Chronic Lymphocytic Leukemia

Mohammed Shanshal, MD, and

Rami Y. Haddad, MD, FACP
Chronic lymphocytic leukemia [chronic lymphoid leukemia (CLL)] is a
monoclonal disorder characterized by a progressive accumulation of
functionally incompetent lymphocytes. The most characteristic feature of
CLL is a peripheral blood absolute lymphocytosis (⬎5.0 ⫻ 109/L, but
usually ⬎15.0 ⫻ 109/L and sometimes ⬎100.0 ⫻ 109/L).
It is the most common form of leukemia (Table 1) found in adults in
Western countries, accounting for approximately 30% of all leukemias in
the USA.1 The proportion of cases diagnosed with the early stages of the
disease [Rai Stage 0 (Table 2)] has risen from 10% to 50%, probably
because of earlier diagnosis (routine automated blood counts). This
expansion is the result of prolonged cell survival, despite a varied cell
turnover.
The affected lymphocytes are of B-cell lineage in 95% of cases that
carry CD5, and the remaining cases involve T lymphocytes, representing
a distinct disorder.
Onset is insidious, and it is not unusual for CLL to be discovered
incidentally after a blood cell count is performed for another reason.
Enlarged lymph nodes are the most common presenting symptom, but
patients may present with a wide range of symptoms and signs.
Chemotherapy is not needed in CLL until patients become symptom-
atic or display evidence of rapid progression of disease. A variety of
chemotherapy regimens are used in CLL. These may include nucleo-
side analogues, alkylating agents, and biologics, often in combination.
Allogeneic stem cell transplantation is the only known curative
therapy.
Epidemiology
The incidence rates among men and women in the USA are approximately
6.75 and 3.65 cases per 100,000 populations per year, respectively.2
CLL is considered mainly a disease of elderly people, with a median age
at diagnosis of 70 years; however, it is not unusual to make this diagnosis

Dis Mon 2012;58:153-167

0011-5029/2012 $36.00 ⫹ 0
doi:10.1016/j.disamonth.2012.01.009

DM, April 2012 153

TABLE 1. General classification of leukemia
A.Acute
1. Myloid
2. Lymphoid
B. Chronic
Chronic myeloproliferative disorders
Chronic myelocytic leukaemia
Polycythemia vera
Myelofibrosis
Essential thrombocythemia
Lymphoid leukemias
Chronic lymphocytic leukaemia
Prolymphocytic leukaemia
Hairy cell leukaemia
Large granular lymphocytosis

TABLE 2. Rai staging system

Stage
Lymphocytosis Low Intermediate High
0 I, II III, IV
Lymphocytosis (⬎5 ⫻ 109/L) ⫹ ⫹ ⫹
Lymphadenopathy-splenomegaly ⫺ ⫺ ⫹ or ⫺
Thrombocytopenia (100 ⫻ 109/L) ⫺ ⫺ ⫹
Anemia (HB ⬍10 g/L) ⫺ ⫺ ⫹
Survival (yr) ⬎10 6-8 1-2

in younger individuals from 30 to 39 years of age.3 The incidence

increases rapidly with increasing age. It is estimated that 14,570 new
cases of CLL will be diagnosed in 2011, 8520 in males and 6050 in
females.4
By contrast, CLL is extremely rare in Asian countries (ie, China, Japan),
where it is estimated to comprise only 10% of all leukemias.

Gender
The male-to-female ratio is 2:1. There is little change with age, as the
male-to-female ratio is 2.1:1 for patients ⬍65 years old, compared with
1.9:1 for those ⱖ65 years old.

Age
The median age at diagnosis is 72 years, and 70% of patients are ⬎65
years of age at diagnosis. CLL is rarely seen in younger patients, with
⬍2% being younger than 45 at the time of diagnosis.
154 DM, April 2012
Race
In the American population, the incidence of CLL is similar in different
races. However, the incidence is much lower in Asia (Japan, Korea, and
China), Latin America, and Africa than in the USA and Western Europe.
Etiology
The etiology of CLL is unclear. However, some factors associated with
CLL have been identified.
Genetic Factors
There is a familial risk for CLL, with family members of patients with
CLL having a twofold to sevenfold higher risk of developing the disease.
CLL with a familial association tends to occur in younger individuals
with subsequent generations, perhaps because of increased screening.
Because CLL is an uncommon cancer, patients who have at least 1
relative with CLL are considered “familial” and others are considered
“sporadic.” In population-based samples, approximately 5% of patients
with CLL reported a family history of leukemia (reviewed in Houlston
et al4).5
Environmental Factors
There is no documented association of CLL with exposure to radiation,
alkylating agents, or known leukemogenic chemicals. However, exposure
to some chemicals used in agriculture may increase the risk of developing
CLL.
CLL shows substantial geographic variation worldwide. Rates show as
much as a 40-fold difference, the highest among whites in North America
and Europe and the lowest in Asians.6
Viral Infections
Associations between CLL and several viruses, including human T-cell
lymphotrophic viruses I and II (HTLV-I and HTLV-II) and Epstein–Barr
virus, have been suggested. However, no conclusive evidence of a causal
relationship exists. Adult T-cell leukemia/lymphoma, a T-cell disorder
that can resemble CLL, is caused by HTLV-I.
Monoclonal B Lymphocytosis
Recent studies suggest that over 4% of the population over 40 years of
age harbor a population of clonal B cells with the phenotype of CLL or
another B-cell malignancy, a condition now called monoclonal B-cell
lymphocytosis (MBL). These asymptomatic individuals have no clinical
DM, April 2012 155
evidence of disease and do not fulfill diagnostic criteria for CLL. All
cases of CLL appear to be preceded by MBL, but most patients with MBL
will not develop a hematologic malignancy.
In one study, 5.1% of patients over the age of 62 in the general
population had monoclonal CLL-phenotype B cells. These asymptomatic
individuals did not have lymphocytosis or clinical evidence of disease and
did not fulfill diagnostic criteria for CLL. Whether these individuals will
eventually develop diagnostic criteria or symptomatic disease is un-
known. CLL requiring treatment develops in subjects with CLL-pheno-
type MBL and with lymphocytosis at the rate of 1.1% per year.

Symptoms
Patients with CLL have a wide range of symptoms and physical and
laboratory abnormalities at the time of diagnosis. Most patients consult a
physician because they have noted painless swelling of lymph nodes,
often in the cervical area, which spontaneously wax and wane, but do not
altogether disappear.
Approximately 25% of patients feel entirely well with no symptoms
when a routine blood count reveals an absolute lymphocytosis, leading to
a diagnosis of CLL. Five to 10% of patients present with the typical “B”
symptoms of lymphoma, which include 1 or more of the following:

● Unintentional weight loss ⱖ10% of body weight within the previous 6

months.
● Fevers of ⬎100.5°F (⬎38°C) for ⱖ2 weeks without evidence of
infection.
● Drenching night sweats without evidence of infection.
● Extreme fatigue (ie, Eastern Cooperative Oncology Group perfor-
mance status 2 or worse; cannot work or unable to perform usual
activities)
● Occasionally, the presenting features are those of an acquired immu-
nodeficiency disorder, manifested by infections, autoimmune compli-
cations, such as hemolytic anemia, thrombocytopenia or pure red cell
aplasia, or exaggerated reactions to insect stings or bites (especially
mosquito).

Signs
Lymphadenopathy. Lymphadenopathy is common at the time of initial
diagnosis, and lymph node enlargement may be generalized or localized
and individual lymph nodes can vary greatly in size. The most commonly
affected sites are cervical, supraclavicular, and axillary. Characteristi-
156 DM, April 2012
cally, enlarged nodes in CLL are firm, rounded, discrete, nontender, and
freely mobile on palpation. Exceptions to these generalizations are
encountered, particularly when the nodes have grown rapidly.
Splenomegaly. The spleen is the second most frequently enlarged
lymphoid organ, as is the case with enlarged lymph nodes. An enlarged
spleen in CLL is usually painless and nontender to palpation, with a sharp
edge and a smooth firm surface.
Hepatomegaly. The liver is usually only mildly enlarged, ranging from
2 to 6 cm below the right costal margin, with a span of dullness to
percussion of about 10-16 cm. On palpation, the liver is usually nontender
and firm with a smooth surface.
Skin. Infiltration with CLL cells may occur in any organ, but, at the time
of diagnosis, the skin (leukemia cutis) is the most commonly involved
nonlymphoid organ. These lesions most commonly involve the face and
can manifest as macules, papules, plaques, nodules, ulcers, or blisters.7
Diagnosis is made based on biopsy of the involved skin.
Membranoproliferative Glomerulonephritis. Membranoproliferative
glomerulonephritis has occasionally been described in CLL and appears
to be a paraneoplastic phenomenon mediated by deposition and possibly
processing of cryoprecipitating or noncryoprecipitating M-components.8
Other Organ Involvement. Virtually any lymphoid tissue may be
enlarged at diagnosis, including Waldeyer’s ring in the pharynx. In
contrast to other lymphomas, gastrointestinal mucosal involvement is
rarely seen in CLL. Similarly, meningeal leukemia is unusual at the time
of initial presentation.

Laboratory Abnormalities
Peripheral Blood
The most noteworthy laboratory abnormality found in CLL is lympho-
cytosis with median values of 30-50 ⫻ 109/L, with more than 5000
B-lymphocytes/␮L. Lymphocytosis must persist for longer than 3
months. Clonality must be confirmed by flow cytometry. The presence of
a cytopenia caused by clonal bone marrow involvement establishes the
diagnosis of CLL regardless of the peripheral B-lymphocyte count.
Patients with fewer than 5000 B-lymphocytes/␮L with lymphadenopa-
thy and without cytopenias more likely will have small lymphocytic
lymphoma, although this diagnosis should be confirmed by lymph node
biopsy.
Patients with a clonal B-cell population less than 5000/␮L without
lymphadenopathy or organomegaly, cytopenia, or other disease-related
DM, April 2012 157
FIG 1. Peripheral smear in a patient with CLL, showing smudge cell (arrow). (Color version of
figure is available online.)

symptoms have MBL, and MBL will progress to CLL at a rate of 1% to

2% per year.9 In a recent study published in the New England Journal of
Medicine, 2228 subjects presenting with lymphocytosis (⬎4000 lympho-
cytes) were tested for the presence of MBL, progressive lymphocytosis
occurred in 51 (28%), progressive CLL developed in 28 (15%), and
chemotherapy was required in 13 (7%). During follow-up over a median
of 6.7 years, 34% of subjects (62 of 185) died, but only 4 of these deaths
were due to CLL. Age above 68 years and hemoglobin level below 12.5 g
per deciliter were the only independent prognostic factors for death.9
Microscopic examination of the peripheral blood smear (Fig 1) is
indicated to confirm lymphocytosis. It usually shows the presence of
smudge cells, depicted in the image in Fig 1, which are artifacts from
lymphocytes damaged during the slide preparation.
Smudge cells are the artifacts produced by the lymphocytes damaged
during the slide preparation.
Peripheral blood flow cytometry is the most valuable test to confirm a
diagnosis of CLL, by detecting the presence of circulating clonal
B-lymphocytes expressing CD5, CD19, and CD20.
The presence of CD23 help to differentiate CLL from mantle cell
lymphoma.
Consider obtaining serum quantitative immunoglobulin levels in pa-
tients developing repeated infections, as ⬎50% of patients with CLL
develop hypogammaglobulinemia, usually affecting immunoglobulin A
(IgA) first, followed by IgM and IgG. Monthly intravenous immunoglob-
ulin administration in patients with low levels of IgG (⬍500 mg) may be
beneficial in reducing the frequency of infectious episodes.
Another blood abnormality is the presence of elevated serum levels of
B2-microglobulin, which has been associated with a poor prognosis,
158 DM, April 2012
TABLE 3. NCI and International Workshop on CLL (IWCLLl) diagnostic criteria for CLL
Cells NCI IWCLL
Lymphocytes ⬎5 ⫻ 109/L ⫹ ⬎1 B-cell marker ⬎10 ⫻ 109/L B-cell
(CD19, CD20, CD23) ⫹ CD5, phenotype or
monoclonal bone marrow
involvement
Atypical cells (eg, ⬍55% Not stated
prolymphocytes)
Bone marrow lymphocytes ⬎30% ⬎30%

although the presence of paraproteinemia or elevated serum lactate

dehydrogenase indicates poor prognosis and (Richter’s) transformation to
diffuse large B-cell lymphoma, respectively.

Bone Marrow Aspiration and Biopsy

The bone marrow is usually hypercellular with more than 30% mature
lymphocytes (Table 3), but usually is not required, except in selected
cases, when the diagnosis is difficult to establish, or to assess other
complicating features, such as anemia and thrombocytopenia.

Other Tests
Liver/spleen ultrasonographic studies may demonstrate splenomegaly
in patients with CLL, but computerized tomography scanning of the
chest, abdomen, or pelvis is generally not required for staging purposes in
CLL. However, care should be taken to not miss lesions, such as
obstructive uropathy or airway obstruction that are caused by lymph node
compression on organs or internal structures.

Chromosomal and Molecular Findings

Chromosomal Abnormalities. Because of the low mitotic rate in CLL,
traditional karyotyping methods failed, whereas chromosomal evaluation
using fluorescence in situ hybridization can identify certain chromosomal
abnormalities of CLL with prognostic significance. Patients with a
deletion in the short arm of chromosome 17 [del(17p)] tend to have a
worse prognosis, as well as resistance to therapy with alkylating agents
and purine analogues.
The most common cytogenetic aberrations identified through conven-
tional karyotyping and fluorescence in situ hybridization are Deletion
13(q14),9 which is associated with a favorable prognosis (median survival
133 months). poor prognosis is associated with deletion of the TP53 gene
DM, April 2012 159
at 17p13 (median survival 32 months) and Deletion 11(q22)-23 (median
survival 79 months).10
Molecular Abnormalities. The identification that some patients with
CLL require immediate therapy and others live without need for treatment
for decades had led to considerable interest in the underlying molecular
mechanisms of this heterogeneity, but no single gene has been implicated
in the pathogenesis of CLL. Instead, several genetic abnormalities have
prognostic significance, for example, the deletion P53 gene (tumor
suppressor gene), which is located on the short arm of chromosome 17
and signifies an aggressive form of CLL, as this deletion confers
resistance to CLL treatment, including purines analogues.11
Other important molecular abnormalities seen in CLL include the
overexpression of bcl-2 (which function to inhibit apoptosis), located on
the long arm of chromosome 14. It is also the site encoding for the
immunoglobulin heavy-chain gene. Cells are frequently resistant to
chemotherapeutic drugs because of their enhanced bcl-2 protein levels
and low growth fraction. Clinical trials have examined the effectiveness
of bcl-2 antisense oligonucleotides in inducing bcl2 mRNA downregula-
tion and antitumor responses in various hematologic and solid tumors.12
Although the bcl-2 antisense approach in general is conceptually straight-
forward, it has not yet been validated in the clinical trials.
Staging of CLL
Two systems for staging CLL are now in use. The revised Rai (USA)
and Binet (Europe) staging systems are based on results of the physical
examination and blood tests.13
Revised Rai Staging System (USA)
Low Risk. Lymphocytosis, lymphocytes in blood ⬎15,000/␮L, and
⬎40% lymphocytes in the bone marrow are considered low risk.
Intermediate Risk. Lymphocytosis are considered low risk with en-
larged node(s) in any site, or splenomegaly or hepatomegaly or both.
High Risk. Lymphocytosis is considered low risk and intermediate risk
with disease-related anemia (hemoglobin level ⬍11.0 g/dL or hematocrit
⬍33%) or platelets ⬍100,000/␮L.
Binet Staging System (Europe)
Stage A. Hemoglobin ⱖ10 g/dL, platelets ⱖ100,000/mm3, and ⬍3
enlarged areas area considered Stage A.
Stage B. Hemoglobin ⱖ10 g/dL, platelets ⱖ100,000/mm3, and ⱖ3
enlarged areas are considered Stage B.
160 DM, April 2012
 Stage C. Hemoglobin ⬍10 g/dL, platelets ⬍100,000/mm3, and any
number of enlarged areas area considered Stage C.
Other Prognostic Factors
Although the stage of the disease remains the major prognostic factor,
other factors also have prognostic implications and include lymphocytes
doubling time, serum levels of CD38 and B2M, and bone marrow
infiltration by lymphocytes.
Somatic hypermutation, which is the process that introduces mutation in
the variable segments of the immunoglobulin heavy chain gene (IgVH),
has also emerged as an important prognostic factor for CLL,14 and CLL
with an IgVH gene with ⬍98% homology to germ line is considered
mutated. Those with ⬎98% homology are considered unmutated.
The lack of IgVH gene mutations was associated with advanced and
progressive disease, as well as a worsened survival, regardless of the Binet
stage of the patient.15 However, determining the mutational status of the
IgVH gene is time-consuming, expensive, and laborious and requires certain
laboratory equipment. Therefore, several alternative biomarkers have been
explored as potential surrogate markers for patient prognosis.
The expression of ␨-association protein is 70 kDa (ZAP-70), which is a
gene that is involved in T-cell receptor signaling. Remarkably, ZAP-70
expression could be used to classify patients with IgVH gene mutations vs
those without mutations with 100% accuracy.16 Flow cytometric analysis
of ZAP-70 was correlated with IgVH gene mutation status. Patients with
20% or more ZAP-70-positive cells had a worse prognosis compared with
those having less than 20% ZAP-70-positive cells.17 Further, determina-
tion of the IgVH gene mutation status or CD38 expression level did not
add any additional prognostic value in cases of ZAP-70-positive expres-
sion. For patients with ZAP-70-negative expression, who had improved
prognosis, IgVH gene mutation status and CD38 expression helped to
classify patients further into low- or intermediate-risk groups. Despite its
obvious value for determining CLL patient prognosis, the main drawback
to the use of the ZAP-70 biomarker is the lack of a standardized method
to determine ZAP-70 expression.
Treatment of CLL
Approach Considerations.
Observation. This includes Binet Stages A and B without symptoms,
and Rai Stages 0, I, and II without symptoms.
The standard treatment of patients with early disease is a watch-and-
wait strategy with controls of blood cell counts and clinical examinations
DM, April 2012 161
every 3-6 months [I, A]. Patients with active disease as defined by rapid
disease progression (eg, lymphocyte doubling time ⬍6 months) should be
treated as patients with advanced disease.
Patients with CLL do not need to be treated with chemotherapy until
they become symptomatic or display evidence of rapid progression of
disease, as characterized by the following:
● Weight loss of more than 10% over 6 months
● Extreme fatigue
● Fever related to leukemia for longer than 2 weeks
● Night sweats for longer than 1 month
● Progressive marrow failure (anemia or thrombocytopenia)
● Autoimmune anemia or thrombocytopenia not responding to glucocor-
ticoids
● Progressive or symptomatic splenomegaly
● Massive or symptomatic lymphadenopathy
● Progressive lymphocytosis, as defined by an increase of ⬎50% in 2
months or a doubling time of less than 6 months
Single Agent Chemotherapy. Previously, the initial therapy for CLL was
chlorambucil with or without prednisone. However, fludarabine had
largely replaced chlorambucil in the USA. Although chlorambucil is a
forgotten drug in the USA, likely primarily because of its low cost, it is
still used as first-line treatment in elderly, fragile populations in Europe,
which make up the bulk of true CLL cases. In the CLL5 study comparing
fludarabine with chlorambucil (median age 70 years), there was a
significantly higher response rate with fludarabine, and progression-free
survival (PFS) was similar (19 vs 18 months). Overall survival was not
significantly affected either, although it was 46 months with fludarabine
compared with 64 months for chlorambucil.18
Bendamustine (Treanda; Cephalon, Frazer, PA) was recently approved
by the US Food and Drug Administration (FDA), an alkylating agent that
resulted in a superior over all response rate (68% vs 31%) and complete
response rate (31% vs 2%) compared to chlorambucil in a randomized,
controlled trial of 319 patients with previously untreated CLL requiring
therapy,19 Based on these results, Bendamustine was approved by the
FDA for use in previously untreated CLL in March 2008, and clinical
trials are ongoing to assess where this agent best fits into the therapy of
CLL. In particular, the German CLL Study Group is currently conducting
a randomized trial comparing fludarabine and cyclophosphamide with
rituximab (FCR) to Bendamustine plus rituximab in previously untreated
CLL patients.
162 DM, April 2012
 Lenalidomide is an immunomodulatory drug currently approved for use
in multiple myeloma and myelodysplastic syndrome with deletion of
chromosome 5q. Studies have used this medication in the treatment of
patients with relapsed and refractory CLL.20 Response rates of 47%-38%
with complete response rates of 9% and elimination of minimal residual
disease have also been reported.
Alemtuzumab is a monoclonal antibody directed at CD52 that is
approved for use in CLL as both a first-line agent and for salvage in
patients with fludarabine-refractory disease. Alemtuzumab has been
shown to be effective in treating CLL with p53 mutations [Del
(17p13.1)]. This is in contrast to rituximab, which is not effective in p53
mutation– bearing CLL. Although very effective in clearing the bone
marrow of disease, alemtuzumab has shown only limited activity in
clearing bulky lymphadenopathy.
A significant complication of therapy with alemtuzumab is that it
significantly increases the risk for opportunistic infections in particular,
reactivation of cytomegalovirus, and pneumocystis infections.
Antiviral prophylaxis and prophylactic antibiotics for Pneumocystis
jiroveci are recommended for use in patients receiving alemtuzumab
during and for 2-4 months after treatment, or until their CD4 count is
⬎250 ⫻ 109 cells. Cytomegalovirus (CMV) polymerase chain reaction is
also recommended to monitor for CMV reactivation. If CMV is detected,
alemtuzumab should be discontinued, and appropriate treatment initiated
until CMV becomes undetectable.
Ofatumumab (Arzerra, Genmab A/S, Copenhagen, Denmark) is a new
anti-CD20 monoclonal fully humanized antibody. It has been approved
by the FDA for the treatment of patients with CLL refractory to
fludarabine and alemtuzumab.
Ofatumumab was evaluated in a study of 138 patients with CLL. The
trial incorporated 2 parallel arms: patients refractory to fludarabine and
alemtuzumab (Campath, Genzyme; Fabrazyme [Genzyme Corp, FA-ref
arm]) and patients with bulky disease refractory to fludarabine and not
clinically suitable for alemtuzumab therapy (BF-ref arm). The observed
objective response rate was 58% for the former group and 47% for the
latter group. In the FA-ref arm, the median PFS was 5.7 months, and the
median overall survival was 13.7 months. In the BF-ref arm, the median
PFS was 5.9 months, and the median overall survival was 15.4
months21,22 based on this trial. Ofatumumab was approved by the FDA in
October 2009 for the treatment of CLL refractory to fludarabine and
alemtuzumab. Other monoclonal antibodies in CLL include hLL1, epratu-
zumab, and lumiliximab.
DM, April 2012 163
 Combination Chemotherapy. The following combinations have been
used for chemotherapy:
Fludarabine, cyclophosphamide, and rituximab (FCR)23
Pentostatin, cyclophosphamide, and rituximab (PCR)
Fludarabine, cyclophosphamide, and mitoxantrone (FCM)
Cyclophosphamide, vincristine, and prednisone (CVP)
Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)
Various drug combinations have been used in CLL; the most frequently
used is the combination of FCR, which has shown clinical response rates
of 76% in trials, with a PFS of about 40 months. This result is better than
those seen with either fludarabine or FC in salvage therapy for patients
with previously treated CLL.24 This regimen is considered now by several
experts in the field to be the standard of care in young (⬍70 years) robust
patients. Bendamustine/rituximab is the alternative preferred choice in
practice, particularly in those older than 70 years or with multiple
comorbid conditions.
Lumiliximab is an anti-CD23 antibody that has been investigated in
Phase I and II clinical trials for the treatment of chronic lymphocytic
leukemia and showed promising results when combined with the FCR
regimen, especially in patients with refractory CLL.25
Other commonly used combination therapy includes cyclophosph-
amide, Oncovin, and prednisone (COP) and the CHOP regimens, with a
response rate between 40% and 85%.
Stem Cell Transplantation. Hematopoietic stem cell transplantation is
not a suitable treatment option for most patients with CLL. The disease
usually follows an indolent course; many patients never require any
therapy and most patients are too elderly to undergo this procedure. Thus,
the optimal timing of transplantation is still being investigated; however,
it is known that a delay of transplantation until development of refractory
disease results in worse outcomes. High-risk patients can be identified
using several clinical and biological features and younger patients are
suitable candidates for enrollment in clinical trials evaluating the role of
stem cell transplant in CLL.
The addition of alemtuzumab to nonmyeloablative conditioning regi-
mens for allogeneic hematopoietic stem cell transplantation appears to
decrease the incidence of graft-versus-host disease, but it may be
associated with increased rates of cytomegalovirus reactivation.
Splenectomy. Splenectomy may be beneficial for patients with refrac-
tory splenomegaly, and pancytopenia is a common problem in patients
with advanced CLL. Rarely, these patients require splenectomy. Substan-
164 DM, April 2012
tial improvements in hemoglobin and platelet counts are observed in up
to 90% of patients undergoing splenectomy. All patients with CLL who
are to undergo splenectomy should be immunized at least 1 week in
advance against the pneumococcus, Haemophilus influenza, and Neisse-
ria meningitidis.
Conclusions
CLL is a chronic lymphoproliferative disorder (lymphoid neoplasm)
characterized by a progressive accumulation of functionally incompetent
lymphocytes, which are monoclonal in origin. The disorder is considered
identical (ie, 1 disease at different stages) to the mature B-cell neoplasm
and small lymphocytic lymphoma.
CLL is the most common leukemia in Western countries, accounting for
approximately 30% of all leukemias in the USA. It has a male predom-
inance and is more common in Caucasians. The median age at diagnosis
is 70 years. There are no clearly discernible occupational or environmen-
tal risk factors.
Most patients present with painless swelling of lymph nodes, often in
the cervical area, which spontaneously wax and wane, but do not
altogether disappear. Approximately 25% of patients are asymptomatic at
diagnosis and only come to the physician’s attention based on abnormal-
ities found on routine blood counts. Less common presentations include
constitutional “B” symptoms of lymphoma, symptoms related to an
acquired immunodeficiency, or autoimmune complications.
Lymphadenopathy, splenomegaly, and hepatomegaly are the most
common findings on physical examination at the time of diagnosis. CLL
cells may infiltrate and disrupt the function of any organ. At the time of
diagnosis, the skin (leukemia cutis) is the most commonly involved
nonlymphoid organ. Gastrointestinal mucosal involvement and meningeal
leukemia are rare. Membranoproliferative glomerulonephritis is seen on
occasion.
Most patients with CLL have a prominent lymphocytosis in the
peripheral blood and bone marrow at diagnosis. Neutropenia, anemia, and
thrombocytopenia may also be observed at the time of initial diagnosis
and are usually of relatively mild degree. These can be related to
autoimmune hemolytic anemia, pure red cell aplasia, autoimmune throm-
bocytopenia, or agranulocytosis.

REFERENCES
1. Elter T, Hallek M, Engert A. Fludarabine in chronic lymphocytic leukaemia. Exp
Opin Pharmacother 2006;7(12):1641-51.
DM, April 2012 165
 2. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States
by subtype and demographic characteristics, 1997-2002. Cancer Causes Control
2008;19(4):379-90.
3. Hernández JA, Land KJ, McKenna RW. Leukemias, myeloma, and other lympho-
reticular neoplasms. Cancer 1995;75(Suppl 1):381-94.
4. Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of
eliminating socioeconomic and racial disparities on premature cancer deaths. CA
Cancer J Clin 2011;61:212-36.
5. Houlston RS, Sellick G, Yuille M, et al. Causation of chronic lymphocytic
leukemia—insights from familial disease. Leuk Res 2003;27:871-6.
6. Linet MS, Devesa SS, Morgan GJ. The leukemias. In: Schottenfeld D, Fraumeni Jr,
eds. JF Cancer Epidemiology and Prevention (3rd ed). New York: Oxford
University Press, 2006. p. 841-71.
7. Agnew KL, Ruchlemer R, Catovsky D, et al. Cutaneous findings in chronic
lymphocytic leukaemia. Br J Dermatol 2004;150(6):1129.
8. Moulin B, Ronco PM, Mougenot B, et al. Kidney glomerulonephritis in chronic
lymphocytic leukemia and related B-cell lymphomas. Kidney Int 1992;
42(1):127-35.
9. Rawstron AC, Bennett FL, O’Connor SJ, et al. Monoclonal B-cell lymphocytosis
and chronic lymphocytic leukemia. N Engl J Med 2008;359:575-83.
10. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in
chronic lymphocytic leukemia. N Engl J Med 2000;343:1910-6.
11. Zenz T, Benner A, Döhner H, et al. Chronic lymphocytic leukemia and treatment
resistance in cancer: the role of the p53 pathway. Cell Cycle 2008;7:3810-4.
12. Morris MJ, Tong WP, Cordon-Cardo C, et al. Phase I trial of BCL-2 antisense
oligonucleotide (G3139) administered by continuous intravenous infusion in
patients with advanced cancer. Clin Cancer Res 2002(8):679-83.
13. NCCN clinical practice guidelines in oncology: non-Hodgkin’s lymphoma. Vol. 2.
2011; Accessed March 28, 2011. Available at http://www.nccn.org/
professionals/physician_gls/pdf/nhl.pdf.
14. Montillo M, Hamblin T, Hallek M, et al. Chronic lymphocytic leukemia: novel
prognostic factors and their relevance for risk-adapted therapeutic strategies.
Haematologica 2005;90:391-9.
15. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes are associated
with a more aggressive form of chronic lymphocytic leukemia. Blood
1999;94:1848-54.
16. Rosenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene expression
phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic
leukemia. J Exp Med 2001;194:1639-47.
17. Rassenti LZ, Jain S, Keating MJ, et al. Relative value of ZAP-70, CD38, and
immunoglobulin mutation status in predicting aggressive disease in chronic
lymphocytic leukemia. Blood 2008;112:1923-30.
18. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine
compared with chlorambucil does not result in a major benefit for elderly patients
with advanced chronic lymphocytic leukemia. Blood 2009;114(16):3382-91.
19. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of
Bendamustine compared with chlorambucil in previously untreated patients with
chronic lymphocytic leukemia. J Clin Oncol 2009;27:4378-84.
166 DM, April 2012
20. Molica S. Immunomodulatory drugs in chronic lymphocytic leukemia: a new
treatment paradigm. Leuk Lymphoma 2007;48(5):866-9.
21. Lemery SJ, Zhang J, Rothmann MD, et al. U.S. Food and Drug Administration
approval: ofatumumab for the treatment of patients with chronic lymphocytic
leukemia refractory to fludarabine and alemtuzumab. Clin Cancer Res 2010;
16(17):4331-8.
22. Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20
immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin
Oncol 2010;28:1749-55.
23. Klepfish A, Gilles L, Ioannis K, et al. Enhancing the action of rituximab in chronic
lymphocytic leukemia by adding fresh frozen plasma: complement/rituximab
interactions and clinical results in refractory CLL. Ann NY Acad Sci 2009;
1173:865-73.
24. Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and
cyclophosphamide prolongs progression-free survival compared with fludarabine
and cyclophosphamide alone in previously treated chronic lymphocytic leukemia.
J Clin Oncol 2010;28(10):1756-65.
25. Byrd JC, et al. Chronic lymphocytic leukemia cyclophosphamide, and rituximab in
patients with relapsed or refractory phase 1/2 study of lumiliximab combined with
fludarabine. Blood J 2010;115:489-95.

DM, April 2012 167