Page 1095 - Clinical Immunology_ Principles and Practice ( PDFDrive )

ChaPTEr 78 Lymphoid Leukemias 1059

13q14 deletion or a normal karyotype is associated with a mutated express exhaustion markers, including programmed death protein
profile and better prognosis. These chromosomal aberrations 1 (PD-1), at higher levels. Accordingly, CLL cells express high
have independent prognostic significance (unrelated to the levels of PD-1 ligand (PD-L1). In addition, NK cells have reduced
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mutational status). effector activities that are associated with low expression levels
Surface membrane antigens typically found on B-cell CLL of the activating receptors NK-cell p30-related protein (NKp30)
cells include CD19, CD21, and CD23. Expression of membrane and NK group 2 member D (NKG2D). Together, these findings
IgM, IgD, and CD79b is reduced and is thus consistent with a provide an explanation for ability of CLL cells to evade immune-
phenotype matching that of mature, activated B lymphocytes. mediated destruction.
The pathological features of biopsy specimens of lymph nodes CLL has been classically characterized by the accumulation
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are those of a small lymphocytic lymphoma. The coexpression of mature B cells that evade apoptosis, with high levels of the
of CD5, a T cell–associated antigen, is a phenotypic characteristic BCL2 antiapoptotic protein. Contradicting this dogma is the
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and part of the disease defining criteria. CD5 B cells can be measurement of CLL kinetics that has shown CLL cells to prolifer-
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found in the peripheral blood of normal adults, suggesting that ate at a high dynamic rate of up to 1% of the clone per day.
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specific subsets of CD5 B cells from the mantle zone may be In addition, proliferation-related genes (e.g., c-MYC and E2F1)
the normal counterparts of B-cell CLL. The low expression of have been found to be upregulated, especially in the unmutated
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the BCR is the hallmark of CLL cells and contributes to impair- CLLs. This finding suggests that CLL is not solely an accumula-
ments in the activation of the cell following BCR stimulation. tive disease but also has a proliferative element.
BCR signaling in CLL has been extensively studied and has
shed considerable light on the pathogenesis of the disease, thus Clinical Features of CLL
aiding in the design of targeted therapies. The BCR is a multimeric
complex containing the antigen-specific surface Ig and the two CLiNiCaL PEarLS
membrane-bound signal transduction elements CD79A and Chronic Lymphocytic Leukemia (CLL):
CD79B. Binding of antigen to the BCR induces activation of Clinical Manifestations
upstream kinases, which, in turn, activate other kinases by means
of their cytoplasmic moieties, including SYK and the Src kinase. • Absolute blood lymphocytosis >5000 /mm sustained over a period
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These kinases further activate the Bruton tyrosine kinase (BTK), of 4 weeks (to exclude transient lymphocytosis related conditions as
PI3K, and other downstream pathways, including phospholipase viral infections)
C gamma 2 (PLC-γ2), calcium signaling, protein kinase C (PKC), • At least 30% lymphocytes in a normo- or hypercellular marrow
nuclear factor (NF)-κB signaling, mitogen-activated protein • Phenotypically monoclonal lymphocytes
• They express mature B-cell markers (e.g., CD19) and CD5
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kinases (MAPKs), and nuclear transcription. The upstream • Morphologically mature-appearing lymphocytes
kinases BTK and PI3K are currently targeted by specific agents, • Most patients having some degree of lymphadenopathy on physical
and other kinases and pathways are being explored for novel examination
therapies. • Progression and the need for treatment depend on lymphocyte doubling
The CD38 surface molecule supports B-cell interactions and time, bulky symptomatic disease, anemia, thrombocytopenia, auto-
differentiation. Under certain circumstances, CD38 also augments immune phenomenon
signaling of BCR, delivering signals that regulate the apoptosis
of B cells. Expression of CD38 correlates with expression of The clinical diagnosis of CLL requires an absolute lymphocytosis
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unmutated V domains and suggests a bad prognosis. Another with a threshold of >5000 × 10 /L mature-appearing lymphocytes
molecule that influences the BCR is the ζ-associated protein 70 in the blood smear, persistence of the lymphocytosis for >4 weeks,
(ZAP70). High levels of this receptor associated protein tyrosine and a distinct immunophenotype (as described above). Approxi-
kinase (usually found in T and natural killer [NK] cells, but not mately a quarter of patients with CLL are asymptomatic at
in normal B cells) are detected in the majority of unmutated diagnosis. The clinical characteristics at presentation include
CLLs and correlate with a poor prognosis. lymphadenopathy (87%), splenomegaly (54%), hepatomegaly
The microenvironment may play a role in the pathogenesis (14%), high white blood cell (WBC) count, anemia, and throm-
of CLL. Interactions with stromal cells rescue CLL cells from bocytopenia (20%). Very high WBC counts are rare but may
apoptosis in vitro. Activated T cells support the growth of CLL develop along the course of the disease. Hyperleukocytosis, which
cells; cytokines, such as IL-4 and vascular endothelial growth causes leukostasis and necessitates emergency treatment, is
factor (VEGF), and chemokines, such as CXCL12, support the extremely rare. Other organs that are involved include other
expansion of CLL clones. When compared with blood-derived lymphoid tissues and rarely solid organs or skin.
cells, expression profiling of CLL cells in the patient’s lymph A prognostic evaluation of the patient with CLL begins with
nodes showed BCR and NF-κB activation promoting cell prolifera- study of the patient’s blood and bone marrow. Lymph node
tion, thus indicating the strong effects of the tumor microenviron- biopsy is not necessary but, if performed, may reveal the diagnosis
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ment. Mesenchymal stromal cells are also commonly found in of small lymphocytic lymphoma (SLL), which is considered a
secondary lymphatic tissues of patients with CLL. There they different manifestation of the same disease. The differential
provide survival and migration signals to CLL cells, as well as diagnosis includes other low-grade lymphoproliferative disorders,
protection from apoptosis and modulation of antigen presenta- such as a leukemic phase of lymphoma and mantle cell lymphoma
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tion. Endothelial cell and follicular dendritic cells (FDCs) may (usually negative for CD23); hairy cell leukemia (CD5 and CD21
also play a role. negative and CD103 and CD25 positive); T-cell leukemia (other
Interaction with and evasion from the normal immune system T-cell markers, such as CD3, CD4, and CD7); and prolymphocytic
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has been shown to be of significance. The number of circulating leukemia (PLL), which is distinguished by morphologically
T cells, oligoclonal in both the CD4 and the CD8 compartments, immature-appearing cells and the presence of FMC7 and CD79b
is increased. The function of these T cells is impaired, and they on the cell surface. T-cell CLL is rare (<5%).