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Chapter 77 Chronic Lymphocytic Leukemia 1245

30 inhibitor idelalisib and syk inhibitors have been shown to antagonize
27.6
26.4 these survival signals and result in clinically meaningful disease
responses.
Percent of new cases 25 9.2 13.6 IGHV Mutational Status
21.2
20
15
Two seminal manuscripts in 1999 demonstrated that the IGHV gene
had undergone somatic mutation, indicating that the patient’s CLL
10
at diagnosis. Detailed epigenetic studies examining the methylation
5 arose after this point in B-cell maturation, in 60% of CLL patients
1.7 changes occurring in normal B cells during development have subse-
0.0 0.2 quently suggested that immunoglobulin mutational analysis may
0 indicate simply where in normal B-cell development transformation
<20 20–34 35–44 45–54 55–64 65–74 75–84 >84 occurred. In an attempt to identify surrogate genes associated with
IGHV-unmutated disease, ZAP-70 overexpression was identified.
Age (y) The majority of IGHV-unmutated CLL cells have ZAP-70 expres-
Fig. 77.1 GRAPH SHOWING THAT CHRONIC LYMPHOCYTIC sion and demonstrate evidence of syk activation and other essential
LEUKEMIA IS A VERY UNCOMMON DIAGNOSIS BEFORE AGE 45 BCR downstream activation signals after ligation of surface immu-
YEARS AND INFREQUENT (<30% OF TOTAL PATIENTS DIAG- noglobulin M (sIgM) that is related to overexpression of this protein.
NOSED) BEFORE AGE 65 YEARS. In contrast, virtually all IGHV-mutated patients lack significant
ZAP-70 expression and do not signal after ligation by sIgM, but can
often weakly signal through other alternative BCRs. Thus, although
gene expression profiling demonstrates all CLL cells to be most
make an understanding of the basic biology of CLL increasingly closely related to memory B cells, IGHV-unmutated and IGHV-
relevant and important to clinicians caring for CLL patients. mutated CLL cells differ significantly with respect to their ability to
For many years, CLL was believed to represent a single disease transduce intracellular signals after sIgM ligation. A common reper-
that had a varied natural history. Basic research focused on under- toire of mutational changes among CLL patients has also been docu-
standing (1) the normal cell of origin from which CLL is derived; (2) mented that differs significantly from that found in the normal adult
the function of the B-cell receptor (BCR) in CLL; (3) the matura- B-cell repertoire. These studies have prompted the hypothesis that
tional point in B-cell development at which CLL occurs; (4) the CLL may represent an antigen-driven disease. Targeting BCR signal-
relevance and contribution of a self- or acquired-antigen to driving ing based on this has already resulted in the development of several
the disease; and (5) the role of the microenvironment in disease therapeutic agents directed against signaling pathways downstream
development and progression. All of these observations are important of the BCR.
scientific areas of active, ongoing study, and readers are referred to
several recent definitive reviews for further information on the basic
biology of CLL. The biology and genetics covered within this chapter Defective Apoptosis
focus predominantly on areas relevant to clinicians who care for
patients with CLL. Since its initial description and early characterization, CLL has been
considered a disease of slow accumulation of tumor cells caused by
B-CELL RECEPTOR PATHWAY AND ITS ROLE IN disrupted or defective apoptosis. Multiple studies have demonstrated
that CLL cells overexpress several antiapoptotic proteins, including
PATHOGENESIS BCL2, MCL1, Bak, and X-linked inactivator of apoptosis protein,
and have diminished expression of compensatory proapoptotic
Modulation of the BCR plays an integral part in the development proteins such as Bax. Overexpression of BCL2 and MCL1 and an
and maturation of B cells. Its constitutive activation through antigen increase of the ratio of these proteins to Bax have correlated not only
dependent or independent signaling provides an important survival with disrupted apoptosis but also shortened OS and poor response
signal for the propagation of CLL B cells. Signal transduction to therapy. Studies have demonstrated that CLL cells are character-
occurs through a variety of kinases including LYN, PI3K, SYK and ized by constitutive activation of several antiapoptotic transcription
Bruton tyrosine kinase (BTK) with resultant phosphorylation of factors, including nuclear factor kappa-B (NFκB), nuclear factor of
phospholipase C (PLC)-γ2 and induction of downstream second activated T cells, and signal transducer and activator of transcription
messengers that further modulate cell survival regulators. These 3. Each of these transcription factors can influence one or more of
kinases can now be effectively pharmacologically targeted, which the antiapoptotic proteins that promote survival in vivo. The source
results in abrogation of the survival signal leading to B-cell apoptosis. of activation of these different transcription factors is not completely
Combinations of these inhibitors with existing and novel therapeu- defined but may be partly attributable to autocrine and paracrine
tic agents have the potential to change the natural history of the networks involving B-cell activation factor (BAFF), a proliferation
disease. inducing ligand vascular endothelial growth factor, interleukin-4
X-linked agammaglobulinemia is a disease characterized by (IL-4), and CD40. CLL cells are also maintained through contact
a severe immunodeficient state that results from deficient BTK. with stromal cells (bone marrow [BM] and dendritic) and similar
Characterization of this defect and its resultant impact on causing nurse cells through a complex interface of adhesion molecules and
severe impairments in B-cell development and humoral immunity stromal survival factors such as stromal cell–derived factor. The
has been critical to our understanding of CLL disease biology. importance of the in vivo environment to CLL survival is sup-
Activating mutations of BTK have not been identified in CLL or ported by the increase in apoptosis when CLL cells are cultured
other cancers but CLL B cells tend to have higher levels of BTK in vitro.
that can be induced through the BCR signaling pathway. Ibrutinib
is the first in class BTK inhibitor that efficiently targets BTK and
results in significant abrogation of downstream survival signaling Genetic Abnormalities
transduced through this pathway and results in the inhibition of
cell survival and proliferation. Similarly, both SYK and PI3K can be Detailed study of the genetics of CLL has been hindered by the
induced by activation of BCR pathway. The PI3-kinase isoform delta inability to effectively induce proliferation of tumor cells for standard