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1530 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1531

progressive disease. Conventional stimulated karyotype analysis and TABLE 92–1. Survival Outcomes and Time to First
interphase FISH cytogenetic study, to evaluate for abnormalities com-
monly seen in patients with CLL, should be performed on all patients Treatment Based on FISH Cytogenetics and IGHV Status
at the time of diagnosis and every time the disease changes character in Prognostic Median Sur- Median Time to
order to determine the extent of a clonal evolution. Patients with atypi- Variables vival (Months) First Treatment
cal presentations, especially those with absent or low CD23 expression 13q– (sole) 133 92 months
should have a negative FISH study for t(11;14) to exclude mantle cell Inter- Trisomy 12 114 33 months

lymphoma. Lymph node biopsy is not typically required for further phase FISH
establishing the diagnosis of CLL. Lymph nodes typically show architec- cytogenetics Normal 111 49 months
tural effacement by diffuse infiltration by cells of a similar morphology 11q– 79 13 months
as observed in the peripheral circulation. 17p– 32 9 months
When anemia is present from CLL, patients typically will have nor-
mocytic and normochromic anemia, often with thrombocytopenia and Unmutated 89 3.5 years
lymphocytosis. Patients with a macrocytic anemia or an isolated ane- IGHV muta- (≥98 percent)
mia should have a Coombs test, haptoglobin test, and reticulocyte count tional status Mutated >152 9.2 years
performed to rule out autoimmune hemolytic anemia. These patients (<98 percent)
should also be evaluated for vitamin B and folic acid deficiencies,
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and malabsorption or gastrointestinal bleeding from CLL involvement FISH, fluorescence in situ hybridization; IGHV, immunoglobulin
should be ruled out. heavy-chain variable region.
Patients with CLL will frequently have hypogammaglobulinemia
with decrease in the serum concentration of immunoglobulin (Ig) G,
IgA, and IgM. The degree of hypogammaglobulinemia correlates with
progressive disease and predisposes patients to recurrent sinopulmo- IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE
nary infections with encapsulated organisms. T-cell defects, which REGION MUTATION ANALYSIS
increase the risks of viral infections, have also been described; however, The assessment of IGHV somatic mutation by a polymerase chain
this is not routinely assessed at the time of initial presentation. A small reaction–based assay has been shown to be an extremely reliable and
percentage of patients also have monoclonal gammopathy with IgM or important prognostic tool for patients with CLL. Patients with less than
IgG or light-chain monoclonal paraproteinemia, which can be detected 2 percent homology in their nucleotide sequence as compared to con-
on serum protein electrophoresis and immunofixation. Excessively high sensus germline sequence are considered unmutated. Patients with a
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heavy-chain paraproteinemia can result in symptoms related to hyper- mutated IGHV, which is present in approximately 60 percent of patients
viscosity as seen in patients with Waldenström macroglobulinemia and with CLL, have a significantly prolonged treatment-free interval, lon-
should be managed as such. 108–110 The presence of a monoclonal para- ger remission durations, and overall survival (OS). These patients
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proteinemia and/or hypogammaglobulinemia may be related to inferior also have a very low incidence of clonal evolution or transformation to
survival outcomes in patients with advanced disease stage, but not nec- an aggressive histology. 114,118 The IGHV mutation status does not vary
essarily in patients with early stage disease. 111,112
over time and does serve as a reliable marker for predicting long-term
disease outcomes. The only known exception to the mutation rule
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PROGNOSTIC MARKERS currently is the presence of IGHV 3–21 somatic mutation, which may
confer an aggressive phenotype similar to leukemic cells from patients
CYTOGENETICS AND FLUORESCENCE IN SITU with unmutated IGHV at least in a subset of patients. 120,121
HYBRIDIZATION
All patients must undergo a comprehensive prognostic evaluation at ZETA-CHAIN–ASSOCIATED PROTEIN KINASE
the time of initial presentation. This allows the clinician to explain the
specific disease characteristic to the patient and also helps the patient OF 70 kDa AND ITS METHYLATION STATUS
with the emotional adjustment process that they have to go through Zeta-chain–associated protein kinase of 70 kDa (ZAP-70) is an intra-
when initially diagnosed with this disease. All patients should undergo cellular tyrosine kinase that is typically associated with T-cell develop-
conventional karyotype analysis and stimulated interphase FISH either ment and T-cell receptor (TCR) signaling. Expression of ZAP-70 in CLL
on blood or marrow aspirate. The minimum FISH panel should include B cells provides a survival advantage through intrinsic and extrinsic sig-
assessment for del 17p13, del 11q23, trisomy 12, and del 13q14, and for nals mediated through the BCR. Cytoplasmic assessment of ZAP-70
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t(11;14) in selected patients suspected of having mantle cell lymphoma. in CLL B cells by flow cytometry correlates strongly with IGHV muta-
Conventional stimulated karyotype analysis is helpful in identifying the tional status and clinical outcomes, with an expression of 20 percent
global structural abnormalities in chromosomes, especially of chromo- or more predictive of poor outcomes. The assessment of ZAP-70 by
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somes 14, 3, and 6, that cannot be routinely detected on FISH anal- flow cytometric testing has been plagued with several issues, including
ysis. Together, these assays have strong prognostic significance with lack of reproducibility and reliability of the reagents. Consequently, the
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regards to treatment-free and overall survival (Table 92–1). Patients National Comprehensive Cancer Network (NCCN) guidelines do not
with CLL acquire additional cytogenetic abnormalities, as detected by recommend the routine use of ZAP-70 as a prognostic marker outside
stimulated karyotyping and FISH analysis, with disease progression and of clinical trials. Given the stability of DNA and epigenetic modification
especially after chemotherapy. This “clonal evolution” is predominantly by methylation, investigators have also sought to assess ZAP-70 expres-
observed in patients with unmutated IGHV and portends poor survival sion by the absence of promoter methylation. Methylation analysis of
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and inferior response to therapy. We therefore recommend repeating select proximal 5′ regions of the ZAP-70 gene correlates very strongly
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the stimulated karyotyping and FISH studies prior to initiation of a new with expression of ZAP-70 and has been established as an important and
line of treatment. reliable prognostic marker with regards to predicting time to treatment

Kaushansky_chapter 92_p1527-1552.indd 1531 9/18/15 10:47 AM