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1532 Part XI: Malignant Lymphoid Diseases Chapter 92: Chronic Lymphocytic Leukemia 1533

and OS. 125,126 This assay can be done by pyrosequencing with significant TABLE 92–2. Outcomes of Selected Prognostic Factors
reproducibility among different laboratories. 126
Unfavorable
Favorable Outcome Outcome
CD38 EXPRESSION Lactate Low or normal Elevated
CD38 is a 45-kDa transmembrane glycoprotein that can be detected dehydrogenase
on the surface of CLL B cells by flow cytometry; a level of expression Lymphocyte >12 months ≤12 months
greater than 30 percent correlates strongly with progression-free sur- doubling time
vival (PFS). Newer reports, however, suggest that an even lower level
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of CD38 expression might also have a prognostic impact. 127,128 CD38 Thymidine kinase Low or normal Elevated
appears to be involved in cellular metabolism by synthesizing cyclic activity
adenosine diphosphate (cADP)-ribose from nicotinic acid adenine β -microglobulin Low or normal Elevated
2
(NAD), and its activity and expression correlates with proliferation of Soluble CD23 levels Low or normal Elevated
129
the lymphocytes and progressive disease as demonstrated by their high
Ki-67 proliferation index. CD38 expression also changes with disease CD38 expression <30 percent >30 percent
130
progression and the assessment of the extent of expression of CD38 is Interphase FISH Normal 11q–
based on nonstandardized, subjective parameters. 131 cytogenetics Trisomy 12 17p–
13q– (sole)
CD49d EXPRESSION IGHV mutational Mutated Unmutated

CD49d can also be used as a reliable predictive marker. CD49d is a status (<98 percent) (≥98 percent)
surface subunit of the integrin heterodimer that is involved in pro- CD49d expression <30 percent >30 percent
moting survival of the CLL cells through growth signals derived from
the microenvironment. 132,133 Patients with 30 percent or greater cells FISH, fluorescence in situ hybridization; IGHV, immunoglobulin
expressing CD49d by flow cytometry are considered to be positive and heavy-chain variable region.
constitute a group of patients with an aggressive disease course and infe-
rior survival. 134
STAGING FOR CHRONIC LYMPHOCYTIC
OTHER PROGNOSTIC MARKERS

Serum lactate dehydrogenase (LDH) and β -microglobulin are readily LEUKEMIA
2
available, validated markers of disease aggressiveness and prognosis. The Rai and Binet staging systems have been used for a long time
152
153
Specifically, β -microglobulin is an independent prognostic marker for patients with CLL (Tables 92–3 and 92–4). These easy-to-use staging
2
for remission duration, PFS, and OS, and a higher level is observed in systems are based on assessment of disease burden as determined by
patients with advanced and extensive disease. 135–137 Elevated LDH is lymphadenopathy and splenomegaly demonstrated on physical exami-
associated with more-aggressive disease and with Richter syndrome. nation and the presence of cytopenias. Further modifications and devel-
Lymphocyte doubling time could also be used as a tool to determine opment of the Binet system established low-risk (stage 0: lymphocytosis
the prognosis of CLL. Patients with a lymphocyte doubling time of only), intermediate-risk (stages 1–2: lymphocytosis with lymphadenop-
12 months or less have worse OS and treatment-free survival. Other athy and hepatosplenomegaly), and high-risk groups of patients with
138
reasons for transient elevation in lymphocyte count should be ruled out CLL (stages 3–4: lymphocytosis with anemia and thrombocytopenia).
153
before making the determination of lymphocyte doubling time. Thy- These classification systems provided an estimate of median OS of 150,
midine kinase is an important intracellular enzyme; the soluble form 90, and 19 months, respectively, and helped classify patients for subse-
can be detected in patients with CLL and predicts for advanced stage quent therapeutic intervention. The staging systems still remain rele-
and progressive disease. However, the assay is not widely available and vant and complementary to molecular testing in the modern era. 154
the test is rarely used in routine clinic care. 139–141 Over the years, vari- Marrow aspirate and biopsy is not routinely required for the initial
ous other serum proteins have been found to be associated with various diagnosis and management of the patient with CLL. Marrow biopsy is
measures of disease outcomes, including soluble factors like CD23, especially helpful in determining the etiology of thrombocytopenia and
142
CD44, vascular cell adhesion molecule (VCAM)-1, CD27, and anemia, which can frequently be related to concomitant autoimmune
144
144
143
matrix metalloproteinase (MMP)-9, IL-6, and IL-8. However, processes. It may also be helpful in determining the extent of involve-
145
146
147
none of these is routinely used for clinical decision making (Table 92–2). ment by large prolymphocytes and in establishing the diagnosis of pro-
Various miRNAs have also been validated as useful prognostic lymphocytic leukemia. A diffuse pattern of involvement of the biopsy
markers. miRNAs are noncoding RNAs that are 19 to 25 nucleotides in specimen by characteristic small lymphocytes is also associated with a
length and modulate mRNA translation and synthesis of various pro- worse prognosis than interstitial or nodular involvement. 106,155 Ideally,
teins. miRNA-15a and miRNA-16–1 were the first ones to be identified a marrow biopsy is performed at the start of therapy to document the
as underexpressed in CLL patient B cells. Genes for these miRNAs are disease extent and to detect any atypical features.
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located in the deleted region of chromosome 13q14 and modulate the Computed tomography (CT) scans are generally not required for
expression of the antiapoptotic bcl-2 protein, which is overexpressed the routine initial evaluation of patients with CLL and conventional
in patients with CLL and other B-cell lymphoproliferative disorders. staging systems rely on physical examination findings. Similarly, rou-
148
Similarly, miRNA-34c is involved in patients with del 11q23 and regu- tine CT scans for the serial evaluation of disease extent have no role
lates the expression of ZAP-70 and other proteins involved in the TP53 in patients with CLL. CT scans should be performed in patients with
pathway. Using mass array methods, miRNA profiles have also been symptomatic disease and prior to starting therapy. Similarly, a positron
149
found to be predictive for disease progression, fludarabine resistance, emission tomography (PET) scan has no role in the routine manage-
and clinical outcomes. 150,151 ment of patients with CLL. CLL lymph nodes are fluorodeoxyglucose

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