Pathobiology of chronic lymphocytic leukemia

INTRODUCTION — Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder (lymphoid neoplasm) characterized by the progressive accumulation of functionally incompetent lymphocytes, which are usually monoclonal in origin.

CLL is considered to be identical (ie, one disease with different manifestations) to the mature (peripheral) B cell neoplasm small lymphocytic lymphoma (SLL), a clinically indolent non-Hodgkin lymphoma. The term CLL is used when the disease manifests primarily in the blood, whereas the term SLL is used when involvement is primarily nodal.

The pathogenesis and disease evolution of CLL/SLL will be reviewed here. The clinical manifestations, diagnosis, staging, prognosis, and treatment of CLL/SLL are discussed separately, as is the related condition monoclonal B cell lymphocytosis.

●(See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

●(See "Staging and prognosis of chronic lymphocytic leukemia".)

●(See "Overview of the treatment of chronic lymphocytic leukemia".)

●(See "Monoclonal B cell lymphocytosis".)

DISEASE EVOLUTION FROM MONOCLONAL B CELL LYMPHOCYTOSIS — The pathogenesis of CLL/small lymphocytic lymphoma (SLL) is a complex, multistep process leading to the accumulation of monoclonal, mature, functionally incompetent B lymphocytes in the peripheral blood, bone marrow, lymph nodes, and spleen (figure 1). This evolution can be conceptualized as a sequential process, with a minority of cases progressing at each step:

●Establishment of MBL – CLL/SLL is preceded by an asymptomatic premalignant B cell proliferative disorder known as monoclonal B cell lymphocytosis (MBL), defined by a monoclonal population of B lymphocytes <5000 cells/microL (<5 x 10⁹/L) in the peripheral blood, with a CLL/SLL phenotype, without other features of a B cell lymphoproliferative disorder (eg, lymphadenopathy, organomegaly, cytopenias, or extramedullary involvement).

MBL with a CLL/SLL phenotype is present in 5 to 10 percent of persons over age 60 and a smaller percentage of younger persons [1,2]. High-count CLL-like MBL (>2000 cells/microL [>2 x 10⁹/L] with a CLL phenotype) progresses to CLL/SLL at a rate of approximately 1 to 2 percent per year [3,4]. While the inciting event is unknown, the development of MBL likely reflects a combination of factors, including antigenic stimulation, changes in the bone marrow microenvironment, genetic changes, and epigenetic modification. (See "Monoclonal B cell lymphocytosis".)

●Progression from MBL to asymptomatic CLL/SLL – Progression to CLL is defined by a rise in this monoclonal population of B lymphocytes with a CLL phenotype in the peripheral blood to ≥5000 cells/microL (≥5 x 10⁹/L). Progression of MBL to CLL/SLL is the result of further insults to the B cell clone, through genetic changes and/or changes in the bone marrow and lymph node microenvironment [5]. A large subset of patients with CLL/SLL remains asymptomatic despite the increased number of circulating monoclonal B lymphocytes. A minority of cases regress spontaneously. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Evaluation and diagnosis'.)

●Progression to symptomatic CLL/SLL – Ultimately, some patients develop signs and symptoms related to the accumulation of functionally incompetent lymphocytes and suppression of normal organ function (eg, lymphadenopathy, hepatosplenomegaly, cytopenias, infections). Complex studies using next-generation sequencing suggest that an individual CLL/SLL tumor is genetically heterogeneous, with several subpopulations of malignant cells evolving over time [6-11]. The relative contribution of each subpopulation to the total tumor volume is likely affected by interactions with other subpopulations, the tumor microenvironment, and therapy.

●Evolution to more aggressive disease – Over time and under the selective pressure of therapy, clonal evolution can result in CLL/SLL that is more aggressive and resistant to treatment. In addition, a minority of cases will undergo histologic transformation to a more aggressive lymphoproliferative disorder, such as diffuse large B cell lymphoma (also known as Richter transformation). (See 'Histologic transformation' below.)

THE CLL CELL

Cell of origin — While CLL/small lymphocytic lymphoma (SLL) cells look like mature small lymphocytes seen in the peripheral blood of normal individuals, they are functionally incompetent clonal B cells arrested in the B cell differentiation pathway at some intermediate stage between the pre-B cell and mature B cell, perhaps in the "activated, antigen-experienced" B cell subset [12-14].

Specific subsets of CD5+ B cells may be the normal counterparts of CLL/SLL [15-17]. Studies using gene expression profiling suggest that the cell of origin likely differs between cases with and without mutated immunoglobulin heavy chain variable region (IGHV) genes [18]:

●CLL/SLL with unmutated IGHV – Expression resembles that of pre-germinal center (unmutated) mature CD5+ B cells; cells are polyreactive and clinically more aggressive.

●CLL/SLL with mutated IGHV – Expression resembles that of CD5+CD27+ post-germinal center B cells; cells have a narrow antigen specificity (more anergic) and are clinically less aggressive.

Several studies have evaluated the pathophysiologic implications of the combination of cell surface markers seen in CLL/SLL. CD5+ B cells with many or all of the characteristics of CLL/SLL cells, including monoclonality, can be found in the lymph nodes and spleen of the normal human fetus, and at the edge of germinal centers of lymph nodes [19-21], as well as in the peripheral blood of normal adults [22,23]. In addition, approximately 15 percent of normal B cells in the peripheral blood express CD5 [24]. A minor subpopulation of normal human CD5+ cells is considered to be a long-lived population circulating between blood and lymph nodes, mostly located in the inner layer of mantle zones; these cells may be the normal counterpart of the neoplastic CLL/SLL cells [25]. The most frequent CLL/SLL phenotype corresponds to one or more cellular subsets within the mantle zone of lymph nodes.

Evaluation of a naturally occurring CD5+ B cell subset that resembles autoantibody-producing CLL/SLL cells showed a restricted expression of IGHV genes [26], raising the possibility that CLL/SLL may arise from a normal B cell subset engaged in autoantibody production [26,27].

Cellular proliferation — CLL/SLL cells can exhibit impaired apoptosis and increased proliferation. The kinetic balance between these impacts disease tempo.

●Impaired apoptosis – Initially, it was thought that the majority of CLL/SLL cells were in the G(0) phase of the cell cycle, with <1 percent spontaneous mitoses in vitro, suggesting that CLL/SLL was a disease of accumulation of long-lived lymphocytes. Indeed, malignant cells accumulate in CLL/SLL at least partly due to their inability to undergo apoptosis. Mechanisms of apoptosis resistance in CLL/SLL include overexpression of B cell leukemia/lymphoma 2 (BCL2) and Fas-inhibitory molecules such as TOSO [28]. (See 'Upregulation of BCL2 proto-oncogene' below.)

●Increased proliferation – In vivo kinetic studies have uncovered a wide range of cellular proliferation and death rates among individual patients. Some exhibit exponential growth with short lymphocyte doubling times and rapidly progressive disease, while others demonstrate a logistic growth which slows and stabilizes as the population size reaches its maximum capacity [29,30]. Those patients with higher proliferation rates are much more likely to exhibit active disease or develop progressive disease than those with lower proliferation rates [31,32]. Proliferation is impacted by genetic features (eg, IGHV mutation status), B cell receptor signaling, and interactions with the tumor microenvironment and/or antigens [33,34]. (See 'Antigen-independent BCR signaling' below and 'Tumor microenvironment' below.)

Defective B and T cell function — Patients with CLL/SLL have abnormal cellular and humoral-mediated immune responses due to qualitative and quantitative defects in immune effector cells. In addition, a subset experience autoimmune phenomena.

●Hypogammaglobulinemia – Hypogammaglobulinemia is present in approximately 25 percent of patients at the time of initial diagnosis and may develop in up to two-thirds of patients later in the course of the disease [35]. Hypogammaglobulinemia is thought to be related to defective functioning of T cells and non-clonal CD5-negative B cells. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Humoral immunity'.)

●Defective antibody response – Patients with CLL/SLL may have defective antibody responses to specific infections and immunizations [36]. Treatment-naïve patients are at increased risk for bacterial infections caused by common pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa [37]. Response to immunizations is suboptimal due to impaired antibody production and defects in antigen presentation. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Spectrum of infections' and "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Immunizations'.)

●Autoimmune disorders – Autoimmune disorders occur in up to 25 percent of patients, depending on the disease phase [17,38]. These include Coombs-positive autoimmune hemolytic anemia, immune thrombocytopenia (ITP), pure red cell aplasia, and autoimmune granulocytopenia [39,40]. (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Autoimmune hemolytic anemia'.)

The development of autoimmune phenomena in patients with CLL/SLL is likely a complex process that involves the malignant B cells, residual polyclonal B cells, and T cells in the tumor microenvironment, and multiple mechanisms may be involved. Interactions between the malignant B cells and residual normal B cells can lead to the production of polyclonal high-affinity immunoglobulin directed against antigens on red blood cells and platelets [41]. In addition, in approximately 25 percent of CLL/SLL cases bearing kappa light chains on the lymphocyte surface, the leukemic cells react against an anti-idiotype antibody to a highly conserved region of one specific kappa gene (cross-reactive idiotype) [15-17]. Alterations in the T cell compartment likely also contribute to autoimmune phenomena. Further insight may be gained by studying other patients with autoimmune disorders. In one study, CD5+ B cells were increased in patients with autoimmune disorders, such as rheumatoid arthritis [42].

BCR stereotypy — CLL/SLL cells express B cell antigen receptors (BCRs) with a limited immunoglobulin repertoire characterized by restricted heavy and light chain usage (referred to as BCR stereotypy).

In large-scale studies that have sequenced these immunoglobulins in unrelated patients with CLL/SLL, >20 percent of cases have near identical immunoglobulin sequences in the heavy variable complementarity determining region 3 (VH CDR3) [43-53]. The similarity of these BCRs is significantly greater than that which would be expected based on chance alone. BCR stereotypy is more common in clinically aggressive CLL/SLL with unmutated IGHV genes.

BCR stereotypy in CLL/SLL cases suggests a role for antigens in the pathogenesis and evolution of CLL/SLL. BCR stereotypes can also be used to group CLL/SLL cases into subsets with presumably different biological backgrounds, prognosis, and response to treatment [54].

GENETIC ABNORMALITIES

Genomic abnormalities — Genetic abnormalities are present in the vast majority of CLL/small lymphocytic lymphoma (SLL) tumors at diagnosis, and additional genetic abnormalities are acquired with disease evolution [55,56]. While the significance of many of these abnormalities is unclear, some are prognostic and a few impact treatment decisions. The role of genetic abnormalities on pathogenesis is discussed here. Their impact on prognosis and treatment decisions is discussed separately. (See "Staging and prognosis of chronic lymphocytic leukemia" and "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Choice of therapy'.)

At least one of four common chromosomal abnormalities can be detected by interphase fluorescence in situ hybridization (FISH) in approximately 80 percent of CLL/SLL tumors [57-59]. The cytogenetic abnormalities appear to be restricted to B cells in CLL/SLL [60]. Given the frequency of these abnormalities, studies have evaluated their potential impact on pathogenesis.

●Del(13q14) – Del(13q14) is detected in 50 to 60 percent of CLL/SLL tumors. The deleted region contains miR15A and miR16A micro-ribonucleic acid (micro-RNA) [61]. These micro-RNA regulate the expression of proteins involved in apoptosis and the cell cycle. Deletion of these micro-RNA leads to the development of CLL/SLL in mouse models [62]. Without them, the cells do not respond appropriately to stress signals that should induce apoptosis. The B cell leukemia/lymphoma 2 (BCL2) gene encodes the antiapoptotic protein BCL2 and is one of the genes upregulated when these micro-RNA are deleted [61]. (See 'Upregulation of BCL2 proto-oncogene' below.)

●Trisomy 12 – Trisomy 12 is detected in 10 to 20 percent of CLL/SLL tumors. CLL/SLL with trisomy 12 has a gene expression profile that includes overexpression of RUNX3 [63]. Further details on whether trisomy 12 impacts CLL/SLL development and evolution are unclear.

●Del(11q22-23) – Del(11q22-23) is detected in 10 to 20 percent of CLL/SLL tumors at diagnosis. The deleted region contains the ataxia telangiectasia (ATM) gene. The ATM gene product is involved in the detection of deoxyribonucleic acid (DNA) damage and plays an important role in cell cycle progression. CLL/SLL cells without normal ATM function are unable to respond appropriately to chemotherapy-induced DNA damage. (See 'Impaired DNA damage response' below.)

●Del(17p12) – Del(17p12) is detected in 4 to 10 percent of CLL/SLL tumors at diagnosis and a larger percentage at relapse. The deleted region contains the TP53 gene, which is essential for a normal DNA damage response leading to apoptosis. CLL/SLL cells without normal TP53 function, either through del(17p12) or through TP53 mutation, cannot trigger apoptosis in response to chemotherapy-induced DNA damage. (See 'Impaired DNA damage response' below.)

In addition, abnormalities in certain genes have been identified in patients with CLL/SLL with or without the presence of chromosomal abnormalities. As described above, CLL/SLL with TP53 mutations are unable to respond appropriately to chemotherapy-induced DNA damage. Other gene mutations have been found that impact signaling pathways within the cell (involved in DNA damage response, the cell cycle, RNA splicing and metabolism, and chromatin modifiers) and those involved in microenvironment dependent signaling (NOTCH1 signaling, BCR and Toll-like receptor signaling, MPK-ERK pathway signaling, NF-kB signaling) [8,9,64,65].

Gene mutations — Complex studies using next-generation sequencing have shown that an individual CLL/SLL tumor is genetically heterogeneous, with several subpopulations of malignant cells evolving over time [6-10]. Most CLL/SLL tumors have thousands of somatic gene mutations. Of these, four are present at diagnosis in >5 percent of patients:

●TP53 – TP53 activity is essential for a normal DNA damage response leading to apoptosis. CLL/SLL cells without normal TP53 function cannot trigger apoptosis in response to chemotherapy-induced DNA damage. (See 'Impaired DNA damage response' below.)

●ATM – The ATM gene product is involved in the detection of DNA damage and plays an important role in cell cycle progression. CLL/SLL cells without normal ATM function are unable to respond appropriately to chemotherapy-induced DNA damage. Rare germline ATM variants appear to be more common in patients with CLL/SLL than in those with other hematologic disorders, and patients with CLL and a germline ATM variant are more likely than others to have ATM-aberrant CLL/SLL (ie, 11q deletion or somatic mutation in ATM) [66]. (See 'Impaired DNA damage response' below.)

●NOTCH1 – Notch proteins are transmembrane receptors that are involved in regulating hematopoietic cell development. A subset of CLL/SLL tumors have activating mutations in coding and noncoding regions of the NOTCH1 proto-oncogene, causing aberrant splicing events, increased NOTCH1 activity, and more aggressive disease [8,67]. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'NOTCH1 mutations'.)

●SF3B1 – The SF3B1 gene encodes for part of a nuclear ribonucleoprotein that complexes with other nuclear ribonucleoproteins to create the spliceosome that is responsible for splicing messenger RNA. SF3B1 mutations can be identified in a subset of patients with CLL/SLL and are associated with a poor prognosis [9,64,68-71]. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'SF3B1 mutations'.)

Many of the other mutations seen in CLL/SLL tumors are involved in a limited number of cellular signaling pathways [6-10,65].

●Microenvironment dependent signaling

•Notch signaling (eg, NOTCH1, FBXW7)

•BCR and Toll-like receptor signaling (BCOR, KLHL6, PAX5, IRF4, CARD11, TLR2, MYD88, IRAK1)

•MAPK-ERK pathway (KRAS, NRAS, PTPN11, GNB1, BRAF, MAP2K1)

•NF-kB signaling (TRAF3, TRAF2, BIRC3, EGR2, NRKBIE, NKAP, NFKB2)

●Intracellular signaling

•Chromatin modifiers (CHD2, SETD2, ZMYM3, KMT2D, SETD1A, ASXL1, ARID1A, BAZ2A, HIST1H1B, HIST1H1E, SYNE1)

•Cell cycle (ATM, TP53, MGA, CCND2, CCKN1B, CDKN2A)

•DNA damage (ATM, TP53, POT1)

•RNA splicing and metabolism (SF3B1, U1, DDX3X, XPO1, RPS15, ZNF292, NXF1, MED12, FUBP1, CNOT3)

Mutational burden and frequency of driver mutations differ between cases with and without mutated immunoglobulin heavy chain variable region (IGHV) genes [8,9,65]. In addition, some specific mutations are primarily seen in one of these groups, while other mutations are seen in both mutated and unmutated CLL/SLL.

●CLL/SLL with unmutated IGHV – These more clinically aggressive tumors have a lower average mutational burden (approximately 2000 somatic mutations) but a greater frequency of driver mutations. Mutations in U1, NOTCH1, and POT1 are primarily seen in this group.

●CLL/SLL with mutated IGHV – These clinically less aggressive tumors have a higher average mutational burden (approximately 3000 somatic mutations) but a lower frequency of driver mutations. Mutations in MYD88 and PAX5 are predominantly seen in this group.

Micro-RNA — Micro-RNAs are a class of small noncoding RNAs that modulate the expression of genes at the post-transcriptional level and are involved in cancer, apoptosis, and cell metabolism [72]. They appear to interact with BCL2 and TP53 in CLL/SLL and may be important in the pathogenesis [73,74]. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'Other markers'.)

●Mutations in micro-RNA transcripts are frequent, some of them germline, and may predispose to CLL/SLL and to a spectrum of associated malignancies [75-77].

●In a study of 56 patients with CLL/SLL, marked overexpression of two micro-RNAs (miR21 and miR155) was seen in almost every sample analyzed [78]. In a larger subsequent study, when compared with normal controls, plasma miR155 levels were significantly increased in patients with monoclonal B cell lymphocytosis and further increased in patients with CLL/SLL [79]. In this study, increased miR155 expression was associated with more refractory disease and worse survival.

●miR15A and miR16A have been shown to interact directly with and result in the upregulation of the BCL2 antiapoptotic protein in many cases of CLL/SLL [61]. These two mRNAs are deleted in CLL/SLL with 13q deletion. (See 'Upregulation of BCL2 proto-oncogene' below.)

●miR150 regulates the expression of genes encoding proteins that impact BCR signaling in CLL/SLL (eg, FOXP1 and GAB1) [80]. Low levels of miR150 are associated with higher levels of FOXP1 and GAB1 and increased signaling through the B cell receptor. (See 'Antigen-independent BCR signaling' below.)

●The expression of micro-RNA may be regulated by tumor suppressor genes or through epigenetic modification. As an example, the expression of a micro-RNA cluster located at 11q (miR34b/miR-34c) appears to be directly activated by TP53 [81]. In contrast, increased histone deacetylase activity appears to downregulate the expression of other micro-RNAs (eg, miR15a, miR16, miR29b), resulting in decreased apoptosis [82]. (See 'Impaired DNA damage response' below.)

ABERRANT SIGNALING PATHWAYS — As described above, genetic studies have revealed several major cellular signaling pathways that may be involved in the development and/or evolution of CLL/small lymphocytic lymphoma (SLL). Of these, pathways that are key to understanding the biology from a clinical perspective include antigen-independent B cell receptor (BCR) signaling, upregulation of the antiapoptotic factor B cell leukemia/lymphoma 2 (BCL2), and impaired DNA damage response.

Antigen-independent BCR signaling — BCR activation is a key feature of CLL/SLL and therapeutic target. CLL/SLL tumor cells express BCRs with a restricted repertoire of mutations that result in antigen-dependent and antigen-independent cell-autonomous signaling [83]. BCR signaling directs many cellular processes including growth, differentiation, survival, and adhesion or cellular migration. The processes impacted in a specific cell depend upon cellular maturation, the antigen ligated, and the microenvironment.

In CLL/SLL cells, constitutive activation of BCR results in increased expression of SYK, LYN, BTK, and PI3K kinase [84]. This increased signaling activates the cytoplasmic domain of an integrin, and it causes a conformation change that increases its affinity for ligand binding. Binding of a ligand to the integrin's extracellular domain results in intracellular signals that promote growth, survival, differentiation, and migration.

The interaction between CLL/SLL tumor cells and antigens is influenced by the somatic hypermutation load of the immunoglobulin heavy chain variable region (IGHV) genes [85,86]:

●CLL with unmutated IGHV – Cells are polyreactive, capable of binding multiple epitopes that can result in sustained BCR signaling. Clones expand more rapidly, and the clinical course is more aggressive.

●CLL with mutated IGHV – Cells have narrow antigen specificity (anergic) and dampened BCR signaling. Clones expand more slowly, and the clinical course is more indolent.

miR150 micro-RNA regulates the expression of genes encoding proteins that impact BCR signaling in CLL/SLL (eg, FOXP1 and GAB1) [80]. Low levels of miR150 are associated with higher levels of FOXP1 and GAB1, and increased BCR signaling. (See 'Micro-RNA' above.)

Mutations within the BCR pathway are uncommon at the time of CLL diagnosis. However, a percentage of CLL/SLL tumors that progress on BCR inhibitor therapy will have mutations in the target. (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'BTK, PLCg2, and BCL2 mutations'.)

Upregulation of BCL2 proto-oncogene — BCL2 expression is elevated in approximately 95 percent of patients with CLL/SLL. BCL2 is an antiapoptotic protein; when overexpressed, CLL cells do not respond appropriately to signals that should induce apoptosis.

Unlike other lymphoid neoplasms with increased BCL2 expression (eg, follicular lymphoma), the increased expression is not due to a t(14;18) chromosomal translocation [87,88]. Overexpression may be due to one or more mechanisms, including the following:

●Deletion of miR15A and miR16A micro-RNA in CLL with del(13q14) can result in BCL2 gene upregulation [61]. (See 'Genetic abnormalities' above.)

●The tumor microenvironment may impact expression with higher levels seen in CLL cells derived from lymph nodes than in CLL/SLL cells derived from the peripheral blood or bone marrow [89].

BCL2 is expressed in CD5+ CLL cells but not in normal CD5+ B cells. In contrast to other proto-oncogenes, BCL2 has little or no ability to promote cell cycle progression or cell proliferation, but rather raises the cellular apoptotic threshold. It suppresses apoptosis (programmed cell death), resulting in prolonged survival of the involved cells [90]. In vitro studies have shown that CLL/SLL cells with higher levels of BCL2 protein survive longer in culture than those with lower levels [87,91].

BCL2 gene mutations are uncommon at the time of CLL diagnosis. However, they can be detected in a percentage of CLL/SLL tumors that progress on BCL2-directed therapy (ie, venetoclax). (See "Staging and prognosis of chronic lymphocytic leukemia", section on 'BTK, PLCg2, and BCL2 mutations'.)

Impaired DNA damage response — At the time of diagnosis, a minority of CLL/SLL tumors will have genetic abnormalities associated with impaired DNA damage response (eg, deletion 17p, TP53 mutation, deletion 11q). These changes become more common as the disease progresses.

●Lost or mutated TP53 – The DNA damage response is impaired in CLL with lost (deletion 17p) or mutated TP53. The normal "wild-type" TP53 gene produces a DNA-binding protein that acts as a transcriptional activator of growth inhibitory genes. Wild-type TP53 may be particularly critical when cells are under stress.

Normally, cells arrest their growth in response to DNA damaging agents and other stressors (eg, hypoxia) via induction/activation of p53 [92-94]. Once activated, p53 induces a variety of growth-limiting responses, including cell cycle arrest (in order to facilitate DNA repair), apoptosis, senescence, and differentiation. p53 produces these responses largely by altering the expression of target genes. CLL/SLL cells with mutated or deleted TP53 are missing this mechanism of growth arrest.

●Lost ATM – Chromosome 11q contains the ataxia telangiectasia mutated (ATM) gene (mapped to chromosome 11q22.3). The ATM kinase is involved in a surveillance mechanism that, in the presence of DNA damage, stalls progression of the cell cycle [95]. This delay allows the cell to repair the damage, rather than passing on inappropriate genetic information to daughter cells.

In the presence of DNA damage, the ATM kinase phosphorylates the tumor suppressor protein p53 [96]. Phosphorylated p53 serves as a transcriptional activator of genes that cause cell cycle arrest or apoptosis. In the absence of ATM kinase, p53 does not become phosphorylated and cannot prevent the cell from moving into the next phase of the cell cycle. (See "Ataxia-telangiectasia", section on 'Genetics and pathogenesis'.)

TUMOR MICROENVIRONMENT — CLL/small lymphocytic lymphoma (SLL) results in the clonal proliferation and accumulation of monoclonal, mature, CD5+ B cells in the peripheral blood, bone marrow, lymph nodes, and spleen. Clonal proliferation primarily occurs in the lymph nodes, in the complex domain of the tumor microenvironment. CLL/SLL cells both influence the composition of the cells around them, and they are highly dependent upon signals from these cells for their own survival and proliferation.

In CLL/SLL, lymph nodes have "pseudofollicles" which mimic normal B cell follicles. Here, CLL/SLL cells interact with the extracellular matrix, T cells, nurse-like cells (monocyte derived macrophages), stromal follicular dendritic cells, and other stromal cells. Complex, bidirectional interactions occur through direct cell-to-cell contact and indirectly through chemokines and cytokines. CLL/SLL cells are dependent on signals from the microenvironment. Interactions with the microenvironment increase the activation of antiapoptotic and proliferation pathways [89,97].

CLL/SLL cells encourage a leukemia-supportive, immunosuppressive microenvironment [33,98,99]. T cell impairments include reduced T cell motility, impaired CD4+ cell function, and CD8+ cell exhaustion [100-104]. Monocytes differentiate towards leukemia-supportive macrophages [99].

Because B cells account for almost 90 percent of all lymphocytes in CLL/SLL, the percentages of T cells and natural killer (NK) cells are relatively decreased. While the absolute T cell count is often high, it may be normal or low. NK cells are usually decreased in number as well as function in CLL/SLL.

Patients with CLL/SLL also may have an unusual T cell subpopulation expressing lower CD4 or CD8 levels than classic T cells, which may derive from nonclassic pathways of T cell development [100,105-107] or through direct interaction with the malignant B cell population [108]. Similar cells have been described in human and murine autoimmune disease [105].

HISTOLOGIC TRANSFORMATION — In a variable percentage of patients with CLL/small lymphocytic lymphoma (SLL), and usually as a terminal event, CLL/SLL transforms into another lymphoproliferative disorder. When compared with the general population, patients with CLL/SLL have a two- to fivefold increased risk of developing a second lymphoid malignancy [109]. In approximately 80 percent of cases, the transformed cells are clonally related to the original CLL/SLL cells while, in the remaining 20 percent, they appear to be derived from a separate cell of origin (clonally unrelated) [110]. The clonal relationship between these two cell populations may impact management.

Transformation of CLL into a more aggressive disease is termed Richter transformation. The following are the most commonly reported transformations:

●Aggressive or highly aggressive lymphoma – 3 to 7 percent

●Prolymphocytic leukemia (PLL) – 2 percent

●Hodgkin lymphoma – 0.5 to 2 percent

●Multiple myeloma – 0.1 percent

While transformation to multiple myeloma has been reported, most cases of multiple myeloma in patients with CLL represent a second malignancy rather than transformation.

It is unknown whether targeted therapies impact the risk of histologic transformation or development of a second lymphoid malignancy. Investigation into this question is hampered by the relatively short follow-up of randomized trials evaluating these agents and trial designs that allowed for crossover to a targeted agent in those who did not attain a response to chemotherapy. The early studies of ibrutinib and venetoclax in high-risk relapsed refractory patient populations showed relatively high rates of transformation [111,112]. These high rates have not been demonstrated in subsequent randomized trials in earlier stage disease, suggesting that disease biology may play a larger role than drug exposure in determining transformation [113-115].

It is also unclear whether treatment with either a purine nucleoside analogue or an anthracycline significantly increases the risk of a second lymphoid malignancy. A potentially increased incidence was initially suggested by an observational cohort study from the Mayo Clinic that followed 962 patients with CLL/SLL for a median of 3.3 years and reported that 26 patients (2.7 percent) developed a second lymphoid malignancy [116]. In this study, prior treatment with a purine nucleoside analog or an anthracycline was associated with a higher likelihood of developing a second lymphoid malignancy. However, this association was not confirmed in the prospective CALGB 9011 study in which 521 patients with previously untreated CLL/SLL were randomly assigned to receive fludarabine, chlorambucil, or both [117]. After a minimum follow-up of 15 years, Richter transformation developed in 34 patients (7 percent) and PLL developed in 10 patients (2 percent). The incidence of Richter transformation and PLL was independent of initial therapy.

Richter transformation — In 1 to 10 percent of patients, CLL/SLL transforms to a clinically aggressive lymphoma (called Richter transformation or Richter syndrome) (picture 1). This transformation is often heralded by sudden clinical deterioration, characterized by increasing lymphadenopathy, splenomegaly, worsening "B" symptoms (ie, fever, night sweats, weight loss), a rapidly progressive clinical course, and increased lactate dehydrogenase (LDH). This subject is discussed in depth separately. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Pathogenesis'.)

Prolymphocytoid transformation — In approximately 10 percent of patients with CLL/SLL, the terminal event is a morphological transformation of blood lymphocytes from the typical small, mature-appearing cell to somewhat larger cells with distinct nucleoli and a less dense nuclear chromatin. This event, called prolymphocytoid transformation, occurs slowly over years and is associated with treatment refractory disease, although it can also be seen in the absence of therapy [118,119]. Prolymphocytoid transformation is clinically and immunophenotypically distinct from de novo prolymphocytic leukemia. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Prolymphocytic leukemia'.)

Acute leukemia — When acute myeloid leukemia (AML) occurs in a patient with CLL/SLL, it is most likely to be a therapy-related myeloid neoplasm or a de novo AML and not likely to have evolved or transformed from the CLL/SLL clone. Therapy-related myeloid neoplasms are discussed in more detail separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

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●Beyond the Basics topics (see "Patient education: Chronic lymphocytic leukemia (CLL) in adults (Beyond the Basics)")

SUMMARY

●Stepwise evolution – Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a lymphoid neoplasm characterized by the progressive accumulation of monoclonal functionally incompetent lymphocytes in the peripheral blood, lymph nodes, and spleen. The term CLL is used when the disease manifests primarily in the blood, whereas the term SLL is used when involvement is primarily nodal.

The pathogenesis of CLL/SLL is a complex, multistep process due to changes within the evolving B cell and its microenvironment (figure 1). This process begins the development of a small, asymptomatic B cell clone, known as monoclonal B cell lymphocytosis (MBL). Evolution can be conceptualized as a sequential process, with a minority of cases progressing at each step (see 'Disease evolution from monoclonal B cell lymphocytosis' above):

•Establishment of MBL

•Progression to asymptomatic CLL/SLL

•Progression to symptomatic CLL/SLL

•Transformation to a more aggressive histology

●Cell of origin – While CLL/SLL cells look like mature small lymphocytes seen in the peripheral blood of normal individuals, they are functionally incompetent clonal B cells with arrested development likely from the "activated, antigen-experienced" B cell subset. The cell of origin likely differs between cases with and without mutated immunoglobulin heavy chain variable region (IGHV) genes (see 'The CLL cell' above):

•CLL with unmutated IGHV – Likely derived from pre-germinal center (unmutated) mature CD5+ B cells; cells are polyreactive, capable of binding multiple epitopes that can result in sustained B cell receptor (BCR) signalling; clones expand more rapidly, and the clinical course is more aggressive.

•CLL with mutated IGHV – Likely derived from post-germinal center B cells; cells have a narrow antigen specificity (more anergic) and dampened BCR signalling; clones expand more slowly, and the clinical course is more indolent.

●Apoptosis and proliferation impact kinetics – CLL/SLL cells can exhibit impaired apoptosis and increased proliferation. The kinetic balance between these impacts disease tempo.

•Impaired apoptosis – Malignant cells accumulate at least partly due to their inability to undergo apoptosis, often due to overexpression of the antiapoptotic protein B cell leukemia/lymphoma 2 (BCL2). (See 'Upregulation of BCL2 proto-oncogene' above.)

•Increased proliferation – Proliferation rates are variable; some cases exhibit exponential growth with short lymphocyte doubling times and rapidly progressive disease, while others demonstrate a logistic growth that slows and stabilizes. Proliferation is impacted by genetic features (eg, IGHV mutation status), BCR signaling, and interactions with the tumor microenvironment and/or antigens. (See 'Antigen-independent BCR signaling' above and 'Tumor microenvironment' above.)

●Immune system abnormalities – Patients with CLL/SLL have abnormal cellular and humoral-mediated immune responses due to qualitative and quantitative defects in immune effector cells. In addition, a subset experience autoimmune phenomena. (See 'Defective B and T cell function' above.)

●Genetic changes and signaling pathways implicated – Genetic abnormalities are present in the vast majority of CLL tumors at diagnosis, and additional genetic abnormalities are acquired with disease evolution. Some appear to play a role in the pathogenesis and evolution of CLL/SLL. The deleted region in CLL/SLL with del(13q14) contains micro-RNA that control the expression of multiple genes, including the gene which encodes BCL2. Deletion 17p, TP53 mutation, and deletion 11q can all lead to impaired DNA damage response. (See 'Genetic abnormalities' above.)

Signaling pathways that are key to understanding the biology of CLL/SLL from a clinical perspective include the following (see 'Aberrant signaling pathways' above):

•Antigen-independent BCR signaling – Constitutive activation of BCR results in intracellular signals that promote growth, survival, differentiation, and migration. (See 'Antigen-independent BCR signaling' above.)

•Upregulation of BCL2 – BCL2 is an antiapoptotic protein; when overexpressed, CLL cells do not respond appropriately to signals that should induce apoptosis. (See 'Upregulation of BCL2 proto-oncogene' above.)

•Impaired DNA damage response – CLL/SLL tumors with deletion 17p, TP53 mutation, or deletion 11q are missing mechanisms to induce cell cycle arrest and apoptosis in response to stressors such as chemotherapy-induced DNA damage. (See 'Impaired DNA damage response' above.)

Most CLL tumors have thousands of somatic gene mutations. Of these, four are present at diagnosis in >5 percent of patients: TP53, ATM, NOTCH1, and SF3B1. Many of the other mutations seen in CLL tumors are involved in a limited number of cellular signaling pathways. (See 'Gene mutations' above.)

●Tumor microenvironment – CLL cells both influence the composition of the cells around them, and they are highly dependent upon signals from these cells for their own survival and proliferation. Bidirectional interactions occur between CLL cells and the extracellular matrix, T cells, nurse-like cells (monocyte derived macrophages), stromal follicular dendritic cells, and other stromal cells. (See 'Tumor microenvironment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael J Keating, MD, who contributed to earlier versions of this topic review.