Page 1554 - Williams Hematology ( PDFDrive )

1528 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1529

tyrosine kinase). Their activation results in phosphorylation of phos- expression of various pro- and antiapoptotic proteins of significant rel-
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pholipase C-gamma-2 (PLCγ ) and induction of downstream second evance to CLL B-cell proliferation, including BCL-2 (miRNA-15 and
2
messengers that further modulate cell-survival regulators. 35,63 Targeting miRNA-16), MCL-1 (miRNA-29), and TCL1 (miRNA-29 and miRNA-
the various kinases involved in the BCR pathway has resulted in sig- 181). 76–78 Recent studies have identified miRNA-150 as potentially the
nificant improvements in the therapeutic options for this disease. Early most abundantly expressed miRNA in patients with CLL and may be
results from studies done with BTK, PI3K, and SYK inhibitors have all involved in the regulation of BCR signaling and subsequent survival
shown excellent efficacy and tolerability, and these agents are currently signals. Multiple studies are currently underway to further define the
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being used in various combinations to improve disease outcomes. full impact of the role of miRNAs in the pathogenesis of CLL and to
BTK was initially characterized as a deficient kinase in patients develop strategies to modulate their expression and function for thera-
with X-linked agammaglobulinemia, a disease characterized by a severe peutic benefit.
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immunodeficient state. Specific mutations in BTK results in severe With regards to other cytogenetic abnormalities, trisomy 12 is
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impairments in B-cell development and humoral immunity. Activat- often found in patients with progressive or relapsed disease or Richter
ing mutations of BTK have not been identified in CLL or other can- transformation. Numerous genes are affected as a result of the trisomy
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cers. However, CLL B cells tend to have higher levels of BTK that can and B cells obtained from patients with this abnormality tend to have
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be induced through the BCR signaling pathway. Efficient targeting higher surface expression of CD19, CD20, CD38, and immunoglobu-
of BTK with the irreversible inhibitor ibrutinib results in significant lins when compared to patients without this abnormality. 80–82 Multiple
abrogation of downstream survival signaling transduced through this genetic alterations have also been described in patients with del 11q22.3,
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pathway and results in the inhibition of cell survival and proliferation. but most importantly, it may involve the loss of the ataxia-telangiectasia
Moreover, ibrutinib irreversibly targets interleukin (IL)-2–inducible mutated (ATM) gene, which normally activates p53 and results in either
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T-cell kinase (ITK) in T cells, thus potentiating T-helper type 1 (Th1)– apoptosis or cellular repair in response to cytotoxic stimuli. More-
driven immune responses and reversing tumor-induced T-cell anergy. 68 over, there is a decrease in the expression of miRNA-29 and miRNA-
Similar to BTK, both SYK and PI3K can be induced by both the 181, which are involved in the down regulation of the T-cell leukemia/
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autonomous and antigen-dependent BCR activation and result in lymphoma protein 1A (TCL1) oncogene. Patients with del 11q22.3
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providing the critical signals that result in leukemic cell survival and tend to have more aggressive disease with bulky lymphadenopathy ;
proliferation. 69,70 Similar to ibrutinib, the PI3K isoform delta inhibi- historically have had a worse prognosis with disease poorly responsive
tor idelalisib antagonizes internal and external survival signals to the to conventional nucleoside analogue-based therapy; and have specifi-
CLL cells and results in significant clinical response. Idelalisib is cur- cally required the addition of alkylating agents like cyclophosphamide
rently approved for the treatment of relapsed CLL. Similar results are to overcome the poor prognostic impact. 86,87
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observed with SYK inhibitors that are currently in early phase clinical The del 17p13.1 is present in less than 10 percent of patients with
trials. 72 CLL and frequently involves the deletion of the tumor protein p53
(TP53) gene that encodes the p53 protein which, as noted above, is
GENETICS OF CHRONIC LYMPHOCYTIC critical for cellular apoptosis or repair specifically in response to cyto-
toxic stimuli. Patients with this abnormality have rapidly progressive
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LEUKEMIA disease with significantly inferior survival outcomes and poor response
to therapy. This mutation also confers chemoresistance; consequently,
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Improved understanding of the genetics of CLL has resulted in signifi- responses to conventional chemotherapy-based regimens have been
cant improvements in our ability to determine the prognosis of this dismal. These patients also have higher risk of Richter transformation
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disease and to tailor therapy for our patients. Initial efforts to study to more aggressive lymphomas over the course of their disease. The
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the cytogenetic abnormalities in CLL were hindered by the inability inferior outcomes observed in patients with del 11q or del 17p appears
of the tumor cells to proliferate in vitro for standard metaphase anal- to persist in the era of treatment with kinase inhibitors, with patients
yses. Improvements in our ability to stimulate the CLL B cells in vitro experiencing a shorter progression-free interval, but are significantly
and the development of interphase fluorescent in situ hybridization better as compared to historic controls. 91,92
techniques (FISH) have significantly improved and refined the study Multiple other cytogenetic abnormalities have been reported from
of cytogenetic abnormalities in this disease. Using these methods, patients with CLL, including del 6q21, those involving the immuno-
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del 13q14 was identified as the most common abnormality in patients globulin heavy chain (IGH) locus on chromosome 14q32, and those
with CLL, being present in approximately 50 percent of all patients, fol- involving the BCL-2 gene located on chromosome 18q21. 93,94 These are
lowed by trisomy 12, which is present in approximately 15 to 20 percent generally associated with progressive, relapsed, and aggressive disease
of patients, and del 11q22.3, which is present in approximately 10 to and frequently observed in patients with an unmutated immunoglobu-
15 percent of patients. Other abnormalities that were identified in sig- lin heavy-chain variable region (IGHV). 93,95
nificant numbers include del 6q21 and del 17p13.1. These abnormalities Other recurring abnormalities in CLL involving SF3B1 (splicing
impart differential prognostic impact on disease outcomes. 74 factor 3B subunit 1), NOTCH1 (Notch homologue 1, translocation-
Functional studies have been performed to determine the associ- associated), MYD88 (myeloid differentiation primary response gene
ation of these cytogenetic abnormalities to disease physiology. Specifi- 88), XPO1 (gene encoding exportin-1), KLHL6 (Kelch-like protein-6),
cally, deletion in the long arm of chromosome 13 results in a loss of the and ERK1 (extracellular signal-regulated kinase 1) have been described
tumor-suppressor gene ARLTS1 with potential physiologic impact. using whole-exon and whole-genome sequencing with potential prog-
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Moreover, this region also includes genes encoding microRNA nostic impact. 96–98 With the advent of single nucleotide polymorphism
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(miRNA) including miRNA-15 and miRNA-16. These abundant and (SNP) arrays, comparative genomic hybridization techniques, and
evolutionarily conserved short, noncoding miRNA, that range in size determination of acquired copy number aberrations, more detailed
from 21 to 25 nucleotides, have the potential to regulate the expression studies can be performed assessing the mechanistic significance and
of a number of different genes at the posttranscriptional level signifi- impact of these genetic mutations on prognosis and customizing
cantly impacting cell signaling. They are also known to modulate the therapy.

Kaushansky_chapter 92_p1527-1552.indd 1529 9/18/15 10:46 AM