical, demonstrating that the CLL cells do not undergo SHM in their V region genes after the H chain CSRref. The leukemic cells of each patient have definable and often substantial birth rates, varying from 0.1% to > 1.0% of the entire clone per day. Those patients with birth rates > 0.35% per day are much more likely to exhibit active or to develop progressive disease than those with lower birth rates Thus, B-CLL is not a static disease that results simply from accumulation of long-lived lymphocytes. Rather, it is a dynamic process composed also of cells that proliferate and die, often at appreciable levelsref.
    Symptoms & signs : CLL follows an extremely variable clinical course with overall survival times ranging from months to decades. Some patients have no or minimal signs and symptoms during their entire disease course and have a survival time similar to age-matched controls. Other patients experience rapidly deteriorating blood counts and organomegaly and suffer from symptoms at diagnosis or soon thereafter necessitating therapy. Clinical variants : Laboratory examinations : Differential diagnosis : lymphoid disorders that can present as "chronic leukemia" and be confused with typical B cell chronic lymphoid leukemia Prognosis :
    Binet's staging, 1981ref
    Rai's staging, 1975ref
    median survival, years
    A (80% at diagnosis) no lymphadenomegaly lymphocytosis > 15,000/ml in peripheral blood or > 40% of bone marrow cells
    1 or 2 lymphoid areas involved (cervical, axillary, inguinofemoral, or liver+spleen) lymphocytosis + lymphadenomegaly
    B >= 3 lymphoid areas involved lymphocytosis + hepatomegaly and/or splenomegaly
     < 5
    C (Fisher-Evans syndrome) autoimmune hemolytic anemia (AIHA) < 10 g/dl in females, < 11 g/dl in males (from activation of non-neoplastic clones) independently from the number of lymphoid areas involved lymphocytosis + autoimmune hemolytic anemia (AIHA) (HGB > 11 g/dl; from activation of non-neoplastic clones)
    autoimmune thrombocytopenia < 100,000/ml (from activation of non-neoplastic clones) independently from the number of lymphoid areas involved lymphocytosis + autoimmune thrombocytopenia (PLT > 100,000/ml; due to activation of non-neoplastic clones)
    However, there is heterogeneity in the course of the disease among individual patients within a single stage group. Most importantly, the clinical staging systems do not allow one to predict if and at what rate there will be disease progression in an individual patient diagnosed with early stage disease. The VH mutation status, 17p deletion, 11q deletion, age, leukocyte count and LDH were identified as independent prognostic factorsref. When the VH mutation status and 11q and 17p aberrations were included in the model, the clinical stage of disease according to the systems of Rai or Binet was not identified as an independent prognostic factor for survival, indicating that in the context of these genetic parameters, the clinical stage of the disease may lose its independent prognostic valueref. 2 other independent series have confirmed the strong prognostic and independent impact of VH mutation status and genomic aberrations on clinical courseref1, ref2. Therefore, 4 subgroups of CLL with markedly differing survival probabilities can be defined by the VH mutation status, 11q deletion and 17p deletion. These molecular features also provide insight into the biological bases of the clinical heterogeneity of CLL and may lead to future risk-adapted treatment strategies for individual patients. Survival probabilities among patients in the following genetic categories: 17p- (17p deletion irrespective of VH mutation status), 11q- (11q deletion irrespective of VH mutation status), unmutated VH (homology  98% and no 17p or 11q deletion), and mutated VH (homology < 98% and no 17p or 11q deletion)ref.
    In order to further improve the understanding of molecular pathogenesis and clinical outcome prediction in CLL, microarray platforms have been developed as tools to evaluate genome wide parameters and defects. On the genomic level matrix CGH (comparative genomic hybridization against a matrix of defined DNA fragments) is a sensitive test allowing the detection of novel recurrent aberrations of potential pathogenic and prognostic importanceref. On the level of gene expression, comprehensive profiling studies of CLL based on DNA chip technology have indicated that the global gene expression "signature" of VH mutated and unmutated CLL is very similar and that only the expression of a small number of genes discriminates between the 2 groupsref1, ref2. In addition to the characterization of expression signatures associated with the VH mutation subgroups of CLL a study of 100 CLL samples characterized for VH status and genomic aberrations described a significant number of differentially expressed genes clustering in chromosomal regions affected by the respective genomic losses or gainsref. Deletions affecting chromosome bands 11q22-q23 and 17p13 led to a reduced expression of the genes in the corresponding genomic region, such as ATM and p53, while trisomy 12 resulted in the upregulation of genes mapping to chromosome arm 12q. The finding that the most significantly differentially expressed genes were located in the corresponding aberrant chromosomal regions suggests that a gene dosage effect may exert a pathogenic role in CLL.
    Validation of prognostic factors in prospective trials : in retrospective series of heterogeneously treated patients with CLL, the relationship between stage of disease and genetic parameters was assessed. Distinct subgroups of CLL patients defined by specific genomic aberrations showed significantly different rates of disease progression as defined by the time from diagnosis to first treatment. In addition, the prognostic impact of VH mutation status and genomic aberrations with regard to overall survival was observed for patients both with early stage (Binet A) and advanced stage disease. However, this data was derived from heterogeneous single center cohorts of patients. Data from patients prospectively enrolled in multicenter trials are just emerging.
    Risk for progression in early stage CLL: in the CLL1 trial of the German CLL Study Group (GCLLSG) CLL patients with Binet A disease are stratified into a high risk arm if they have a LDT < 12 months and/or a diffuse bone marrow infiltration pattern and a TK level > 7 U/L and/or ß2-MG level > 3.5 mg/Lref. Based on this stratification the high risk group is randomized between immediate treatment with fludarabine versus watch and wait while the low-risk group is followed up. In addition at enrollment genomic aberrations and VH mutation status are analyzed. Table 1 gives a summary of the genetic results obtained so far. These results show that high-risk aberrations (11q- or 17p-: 14%) and unmutated VH (41%) occur in a significant number of asymptomatic early stage patients. When comparing the results from CLL1 with our single center study containing patients diagnosed in all stages and the CLL4 study (fludarabine vs fludarabine/cyclophosphamide for untreated Binet B/C patients, see also www.dcllsg.de) (Eichhorst B, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide (FC) induces higher remission rates and longer progression free survival (PFS) than fludarabine (F) alone in first line therapy of advanced chronic lymphocytic leukemia (CLL): results of a Phase III study (CLL4 Protocol) of the German CLL Study Group (GCLLSG) [abstract]. Blood. 2003;102: #243.) it is interesting to note that the incidence of low-risk markers (mutated VH, 13q- single) is higher and the percentage of high-risk markers (unmutated VH, 11q-, 17p-) is lower. The low incidence of 11q- in the CLL1 trial as compared to the other studies is likely due to the strong association of this abnormality with marked lymphadenopathy and rapid disease progression leading to recruitment of such patients in a trial for advanced stage symptomatic disease. In the CLL1 study preliminary correlations of genetic parameters with progression-free survival (PFS) among untreated patients showed that unmutated VH as well as +12q, 11q- and 17p- are associated with more rapid disease progressionref. Moreover, the genetic parameters and the other parameters used for risk stratification appear to be correlated. Unmutated VH and high-risk aberrations (17p-, 11q-, +12q) were significantly associated with the trial-defined high-risk group and with the individual parameters defining this group. However, there was discordance in 20–40% of cases between individual parameters, i.e. among the trial-defined "high-risk" patients 37% had mutated VH, while in the "low-risk" group 28% had unmutated VH. In univariate analysis the following prognostic indicators were significant for a shorter PFS: TK (P < .001), LDT (P = .001), lymphadenopathy (P = .002), ß2-MG (P = .006), absolute lymphocytes (P = .004), unfavorable genomic aberrations (11q-, 17p-, +12q) (P < .001) as well as unmutated VH status (P = .003). In multivariate analysis TK, LDT, unfavorable genomic aberrations (11q-, 17p-, +12q) as well as unmutated VH status were identified as independent variables. Therefore, it appears that a combination of several different factors may allow the best prediction of an individual patient’s risk for disease progression. The future CLL7 trial will therefore include the parameters TK, LDT, genomic aberrations and VH mutation status for initial risk stratification among Binet A CLL patients. Furthermore, young early stage patients in the "high risk" group as defined in the CLL1 trial or by genetic risk factors (unmutated VH, 11q-, 17p-) and active disease as defined by National Cancer Institute (NCI) criteria are eligible for the autologous and allogeneic transplantation protocols of the GCLLSG. Progression-free survival (PFS) assessed according to genetic markers in the multicenter prospective CLL1 trial of the GCLLSGref1, ref2. Predictors for response to treatment and survival in advanced stage CLL : the observation that the rate of disease progression is associated with genomic aberrations and VH mutation status indicates that these factors may determine the behavior of the disease. However, overall survival reflects additional parameters such as response to treatment. The fact that overall survival was inferior for the subgroups with unmutated VH, 11q-, or 17p-, despite the fact that comparable treatment modalities were used for patients with or without these markers, suggests that response to therapy may be different in genetic subgroups. In particular, the deletion 17p- and/or abnormalities of the p53 gene involved in this aberration have been associated with failure after treatment with alkylating agents, purine analogs and rituximabref1, ref2, ref3, ref4. In a chromosome banding study of patients treated in a prospective trial based on alkylating agents, 17p aberrations were the only chromosomal aberration of prognostic relevanceref. An interphase-FISH study also showed that patients whose leukemia cells showed a 17p-/p53 deletion had significantly shorter survival times than patients without this aberration, and a relationship was found between the deletion and the response to treatmentref. While 56% of patients without p53 deletion went into remission after treatment with purine-analogs, none of the patients with p53 deletion showed a response. Similarly, the monoclonal anti-CD20 antibody rituximab did not show efficacy in CLL with p53 deletionref. In contrast, there is anecdotal evidence that durable therapeutic success can be achieved in CLL with 17p-/p53 mutation using the monoclonal anti-CD52 antibody alemtuzumabref. This observation has been expanded in a retrospectively evaluated series of CLL cases mostly refractory to fludarabine therapyref. Treatment with intravenous alemtuzumab resulted in a CR or PR in 11 of 36 (31%) and in 6 of 15 (40%) patients with p53 mutations or deletions. In the CLL2H study of the GCLLSG (alemtuzumab for fludarabine refractory CLL) a high incidence (27%) of 17p- aberrations was observed, confirming the association of this abnormality with fludarabine-resistant disease. An interim analysis of this ongoing prospective trial has shown a response (CR or PR) in 10 of 21 VH unmutated, 5 of 10 11q-, and 6 of 10 17p- cases, providing evidence from a controlled trial that alemtuzumab may be effective in CLL with 17p-/p53 mutation. The observation that in a multivariate analysis 17p-, 11q-, and unmutated VH were independent adverse prognostic markers with regard to overall survival indicated that these factors may be associated with different outcomes after treatment. Support for this hypothesis requires prospective evaluation of the best currently available prognostic markers in controlled clinical trials. VH mutation status, genomic aberrations, ZAP-70, etc. are currently being evaluated in different treatment trials from which so far only preliminary data have been available (Orchard J, Davis Z, Ibbotson R, Richards S, Catovsky D, Oscier D. Comparison of ZAP-70, IgVH gene mutational status and CD38 in CLL patients requiring therapy: preliminary report from the UK CLL IV trial [abstract]. Blood. 2003;102:#105; Eichhorst B, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide (FC) induces higher remission rates and longer progression free survival (PFS) than fludarabine (F) alone in first line therapy of advanced chronic lymphocytic leukemia (CLL): results of a Phase III study (CLL4 Protocol) of the German CLL Study Group (GCLLSG) [abstract]. Blood. 2003;102: #243; Maloum K, Magnac C, Cazin B, et al. Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia. Predictive value of mutational IgVH gene status for incomplete response and relapse after oral fludarabine phosphate (fludara oral) and cyclophosphamide in previously untreated CLL patients [abstract]. Blood. 2003;102:#110)
    Clinical evolutions : more aggressive B-cell cancers that develop in about 10% of affected persons. Progression to more aggressive B-cell cancers in persons with CLL can result from either clonal evolution or from an independent transforming eventref : Therapyref : because the initiation of therapy for early stage patients has not been shown to prolong survivalref, therapeutic procedures traditionally have been aimed at palliation and were instituted only for advanced stage or symptomatic disease. More recently, however, highly effective and potentially curative approaches such as antibody-chemotherapy and autologous or allogeneic stem cell transplantation have been developed. The therapeutic options vary markedly with regard to efficacy, toxicity and cost, and new risk-stratified algorithms of therapy are becoming increasingly necessary. The definition of more accurate prognostic factors has made possible a risk-adapted approach to therapy for patients with CLL akin to what has been commonplace for patients with acute leukemia for years. Clearly, one can define patient populations with wide divergent survival expectations as one can with acute leukemia. However, in patients with acute myeloid leukemia (AML) the outcome is quite black and white. Patients either are cured of their disease or they are not. For patients with CLL, the outcome is closer to shades of gray. With the possible exception of allogeneic HSCT, no one will be cured of their disease. Furthermore, the anticipated survival for even the worst group of patients with CLL is several years. Thus, the decision of when to initiate treatment and what type of therapy to initiate with a CLL patient is not straightforward. In fact, treatment of low-risk patients may actually have deleterious effects on survival as has been shown by the French Cooperative Groupref. Currently the decision to treat patients is based on multiple factors including advanced clinical staging, symptomatic disease, burden of disease, age, co-morbid illnesses, adverse prognostic factors, and availability of treatments that alter survival. Patients in early clinical stages with enough poor prognostic criteria could be considered candidates for enrollment in clinical trials or therapies such as stem cell transplantation that offer the potential for cure. Once the decision to treat a patient has been made, there are multiple treatments known to be effective for CLL. Standardized response criteria : Experimental animal models : Web resources :
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