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Chronic lymphocytic leukemia

Vicki A. Morrison and Grzegorz S. Nowakowski

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CHAPTER

22
Chronic lymphocytic leukemia
Vicki A. Morrison and Grzegorz S. Nowakowski
)NTRODUCTION 0ROGNOSTICFACTORS /THERRELATEDLYMPHOPROLIFERATIVE
#LINICALPRESENTATION 4HERAPY DISORDERS
#LINICALANDLABORATORYFEATURES #OMPLICATIONSOF#,,
Introduction
Incidence, epidemiology, and demographics
Chronic lymphocytic leukemia (CLL) is one the most preva-
lent lymphoid malignancies. The disease is identical to small
lymphocytic lymphoma (SLL), an indolent B-cell non-
Hodgkin lymphoma. The incidence of CLL in the United
States are 6.75 and 3.65 cases per 100,000 population per year
in males and females respectively, resulting in a male to female
ratio of 1.7:1. The incidence of the disease shows significant
geographic differences. The disease is considerably less com-
mon in the approximately Far East than in Western countries.
Genetic and environmental factors may play a role in geo-
graphic differences, since the incidence in the Asian popula-
tion in the United States appears to be lower as well. CLL
incidence is higher among Caucasian than African Americans
and Asians and Pacific Islanders. There are no clearly identifi-
able environmental factors known to predispose to CLL.
The incidence of CLL increases with age, with a median
age at diagnosis of 70 years. The disease rarely is diagnosed in
people <30 years of age. Although the disease in younger and
elderly patients is phenotypically indistinguishable, age may
have a significant impact on selection of therapy (see the sec-
tion on therapy).
Familial CLL
Approximately 5%–10% of CLL patients have a family history of
CLL and other lymphoid malignancies. First-degree family
Conflict-of-interest disclosure: Dr. Morrison: SPEAKERS BUREAU
!MGEN MEMBERSHIP ON BOARD OF DIRECTORS OR ADVISORY COMMITTEE
"IBLIOGRAPHY
members of patients with CLL are at increased risk of CLL,
monoclonal B-cell lymphocytosis, and other lymphoid malig-
nancies. It appears that familial CLL tends to present at a younger
age, with a higher proportion of affected females than in the gen-
eral population. Familial CLL is phenotypically and biologi-
cally indistinguishable from sporadic CLL. Currently, there are
no known genetic factors predisposing to CLL. Screening of fam-
ily members outside of clinical studies is not recommended.
+EYPOINTS
s #,,ISMORECOMMONIN7ESTERNCOUNTRIES
s 4HEINCIDENCEOF#,,INCREASESWITHAGE
s #,,CANBEAFAMILIALDISEASE
Clinical presentation
Diagnosis
CLL is identical to SLL, and these two entities represent oppo-
site ends of the spectrum of the disease. Although patients
with CLL present with lymphocytosis, sometimes extreme,
patients with SLL present with predominantly nodal or extra-
nodal disease without or with minimal blood involvement
(<5,000 monoclonal B-cells/µL [5 × 109/L], see also the sec-
tion International Workshop on CLL Criteria for Diagnosis).
Diagnosis of CLL can be established based on a review of
peripheral blood and peripheral blood flow cytometry. No
single genetic abnormality or molecular marker would be
specific for a diagnosis of CLL, although recurrent genetic
alterations can be seen and have prognostic value (see also the
#ELGENE-ERCKDr. NowakowskiDECLARESNOCOMPETINGlNANCIALINTEREST
Off-label drug use: Dr. Nowakowski WILL DISCUSS LENALIDOMIDE section Differential Diagnosis: Cytogenetic, Immunopheno-
IBRUTINIBEVEROLIMUSmAVOPIRIDOLAND'3 typic, and Molecular Aspects). Peripheral blood smears show
| 579

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 | Chronic lymphocytic leukemia
a population of morphologically mature-appearing small
lymphocytes with often prominent fragile or “smudge” cells
(Figure 22-1). Peripheral blood flow cytometry demonstrates
monoclonal population of B-cells with a characteristic
immunophenotype: low levels of surface immunoglobulin,
either κ- or λ-light chains; expression of CD19, CD20, and
CD23; and aberrant expression of CD5. CD10 is usually neg-
ative (see also the section Differential Diagnosis: Cytogenetic,
Immunophenotypic, and Molecular Aspects).
Bone marrow biopsy or lymph node biopsy is not required
to establish the diagnosis, as CLL diagnosis can be estab-
lished solely based on peripheral blood flow cytometry and
blood smear. If a lymph node biopsy is performed in CLL
patients, it shows findings consistent with SLL—that is, pre-
dominantly composed of small lymphocytes with condensed
chromatin and round nuclei. Larger lymphoid cells (prolym-
phocytes) are present and clustered in pseudofollicles often
referred to as proliferation centers, which is a characteristic
feature of SLL/CLL.
International Workshop on CLL criteria
for diagnosis
Because there is a continuum of the disease between SLL and
CLL, for classification purposes, the International Workshop
on CLL developed guidelines on the diagnosis and treatment
of CLL and established criteria for CLL diagnosis. Two of the
following are required:
s Absolute B-cell count in the peripheral blood ≥5,000/µL
(5 × 109/L) for at least 3 months, with a preponderant
population of morphologically mature-appearing small
ASH-SAP_5E-12-1201-022.indd 580
lymphocytes. Because the definition is based on absolute
B-cell count, not absolute lymphocyte count, flow cytom-
etry assessment of B-cell number is required.
s Demonstration of clonality of the circulating B-cell by
flow cytometry with a characteristic phenotype: low level
of surface immunoglobulin, either κ- or λ-light chain
expression, CD5+, CD19+, CD20+(dim), CD79b+(dim).
Patients with a monoclonal B-cell population <5,000/µL
(5 × 109/L) and without evidence of lymphadenopathy or
extranodal involvement are characterized as patients with
monoclonal B-cell lymphocytosis (MBL, see also the section
Monoclonal B-cell Lymphocytosis). Patients with lymphade-
nopathy or extranodal involvement histologically proven to
be consistent with SLL, with an absolute peripheral B-cell
count that is <5,000/µL (5 × 109/L) are given the diagnosis of
SLL rather than CLL (Table 22-1).
The cutoff of 5,000 B-cells in the current definition is arbi-
trary, and there is controversy regarding the ideal cutoff and
its clinical significance. In clinical practice, many patients
present with a high number of lymphocytes at diagnosis,
which facilitates a diagnosis of CLL.
Table 22-1 Classification of CLL, SLL, and MBL.
Lymphadenopathy/extranodal
Diagnosis B-cell count involvement
CLL ≥5,000 +/−
SLL <5,000 +
MBL <5,000 −
CLL = chronic lymphocytic leukemia; SLL = small lymphocytic
lymphoma; MBL = monoclonal B-cell lymphocytosis.
Figure 22-1 Peripheral blood smear of patient with CLL.
Increased number of mature small to medium
lymphocytes can be seen with presence of fragile or
smudge cells. Although smudge cells are not
pathognomonic for CLL, presence of ruptures cells is often
a prominent feature, and the high number of smudge cells
has been associated with improved prognosis.
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Differential diagnosis: cytogenetic,
immunophenotypic, and molecular aspects
With the use of interphase fluorescent in situ hybridization
(FISH) techniques preferentially performed on peripheral
blood samples, >80% of CLL patients will be found to have a
chromosomal abnormality. The most common aberrations
are deletion 13q14 (55% of cases), deletion 11q22-23 (18%),
trisomy 12 (16%), and deletion 17p13 (7%). Other defects
less commonly found (<10% of cases) include deletion 6q,
total or partial trisomy 3, and 14q32 translocation. The inci-
dence of these chromosomal defects increases with advanc-
ing disease stage. In addition, new defects may be acquired in
clonal evolution of the disease process. More than a decade
ago, a prognostic model for disease progression and survival
based on cytogenetic parameters was developed. Patients
with 13q deletion as the sole cytogenetic abnormality were
found to have the most favorable prognosis, followed by
those with no defects detected by FISH, trisomy 12, and 11q
deletion; those patients with 17p deletion had the worst
prognosis. Associated genes involved with these defects
include TP53 (deletion 17p13), ataxia telangiectasia mutated
(ATM) gene (deletion 11q22-23), and the micro-RNA genes
miR15a and miR16-1 (two micro-RNAs) (deletion 13q14).
Characterization of the CLL immunophenotype by
peripheral blood flow cytometry is used to establish the diag-
nosis and to differentiate the disease process from other
B-cell lymphoproliferative disorders (Table 22-2). CLL cells
generally coexpress CD19, a pan B-cell marker, CD20 (with
dim expression), CD23, and CD5 (a T-cell marker), and they
typically have dim light chain and CD79b expression. CD22
is variably expressed. The low affinity anti-CD20 antibody
FMC7 is usually negative, as are CD10, CD103, and cyclin
D1. Surface immunoglobulin expression (generally immu-
noglobulin M [IgM], or IgM plus immunoglobulin D [IgD],
either κ or λ) is dim. In contrast, mantle cell lymphoma cells
usually have higher levels of expression of CD20 (FMC7 pos-
itive) and light chains, and do not express CD23. Surface
immunoglobulin is expressed, and CD23 expression is vari-
able, in marginal zone lymphoma, in contrast to dim-surface
immunoglobulin and consistent with CD23 expression in
CLL cells.
Table 22-2 Chronic B-cell
lymphoproliferative disorders:
prototypic immunophenotype. Chronic lymphocytic leukemia
Lymphoplasmacytic lymphoma
Mantle cell lymphoma
Marginal zone: Nodal/MALT lymphoma
Splenic marginal zone lymphoma
Follicular lymphoma
Hairy cell leukemia
ASH-SAP_5E-12-1201-022.indd 581
Clinical presentation | 
Data regarding the molecular disease aspects are being
reported increasingly. Patients with a somatically hypermu-
tated immunoglobulin variable heavy chain (IGVH) gene
(55%-65% of cases) usually have a more indolent disease
and a more favorable prognosis than those patients with
unmutated IGVH genes. Deletions in 17p are associated with
the loss of one allele of p53, conferring a poor prognosis.
Bcl-2 protein, which suppresses apoptosis and is associated
with hypomethylation of the promoter region of the Bcl-2
gene, is found in 85% of cases. CD38 expression as well as
ZAP-70 expression may be detected by flow cytometric tech-
niques and may be utilized in combination with IGVH gene
mutational status to predict disease prognosis. Molecules
such as ang-2, which are involved in angiogenesis, also are
being examined with regard to prognostic impact.
Monoclonal B-cell lymphocytosis
MBL is defined as a monoclonal B-cell population that does
not exceed 5,000/µL (5 × 109/L) in a patient who does not
have lymphadenopathy, organomegaly, cytopenias, or dis-
ease-related symptoms. Per definition, MBL requires flow
cytomery to document monoclonal B-cell population. In
clinical practice, MBL frequently is diagnosed during: (i)
evaluation of asymptomatic patients with mild, incidentally
noted lymphocytosis; or (ii) flow cytometric analysis of
blood of patients with normal lymphocyte count done for
other reasons. The majority of patients with MBL will have a
CLL immunophenotype (CD19, CD5, and CD23 positive
and dim expression of CD20, CD79b, and immunoglobulin
light chain), but this is not a requirement for diagnosis.
Using multicolor flow cytometry, about 3% of healthy peo-
ple have a clonal population of B-cells in their blood (MBL).
The incidence of MBL increases with age and is found in
~5% of patients >60 years of age with normal blood counts
and 14% of patients >60 years of age with lymphocytosis.
Several recent studies have found that ~1%-2% of people
with MBL and lymphocytosis will progress to CLL per year.
Conversely, a monoclonal B-cell population appears to be
present years before the diagnosis in virtually all patients
with CLL. Interestingly, for individuals with MBL who have
sIg CD20 CD5 CD23 CD10 CD103
Dim Dim + + − −
Mod + −/ + +/− − −
Mod + + − (partial) − −
+ + − −/ + − −
+ + −/ + −/ + − −/ +
+ + − −/ + +/− −
+ + − − − +
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 | Chronic lymphocytic leukemia

a CLL immunophenotype, the monoclonal B-cells frequently
exhibit cytogenetic abnormalities and other biomarkers typ-
ically seen in CLL (see the section Novel Prognostic Factors).
The role of these biomarkers in predicting MBL progression
to CLL remains largely unknown. Importantly, most people
with MBL will never develop CLL or other lymphoid malig-
nancies. Although the MBL clone may disappear overtime,
little is known about the rate of spontaneous resolution of
MBL. There are no known interventions that can prevent
development of CLL. Although most experts recommend
yearly follow up, there are no standard evidence-based guide-
lines in regard to follow-up of individuals with MBL.
over time, an autoimmune hemolytic anemia or thrombocy-
topenia may occur in 10%-20% of patients. Hypogamma-
globulinemia is a hallmark of this disorder, with increasing
prevalence and severity with advanced disease stage and lon-
ger disease duration. A serum monoclonal paraprotein (usu-
ally IgM) is present in <5% of cases. The bone marrow is
generally normocellular or hypercellular, with involvement
in either a nodular, interstitial, or diffuse pattern.
+EYPOINTS
s !TPRESENTATION#,,PATIENTSAREOFTENASYMPTOMATICSOME
MAYPRESENTWITHLYMPHADENOPATHYHEPATOSPLENOMEGALYOR
CLASSICAL"
SYMPTOMSFEVERNIGHTSWEATSWEIGHTLOSS 
+EYPOINTS
s !PREDOMINANCEOFMATURELYMPHOCYTESANDSMUDGECELLSARE
s 4HEREISNOSINGLEGENETICABNORMALITYDIAGNOSTICFOR#,, SEENONTHEPERIPHERALBLOODSMEAR
HOWEVERCYTOGENETICABERRATIONSARECOMMONIN#,,PATIENTS s (YPOGAMMAGLOBULINEMIAISAHALLMARKOFTHISDISEASE
ANDPREDICTIVEOFPROGNOSIS
s #,,CELLSARE#$#$#$AND#$POSITIVEWITH
DIM
SURFACEIMMUNOGLOBULINAND#$EXPRESSION4HIS
IMMUNOPHENOTYPICPATTERNDISTINGUISHES#,,FROMOTHER"
CELL
Prognostic factors
DISORDERS Traditional prognostic factors
s !DIAGNOSISOF#,,CANBEESTABLISHEDFROMTHEPERIPHERAL
BLOOD!BONEMARROWBIOPSYISNOTREQUIREDFORDIAGNOSIS The clinical course of patients with CLL is variable, ranging
s -",ISDElNEDASAMONOCLONAL"
CELLPOPULATION<µ, from an indolent process to one with a more accelerated
×9, INTHEABSENCEOFOTHERlNDINGSUGGESTIVEOFA course. Before the advent of cytogenetic and molecular
LYMPHOPROLIFERATIVEDISORDER
s -",WITHLYMPHOCYTOSISISASSOCIATEDWITH
ANNUALRISK nized. The Rai and Binet staging systems correlate with
OFPROGRESSIONTO#,,
Clinical and laboratory features
CLL often is diagnosed incidentally, when a complete blood
count (CBC) done for other purposes reveals an absolute
lymphocytosis, and immunophenotyping demonstrates a
monoclonal B-cell population >5 × 109/L with a CLL immu-
nophenotype. Patients generally present with symptoms
referable to lymphadenopathy, splenomegaly, or anemia,
fatigue, and recurrent infections. Only a minority of patients
will present with classical B-symptoms (fever, night sweats,
weight loss). On physical examination, localized or diffuse
lymphadenopathy may be present, as well as hepatomegaly
or splenomegaly.
The predominant laboratory feature with this disease is
the peripheral blood mature lymphocytosis. Smudge or bas-
ket cells are common on the peripheral blood smear. Fewer
than 10% of patients will have mild anemia (hemoglobin <11
g/dL) or thrombocytopenia (platelet count <100 × 109/L) at
diagnosis. A relative neutropenia is also common. Approxi-
mately 25% of patients will have or develop a positive direct
Coombs test (DAT) over the course of their disease. Likewise,
ASH-SAP_5E-12-1201-022.indd 582
markers, a series of traditional prognostic factors were recog-
median survival, which was initially reported as >13 years
with Rai stage 0 disease, 8 years for stage I, 6 years for stage II,
2-6 years for stage III, and 1.5-4 years for stage IV disease. In
a more recent update from the Mayo Clinic, median overall
survival (OS) in patients with Rai stage III or IV disease was
5-6 years. It has also been suggested that in patients with
early stage disease, which constitutes ~ 70% of the CLL pop-
ulation at diagnosis, an elevated β-2 microglobulin level
(>3.5 mg/L), CD38 expression, degree of lymphocytosis, and
serum thymidine kinase (sTK) levels are predictive of the
clinical course. A lymphocyte doubling time (LDT) of <12
months, compared with >12 months, also is associated with
a shorter median survival. A diffuse pattern of bone marrow
involvement also correlates with a poorer prognosis than a
nodular or interstitial pattern of involvement. Other poor
prognostic factors include male gender, initial lymphocytosis
of >50 × 109/L, elevated serum lactate dehydrogenase (LDH),
African American ethnicity, number of nodal groups
involved, and advanced age, in some but not all, series.
Molecular prognostic factors
Approximately 70% of patients with CLL are diagnosed at
early Rai stage disease. Consequently, although Rai staging
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system remains clinically useful, particularly in assessing
need for initiation of therapy, it does not provide risk strati-
fication for the majority of patients diagnosed at early stage.
This has led to an effort to identify novel biomarkers able to
risk stratify patients with early clinical stage disease. In addi-
tion to OS, the frequently used endpoint in biomarker stud-
ies is time from diagnosis to initial therapy (TTT). A number
of prognostic factors have been identified, and there is an
overlap in their prognostic value, as many were developed as
surrogates of earlier biomarkers to overcome some of the
technical difficulties in assessing these. For practical pur-
poses, prognostic markers commonly in use can be divided
in four major categories: mutational status of IGVH,
cytogentic studies, flow cytometry–based markers, and
mutations in TP53 gene. A number of prognostic models
combining these markers have been or are in development.
Outside of clinical trials, however, the presence of adverse
biomarkers is not an indication for initiating therapy in
patients with early Rai clinical stage disease. As of now, bio-
markers do not affect selection of therapy, with possible
exception of deletion of 17p deletion, which is associated
with resistance to purine analogues.
IGVH mutation status
IGVH undergoes somatic hypermutation in patients with
CLL that can be detected by direct sequencing. Patients with
≤98% homology of IGVH gene with germline DNA are char-
acterized as “mutated,” whereas those with >98% homology
are considered “unmutated.” Approximately 50%-55% of
patients have unmutated IGVH. In contrast to cytogentic
markers, the mutational status of IGVH does not change dur-
ing the course of the disease. The median survival of patient
with unmutated versus mutated IGVH is 5-10 years versus
10-20 years. The biological reasons for these differences in
outcomes are not understood, but data do suggest a role for
antigen stimulation through unmutated IGVH. Differences in
the origin of the CLL cells also have been postulated. Although
IGVH mutation status is not readily available in many clinical
laboratories, it has been reported in many clinical studies, and
it remains an important biomarker in ongoing studies.
CD38 and ZAP70
Expression of CD38 as evaluated by flow cytometry is associ-
ated with shorter time to initial therapy and shorter OS. The
correlation between unmutated IGVH and CD38 expression
is about 70%. In contrast to IGVH mutation status, CD38
expression may change in some patients during the course of
the disease.
ZAP70 is an intracellular tyrosine kinase that is expressed
aberrantly in CLL. Expression of ZAP70 is associated with
ASH-SAP_5E-12-1201-022.indd 583
Prognostic factors | 
inferior outcome with median survival of 8-9 years versus
24 years for patients who do not express this protein. The
correlation between unmutated IGVH and ZAP70 expres-
sion is about 70%-80%, and the prognostic value of ZAP70
expression appears to be independent of IGVH mutation
status.
Fluorescent in situ hybridization
A low proliferative rate of CLL in culture precludes classical
cytogenetic studies in most patients. In contrast, FISH can be
performed on interphase cells and can identify abnormalities
in 80% of patients. The studies of FISH detected abnormali-
ties allow development of hierarchical prognostic model
(Figure 22-2). Deletion of 13q14 is the most common and is
seen in 45%-55% of patients. A deletion of 13q14 as a sole
abnormality is associated with favorable outcome.
In contrast, deletion of 17p13 is associated with poor out-
come with median time from diagnosis to treatment of 9
months and median OS of 32 months. Indeed, presence of
17p13 appears to be associated with resistance and shorted
progression-free survival (PFS) after purine analogue–based
therapies (see the section Therapy). 11q22 deletion is associ-
ated with shorter PFS and OS. Patients with 11q22 deletion
tend to present at a younger age with predominance of
extensive adenopathy. Some studies suggested that patients
with 11q22 deletion may benefit from the addition of alkyl-
ator to the therapy. The prognostic value of trisomy 12 is well
less defined. Patients with trisomy 12 appear to have similar
outcome to patients with normal karyotype. The cytogentic
abnormalities may change in the course of the disease in sig-
nificant proportion of patients (clonal evolution). Particu-
larly, acquisition of 17p deletion in patients with accelerated
course of the disease may be seen and repeating FISH testing
in patients with rapid acceleration of disease is recom-
mended. Similarly, repeated 17p testing should be consid-
ered in previously observed patients who are to initiate
therapy because of progressive disease.
CLL cells can be stimulated in vitro to enter the cell cycle
through a number of stimuli, allowing for classical karyotype
analysis. Complex karyotypes detected by utilizing this
approach have been reported to be associated with worse
outcomes. This method, however, is not used routinely in a
clinical setting.
TP53 mutations
TP53 is a tumor-suppressor gene located on the short arm of
chromosome 17 (17p13). It can be inactivated by deletion
(17p13) and by somatic mutations within the gene. TP53-
inactivating mutations have been identified in 5%-10% of
CLL patients and are associated with shortened OS and
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 | Chronic lymphocytic leukemia

Figure 22-2 Probability of survival

from the date of diagnosis among the
patients in the five genetic categories.
The median survival times for the
groups with 17p deletion, 11q deletion,
12q trisomy, normal karyotype, and
13q deletion as the sole abnormality
were 32, 79, 114, 111, and 133 months,
respectively. Twenty-five patients
with various other chromosomal
abnormalities are not included in the
analysis. Dohner H, et al. N Engl J Med.
2000;343:1910-1916.

inferior response to therapy in a manner that is similar to

+EYPOINTS
TP53 inactivation by 17p deletion.
s 0ROGNOSISOF#,,PATIENTSATDIAGNOSISMAYBEASSESSEDBY
TRADITIONALCLINICALANDLABORATORY
BASEDPARAMETERSASWELLAS
Prognostic models and ultra-high-risk patients
The development of novel prognostic biomarkers led to an
effort to combine those in a number of prognostic models.
BYNEWERCLINICALANDMOLECULARDIAGNOSTICTECHNIQUES
s -ODELSINCORPORATINGTRADITIONALANDNOVELBIOMARKERSARE
NOWAVAILABLETOAIDINCOUNSELINGPATIENTSONCLINICALOUTCOME
s 4HEBONEMARROWMAYBENORMO
ORHYPERCELLULARWITH#,,
Although many of these proposed prognostic models will
INVOLVEMENTINANODULARINTERSTITIALORDIFFUSEPATTERN
require verification in prospective studies, there appear to be
groups of patients with particularly high-risk disease. In this
regard, the presence of 17p deletion or TP53-inactivating muta-
tions regardless of IGVH mutation status and status of other
biomarkers identifies group of patients at high risk of progres-
sion and death from the disease. In addition to these abnormali-
ties, in the relapsed disease setting, patients within the
ultra-high-risk group are defined as those having disease pro-
gression <24 months after purine analogue–containing che-
moimmunotherapy (CIT) and those refractory to purine
analogue therapy. There is no evidence that early therapy of
ultra-high-risk patients (eg, not meeting standard criteria for
initiation of therapy) is beneficial (see the section Therapy).
These patients should be strongly considered for participation
in clinical trials, including trials designed for high-risk early
stage disease. In the case of younger patients with PFS of <24
months following purine-based therapy or purine analogue
refractoriness, allogeneic stem cell transplantation (SCT) should
be considered (see the section Stem Cell Transplantation).
ASH-SAP_5E-12-1201-022.indd 584
s 3OMEPATIENTSWITHEARLYSTAGEDISEASE2AISTAGE"INET
STAGE! MAYPROGRESSMORERAPIDLYTHANOTHERS
s %XPRESSIONOF#$OR:!0ANDUNMUTATED)'6(ARE
ASSOCIATEDWITHSHORTENED0&3AND/3
s $ELETIONOFPAND40INACTIVATINGMUTATIONSAREASSOCI
ATEDWITHPARTICULARLYAGGRESSIVEDISEASEANDREFRACTORINESSTO
THERAPY
Therapy
Initial therapy
Approaches to initial CLL therapy have evolved over the past
several decades (Table 22-3). Alkylators were the backbone of
therapy for many years. In the 1990s, purine analogues were
introduced, and in the following decade, they became the
backbone of CIT approaches, with the addition of such agents
as rituximab and cyclophosphamide. Over the past decade,
the utility of alemtuzumab was established, followed by the
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Therapy | 

Table 22-3 CLL clinical staging systems.

Binet classification Rai classification Median overall
Stage Definition Patients (%) Risk group Stage Definition Patients (%) survival, y
A <3 lymphoid areas 60 Low 0 Lymphocytosis only 30 >10
B >3 lymphoid areas 30 Intermediate I Lymphadenopathy 25 5–7
II Hepato- or splenomegaly 25
± lymphadenopathy
C Hemoglobin <10 g/dL 10 High III Hemoglobin <11 g/dL 10 1–3
or platelets VI Platelets <100 × 103/dL 10
<100 × 103/dL

Two systems have been used widely to classify stage of progression of CLL: Rai and Binet staging.
They define early (Rai 0, Binet A), intermediate (Rai I/II, Binet B), and advanced (Rai III/IV, Binet C) stages of CLL on the basis of the extent of
lymphoid areas involvement and on the presence of anemia and thrombocytopenia.
Kokhaei et al. Ann Oncol. 2005;16(S2):ii113-i123.

introduction of bendamustine. Unfortunately, recommenda-
tions for initial therapy predominantly are based on pub-
lished phase II trials, instead of phase III comparison trials.
Alkylator-based therapy
Alkylator-based therapy, generally chlorambucil and less
commonly cyclophosphamide, was the mainstay of therapy
for many years, given as single agents or with corticosteroids,
despite no demonstration of a survival advantage. Chloram-
bucil may be administered in various schedules, including
daily (0.1 mg/kg/d) and pulse intermittent dosing (0.4-1.0
mg/kg, every 3-4 weeks). Reduction in lymphadenopathy,
organomegaly, and symptoms occurs, with overall response
rates (ORR) ranging from 38% to 75%, but with complete
remission (CR) rates ranging from only 3% to 5%. Toxicities
include myelosuppression as well as the potential for ther-
apy-related dysplasia with long-term usage. This therapy is
still utilized for many elderly or poor performance status
patients because of its tolerability. In addition, preliminary
results of phase II chlorambucil plus rituximab trials in older
patients have demonstrated the efficacy and tolerability of
this combination.
Fludarabine
Although fludarabine, 2-chlorodeoxyadenosine, and pento-
statin have been utilized for CLL therapy, fludarabine has
the widest usage. All cause defects in cell-mediated immu-
nity occur early in treatment and persist for up to a year
after discontinuation of therapy. In phase II studies, ORR
range from 40% to 65%, with CR rates of 15%-30%. The
addition of prednisone to fludarabine resulted in no
improved response rate, but opportunistic infections did
occur. Several large prospective randomized trials com-
pared fludarabine to alkylator-based regimens for the initial
CLL therapy. Fludarabine resulted in higher ORR and CR
rates, as well as prolonged remission durations of PFS, and
OS. The most common toxicities are myelosuppression,
fever, and infections. An oral preparation of fludarabine
with similar efficacy to the intravenous form is now
available.
Rituximab
The anti-CD20 antibody rituximab has gained widespread
usage in the therapy of lymphoproliferative disorders, includ-
ing CLL. As a single agent, ORR approach 50%, but with <5%
CRs. This may be related to dim CD20 expression on the
malignant lymphocyte. Single-agent rituximab has been stud-
ied in a dose-escalated manner, with slightly higher response
rates seen. Weekly rituximab has been combined with high-
dose methylprenisolone (1 g/m2, days 1-3) for a nonmyelo-
suppressive, although immunosuppressive, therapy option.
This regimen has demonstrated efficacy in patients with 17p
deletions.
Combination purine analogue–based chemo- and
chemoimmunotherapy
Fludarabine subsequently was incorporated into combina-
tion chemotherapy or CIT regimens to enhance both short-
and long-term outcome. Fludarabine plus cyclophosphamide
(FC) had been compared with single-agent fludarabine in
three large randomized phase III trials. In all, FC resulted in
an improved ORR and CR rate, and prolongation in PFS,
but not in OS, and it also resulted in more myelosuppres-
sion. As only a small number of elderly patients were
enrolled on these trials, tolerability data in these patients are
limited.
Fludarabine plus rituximab (FR) has been studied in
concurrent and sequential schedules. In a randomized

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 | Chronic lymphocytic leukemia
phase II study, concurrent administration resulted in a
higher CR rate than sequential therapy (47% vs. 33%), but
with more neutropenia but no increased infection rate.
When these results were compared with those of single-
agent fludarabine in the U.S. intergroup trial, FR demon-
strated greater efficacy, with improved ORR (84% vs. 63%),
CR rate (38% vs. 20%), 2-year PFS (67% vs. 45%), and
2-year OS (93% vs. 81%). Now with long-term follow-up,
median PFS and OS are 42 and 85 months, respectively, and
27% PFS at five years. IGVH mutational status was prog-
nostic for both PFS and OS; cytogenetic abnormalities were
prognostic only for OS.
The fludarabine, cyclophosphamide, rituximab (FCR)
combination regimen has been examined in multiple large
trials. In the initial phase II trial with a median follow-up of
6 years, ORR and CR rates were 95% and 72%, respectively.
Median time to progression was 80 months, with 6-year
failure-free survival and OS of 51% and 77%, respectively.
In addition, molecular remissions were demonstrated in
>40% of patients achieving a CR. In this single-institution
setting, toxicities, including infectious complications, were
manageable. Only 13% of patients were >70 years of age,
however. In a subsequent trial of the German CLL Study
Group, FCR was compared with FC (CLL8). In this trial, the
addition of rituximab resulted in a survival advantage.
Three years after initiation of therapy, 65% of FCR, com-
pared with 45% of FC patients, were free of progression.
Although grade 3/4 neutropenia was more common with
FCR than FC (34% vs. 21%), the rate of severe infections
was comparably low in both groups. The FCR-lite regimen,
consisting of lower dose cyclophosphamide and fludarabine
and higher dose rituximab has been studied, with ORR and
CR rates of 100% and 79%, respectively, with median
response duration of 22%, median PFS of 5.8 years, and
only 13% grade 3/4 neutropenia. The FCR regimen also has
been studied with each agent given sequentially, with favor-
able results. The FCR regimen has a significant impact on
minimal residual disease (MRD), with low MRD levels dur-
ing and after therapy being associated with longer PFS and
OS. The IGVH mutational status does not appear to affect
the CR rate; however, CR duration is shorter in patients with
unmutated IGVH status. The prospective U.S. intergroup
trial comparing the FCR and FR regimens has just com-
pleted accrual. This trial also examines the issue of mainte-
nance lenalidomide therapy.
Mitoxantrone has been added to the FCR regimen for
patients <70 years of age in several phase II trials, with ORR
of 93%-96% and CR rates of 82-83%, with some patients
achieving MRD negativity. Treatment toxicities have been
acceptable and comparable to that with FCR therapy. The
addition of epirubicin to FR therapy resulted in similar ORR
and CR rates, but myelosuppression was considerable.
ASH-SAP_5E-12-1201-022.indd 586
Other purine analogues
The two other purine analogues, pentostatin (deoxycofor-
mycin) and cladribine (2-chlorodeoxyadenosine [2CDA]),
have been studied in CLL patients. Therapy with the combi-
nation of pentostatin with cyclophosphamide and rituximab
(PCR) resulted in an ORR of 91% with 41% CR, and no evi-
dence of MRD in some patients attaining a CR. Although
efficacy was less in patients with deletion 17p, it demon-
strated activity in those with deletion 11q22. Efficacy was
comparable in patients less than and older than 70 years, as
well as in those patients with modest decreases in renal func-
tion. Median remission duration was 36 months in CR
patients. The regimen was well tolerated with no excess mor-
bidity. In a follow-up study of higher dose pentostatin plus
rituximab (PR), the ORR (76% vs. 91%), CR rate (27% vs.
41%), and median treatment-free survival (16 vs. 30 months)
were inferior to results with PCR.
Cladribine (2CDA) monotherapy has had efficacy similar
to alkylator-based regimens, but with more cytopenia and
immune suppression. When subcutaneous cladribine was
given with rituximab, ORR was 88% with 54% CR, with a
median time to failure (TTF) of 38 months, and was well
tolerated. In a phase III study, cladribine plus cyclophos-
phamide was compared with FC, with comparable results
(ORR 88% vs. 82%, CR rate 47% vs. 46%, respectively).
Grade 3/4 toxicities, PFS, and OS were comparable with
both regimens.
Alemtuzumab
Alemtuzumab, an anti-CD52 monoclonal antibody, is highly
effective as in eradicating peripheral blood and marrow dis-
ease and less effective against bulky nodal disease. It may be
administered by either a subcutaneous or intravenous route,
both being associated with a significant risk of infectious
complications, especially cytomegalovirus (CMV) reactiva-
tion. Approval for initial therapy with this agent was based
on results of a phase III study in which patients were ran-
domized to initial therapy with alemtuzumab or chlorambu-
cil, with ORR 83% versus 56%, and CR rates 24% versus 2%,
respectively. CMV reactivation occurred in 11% of alemtu-
zumab subjects.
Alemtuzumab also has been a component of combina-
tion regimens. In a series of TP53-deleted CLL patients,
therapy with alemtuzumab plus high-dose methylpred-
nisolone resulted in an ORR of 88%, 65% CR rate, median
PFS of 18 months, and median OS of 39 months. Although
effective in this high-risk population, toxicity was consider-
able with grade 3/4 toxicities of myelosuppression (67%),
infection (51%), and 5% treatment-related mortality.
With the addition of alemtuzumab to FCR in patients <70
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years of age, ORR was 92% with a 70% CR rate, including a
57% CR rate in patients with 17p deletion. Grade 3/4
neutropenia and thrombocytopenia were 33% and 13%,
respectively.
This agent also has been utilized for consolidation therapy
in multiple past trials, as MRD negativity may be achieved
with its use. When it was used after initial therapy with
fludarabine alone or with cyclophosphamide, one trial was
stopped because of severe infections. In those patients who
received this agent, however, PFS was prolonged as com-
pared with those who received no consolidation. In another
trial, in which 5 weeks of alemtuzumab consolidation fol-
lowed six cycles of FR induction therapy, although ORR, CR,
and MRD-negativity rates were high (90%, 57%, 42%,
respectively), five infectious deaths occurred in patients in
CR after FR.
Bendamustine
Bendamustine is a bifunctional agent with an alkylating
group and a purine-like benzamidazole ring. When com-
pared with chlorambucil in a phase III study, ORR and CR
rates were higher with bendamustine (68% vs. 31%, 31% vs.
2%, respectively), and median PFS also was prolonged (22 vs.
8 months). This agent was well tolerated, with the most com-
mon toxicity being hematologic, and with hypersensitivity
reactions infrequently seen. In a phase II study of bendamus-
tine plus rituximab (BR), ORR was 88% (23% CR), which is
inferior to purine analogue–based CIT regimens. At
18-month follow-up, 76% of patients were still in remission.
The ORR approached 90% in patients with 11q deletions or
trisomy 12. ORR dropped to 43% in those with 17p dele-
tions, however. In an ongoing phase III study, BR is being
compared to FCR for frontline therapy.
Ofatumumab
Ofatumumab is a fully human CD20 antibody that targets a
membrane epitope that is different from the binding site of
rituximab. In a phase II study, this agent was combined with
fludarabine and cyclophosphamide (O-FC), with O being
administered at either 500 or 1,000 mg. The ORR and CR
rate were 77% and 32%, respectively, for the 500 mg dose
cohort, and 73% and 50% for the 1,000 mg cohort. Grade 3/4
toxicities included neutropenia (48%), thrombocytopenia
(15%), anemia (13%), and infection (8%). In a preliminary
report of a phase II trial of pentostatin, cyclophosphamide,
and ofatumumab (PCO), ORR was 94% (CR 45%), similar
to results with PCR, and the regimen was well tolerated.
Ongoing phase II trials with this agent include its single-
agent use as induction and maintenance therapy, as well as in
combination with chlorambucil and FC.
ASH-SAP_5E-12-1201-022.indd 587
Therapy | 
Lenalidomide
Lenalidomide is an immunomodulatory agent with activity
in CLL that may be related to alteration of cytokine levels
and T- and natural killer cell function. In a single-agent
study, a 2.5 mg daily dose for 21 of 28 days was utilized,
with monthly dose escalations up to a daily dose of 10 mg.
The ORR was 56% with no CR, with an 88% incidence of
tumor flare and a 72% incidence of grade 3/4 neutropenia.
Although lymphocyte counts fell rapidly, rebound was
common in the week off of therapy. In another study of
patients >65 years of age, a 5 mg daily dose was utilized for
8 weeks, with subsequent dose titration to 25 mg daily as
tolerated. The ORR and CR rate were 65% and 10%, respec-
tively, with an estimated 2-year PFS of 60%. Grade 3/4 neu-
tropenia and infections occurred in 34% and 13% of
patients, respectively. In a small phase I trial of lenalido-
mide plus FR, the regimen was found not to be tolerable
because of idiosyncratic drug reactions, tumor flare, and
myelosuppression. The occurrence of tumor flare, which
can be managed with anti-inflammatory agents, appears to
correlate with disease response. In preliminary study, this
agent appears to have activity in patients with poor-risk
cytogenetic features.
Proposed initial treatment algorithms
Many of the frontline regimens previously discussed have
not been compared in prospective randomized studies, thus
making definitive treatment algorithms problematic. The
following are proposed initial therapy recommendations of
the National Comprehensive Cancer Network, in order of
preference:
s Age <70 years, or older patients with no significant comor-
bidities:
s FCR
s FR
s PCR
s BR
s Age >70 years, or younger patients with comorbidities:
s Chlorambucil +/- rituximab
s BR
s Cyclophosphamide, prednisone, +/- rituximab
s Alemtuzumab
s Rituximab
s Fludarabine +/- rituximab
s Pentostatin, rituximab +/- cyclophosphamide
s Cladribine
s Presence of 17p deletion:
s FCR
s FR
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 | Chronic lymphocytic leukemia

s High-dose methylprednisolone + rituximab Patients with CLL relapse <12-24 months after initial
s Alemtuzumab +/- rituximab purine analogues therapy, patients with primary refractory
s Presence of 11q deletion: disease to purine analogues, and patients with 17p deletion
s Age <70 years, or older patients with no significant comor- or TP53 mutations are particularly difficult to treat and
bidities: should be considered for participation in clinical trials when
s FCR possible or allogeneic SCT. The median survival in this group
s BR is 18-24 months. Alemtuzumab alone or in combination
s PCR with high-dose methylprednisolone or rituximab has activ-
s Age >70 years, or younger patients with comorbidities: ity in patients with 17p deletion and TP53 mutations, includ-
s Chlorambucil +/- rituximab ing purine analogue refractory patients with ORR of
s BR 45%-50% and PFS of 7 months. Alemtuzumab is less effec-
s Cyclophosphamide, prednisone, +/- rituximab tive in patients with bulky lymphadenopathy and often is
s Reduced-dose FCR associated with 11q deletion. Combination regimens using
s Alemtuzumab alemtuzumab with FCR (CFAR) or pentostatin and ritux-
s Rituximab imab (PAR) have been developed, but these combinations
s Pentostatin, rituximab +/- cyclophosphamide can be associated with significant toxicity. Ofatumumab, a
human anti-CD20 antibody has ~50% response rate in
patients with fludarabine or alemtuzumab refractory dis-
+EYPOINTS ease. The responses are usually partial with median survival
s 4HETREATMENTAPPROACHTO#,,HASEVOLVEDFROMINITIAL of 13-15 months. Bendamustine alone or in combination
THERAPYWITHALKYLATOR
BASEDREGIMENSTOSINGLE
AGENTPURINE with rituximab (BR) is associated with ORR of ~50% in pat-
ANALOGUETHERAPYFOLLOWEDBY#)4COMBINATIONREGIMENS ents with relapsed/refractory CLL.
s !LEMTUZUMABHASBEENUSEDASINITIALTHERAPYORASCONSOLIDA
The combination of rituximab and high-dose methyl-
TIONTHERAPYTOATTAINASTATEOF-2$3IGNIlCANTINFECTIOUS prednisolone may induce significant responses in this group,
COMPLICATIONSHAVEBEENREPORTEDHOWEVERINSOMETRIALSWITH especially in patients with bulky disease, but these responses
ALEMTUZUMABCONSOLIDATION are often of short duration.
s 4HEPURINEANALOGUESANDALEMTUZUMABHAVEANIMPACTON
CELL
MEDIATEDIMMUNITYRESULTINGINUNIQUEINFECTIOUSCOMPLICA

TIONSWITHIMPLICATIONSFORPROPHYLACTICANTIMICROBIALTHERAPY Investigational agents
s 4HEMOSTRECENTLYAPPROVEDAGENTSFOR#,,THERAPYAREBENDA

A number of investigational therapies have been developed,
MUSTINEANDOFATUMUMAB
s #ONSIDERATIONSFORAGECOMORBIDITIESANDPOOR
RISKCYTOGE
NETICSARENEEDEDINCHOOSINGANINITIAL#,,THERAPEUTIC
REGIMEN
Relapsed/refractory CLL
There is no standard treatment of relapsed/refractory CLL.
The treatment choice is based on previous treatment history,
patient’s factors like age and fitness and risk assessment as
identified by biomarkers, particularly 17p deletion or TP53
mutations. In patients with significant benefit from initial
purine-based therapy defined as PFS of 24 months or longer,
repeating purine-based therapy often results in durable
remissions. Although patients treated previously with alkyl-
ator-based regimens and achieving durable remission could
be considered for repeated therapy with the same agent, fre-
quently, purine-based second-line therapy is used effectively.
There are limited data in regards to efficacy of repeating
therapy with other agents, including bendamustine and
alemtuzumab; however, retreatment in the setting of previ-
ous durable response to a given agent is reasonable.
ASH-SAP_5E-12-1201-022.indd 588
and studies on their role in the management of CLL are
ongoing. Inhibitors of B-cell pathway-signaling appear
promising. Bruton’s tyrosine kinase (BTK) inhibitors, such
as ibrutinib, can be effective in patients with refractory/
relapsed CLL with no alternative treatment options. The
response rate to ibrutinib in patients with heavily relapsed
and refractory pretreated CLL was reported to be 50%-70%,
including patients with 17p deletion. The PI3 kinase inhibi-
tor GS1101 (CAL101) and the mTOR inhibitor everolimus
as well as several other BCR pathway-signaling small mole-
cule–targeted inhibitors currently are under investigation in
clinical trials. Lenalidomide is associated with a 30%-45%
response rate. Patients treated with lenalidomide frequently
develop “tumor flare,” which is characterized by the develop-
ment of painful and swollen lymphadenopathy after the ini-
tiation of therapy. The other common side effect is
myelotoxicity, requiring dose reductions or therapy inter-
ruption. Flavopiridol, a cyclin-dependent kinase inhibitor,
showed significant activity and is active in patients with 17p
deletion. The drug is associated with a high risk of tumor
lysis and aggressive tumor lysis syndrome management is
required.
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Therapy | 

long-term disease control. In a large series of myeloablative

+EYPOINTS
SCT, however, TRM and graft-versus-host disease (GVHD)–
s 4HEREISNOSTANDARDTHERAPYFOREARLYRELAPSEDORPURINE related mortality approached 50% and 20%, respectively.
ANALOGUEREFRACTORY#,, Overall, approximately one-third of patients will be cured of
s 0ATIENTSWITHRELAPSEDDISEASEWHOPREVIOUSLYHADADURABLE their disease. Although data are limited, preparative regi-
>
MONTHS RESPONSETOPURINEANALOGUEnBASED#)4CANBE mens with total body irradiation appear to result in better
RETREATEDWITH#)4PROVIDEDTHATTHEYHAVENOTHADCLONAL outcomes than chemotherapy-only regimens. Although
EVOLUTIONWITHACQUISITIONOFP
 autologous and allogeneic SCT procedures have not been
s 0ATIENTSWITHPURINEANALOGUEREFRACTORYDISEASEORRELAPSE
prospectively compared, in examining series with longer
WITHINYEARSFOLLOWINGPURINEANALOGUETHERAPYHAVEPOOR
follow-up intervals, although PFS was longer in the autolo-
PROGNOSISANDSHOULDBECONSIDEREDFORCLINICALTRIALSOR
gous recipients, there was no difference in OS.
REDUCED
INTENSITYCONDITIONING2)# ALLOGENEIC3#4
s !LEMTUZUMABISACTIVEINPATIENTSWITHPDELETIONAND40
The utilization of nonmyeloablative or RIC allogeneic
INACTIVATINGMUTATIONSBUTSINGLE
AGENTTHERAPYISLESSEFFECTIVE SCT procedures has expanded the number of CLL patients
INPATIENTSWITHBULKYDISEASE
s 3EVERALNOVELAGENTSSHOWPROMISINGACTIVITYANDCURRENTLYARE
BEINGEVALUATEDINCLINICALTRIALS
Stem cell transplantation
Hematopoietic SCT is applicable only for a minority of
patients with CLL. Many patients will have an indolent dis-
ease course, and likewise, many are of advanced age or have
comorbidities that make them unsuitable candidates for this
procedure. SCT, however, may be considered for those
patients with high-risk disease, including fludarabine resis-
tance (nonresponse or relapse <1 year after purine analogue–
based therapy), defective p53 function, or relapse <2 years
after purine analogue–based therapy.
Autologous SCT should be undertaken only in the context
of a clinical trial. Multiple phase II trials have demonstrated
the feasibility of this procedure, with transplant-related
mortality (TRM) ranging from 1% to 10%. In a recent mul-
ticenter randomized trial, previously untreated CLL patients
received initial cytoreductive therapy, with those attaining a
CR then randomized to further chemotherapy or autologous
SCT. Although a higher response rate and longer TTP was
seen in those undergoing SCT, no prolongation in OS was
seen. Autologous SCT is complicated by the presence of
clonal cells in the stem cell product, the possibility of preex-
eligible for SCT. Donor engraftment and CR rates are high
with these procedures, with the benefit of a GVL effect. From
a large series with 5-year follow-up, TRM rates were lower,
approaching 20%-25% at 5 years, disease-free survival of
50%, and PFS of 40%. Chronic GVHD, however, may be seen
in up to 75% of patients. Complication rates are higher with
unrelated donors; however, CR rates are higher and relapse
rates are lower, demonstrating more GVL effect in this set-
ting. Monoclonal antibodies, such as rituximab, have been
used to reduce GVHD incidence posttransplant. Likewise,
alemtuzumab has been used in conditioning regimens to
reduce GVHD, with the complications of delayed immune
reconstitution, increased infection risk, and higher relapse
rates because of reduced GVL effect.
SCT may be considered as a treatment option for patients
<70 years of age. Ideally, it is undertaken in the setting of low
disease burden, treatment-sensitive disease. Potential indica-
tions for SCT include: (i) patients attaining less than a CR to
initial therapy, (ii) those with 17p deletions at diagnosis, (iii)
the occurrence of Richter transformation, (iv) fludarabine-
or alemtuzumab-refractory disease, and (v) relapse from
FCR or similar therapy. At present, SCT is best considered for
patients as part of a clinical trial.
+EYPOINTS
s (EMATOPOIETIC3#4ISATREATMENTOPTIONFOR#,,PATIENTS
istent myelosuppression from prior therapy that may limit
ALBEITWITHLIMITATIONS
stem cell mobilization, and the issue that the adverse impact
s !UTOLOGOUS3#4ISLIMITEDBYCONTAMINATIONOFTHESTEMCELL
of biologic markers as unmutated IGVH status is not over-
PRODUCTBYTHEMALIGNANTCLONETHERAPY
RELATEDMYELODYSPLASIA
come by this procedure. The development of secondary AHIGHERRISKOFSECONDSOLIDTUMORMALIGNANCIESANDIMPOR

myelodysplastic syndrome or acute myeloid leukemia (AML) TANTLYACONTINUINGPATTERNOFRELAPSE
is of concern, with an incidence approaching 10% in several
large series. A greater risk of this complication is seen with
total body irradiation–containing regimens. In a series with
long-term follow-up, an incidence of solid tumors up to 19%
TERMSURVIVALCOMPAREDWITHMYELOABLATIVE
also has been reported. A pattern of continuing relapse is
found in these patients, with no plateau in survival seen.
Allogeneic SCT confers the benefit of a graft-versus-
leukemia (GVL) effect, thus increasing the likelihood of
s !LLOGENEIC3#4HASTHEADVANTAGEOFENHANCED'6,EFFECTBUT
ISLIMITEDBYOLDERPATIENTAGEANDHIGH42-
s .ONMYELOABLATIVEALLOGENEIC3#4PROCEDURESOFFERLOWER42-
ANDIMPROVEDLONG
ALLOGENEICPROCEDURES
s !LLOGENEIC3#4SHOULDBECONSIDEREDFORTHOSEPATIENTSWITH
EARLY<YEARS DISEASEPROGRESSIONFOLLOWINGPURINEANALOGUEn
BASED#)4

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 | Chronic lymphocytic leukemia
Complications of CLL
Autoimmune complications
An accumulation of largely immunologically incompetent
cells in CLL has a profound impact on the immune system,
resulting in immune dysfunction. The dysfunction results
not only results in immune deficiency but also is associated
with defects of immune functions resulting in immune-
mediated cytopenias and impairing immune surveillance
against second malignancies.
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) develops in
4%-10% of patients with CLL. AIHA can occur at any time
during the disease course with the prevalence increasing as
the disease progresses. Purine analogues therapy is a risk
factor for the development of AIHA. Indeed, in patients
with AIHA, purine analogues should be avoided, as severe
and sometimes fatal hemolysis may occur. AIHA that is
associated with CLL usually is mediated by warm immuno-
globulin G (IgG) antibodies, although cold agglutinins also
can be seen. The diagnosis is established by documentation
of anti–red cell antibodies (direct Coombs test) accompa-
nied by other features of hemolysis, including an increase in
LDH, hyperbilirubinemia, and reticulocytosis. The differ-
ential diagnosis for anemia in CLL patients includes bone
marrow failure from progressive disease, AIHA, pure red
cell aplasia, hypersplenism, and chemotherapy-induced
anemia and bleeding. Additional difficulties result from the
fact that 30%-50% of patients with CLL have a positive
Coombs test in the course of their disease, which usually is
not associated with significant hemolysis. Therefore, the
presence of a positive Coombs test may not necessarily sig-
nify the presence of AIHA. The distinction between AIHA
and anemia resulting from the suppression of hematopoie-
sis because of disease progression is particularly important,
as the former would not necessarily require the initiation of
anti-CLL therapy. In these patients, bone marrow biopsy
should be performed.
The management of AIHA (and other autoimmune cyto-
penias) in the setting of CLL is similar to the management
of idiopathic AIHA unless the CLL is progressive and also
requires therapy. Steroids usually are used as first-line ther-
apy, although rituximab has significant activity in steroid
refractory or relapsed disease. A splenectomy also is used in
refractory cases but frequently is ineffective. In patients with
purine analogue–associated AIHA, purine analogues should
be stopped and hemolysis should be treated with corticoste-
roids. Significant transfusion support frequently is needed
because of the brisk nature of purine-induced hemolysis.
ASH-SAP_5E-12-1201-022.indd 590
Pure red cell aplasia
Pure red cell aplasia (PRCA) is characterized by the autoim-
mune destruction of erythroid progenitors within the bone
marrow. Profound reticulocytopenia is a characteristic fea-
ture of the disease. PRCA occurs in 0.5% of CLL patients. A
differential diagnosis from bone marrow failure in the set-
ting of progressive CLL is important. In PRCA, a bone mar-
row biopsy reveals a lack of erythroid progenitors with
relatively intact other hematopoietic elements. In addition
to the autoimmune etiology, PRCA may be associated with
viral infections, mainly parvovirus B19 reactivation, and
less often with CMV and Epstein-Barr virus (EBV) reacti-
vation or infection. Ruling out of viral infections is impor-
tant. In this regard, patients with CLL may not be able to
mount an antibody response against parvovirus B19, and
serology testing might be negative. Therefore, performing
PCR for direct virus detection is preferred. The manage-
ment of PRCA includes the treatment of underlying viral
infection, immunosuppressive therapy with corticosteroids,
or cyclosporine. Rituximab also was shown to be effective
in some cases.
Immune thrombocytopenic purpura
Immune thrombocytopenic purpura (ITP) is a common
feature in CLL. Similarly to AIHA, ITP needs to be distin-
guished from other cases of thrombocytopenia, including
bone marrow failure, hypersplenism, chemotherapy and
drug induced, infection associated, and disseminated intra-
vascular coagulation (DIC). Typically, thrombocytopenia
in the setting of hypersplenism is mild to moderate. Severe
thrombocytopenia with large platelets on the peripheral
blood smear suggests ITP; however, a bone marrow biopsy
might be required to differentiate ITP from bone marrow
failure. Clinically significant ITP is seen in 2%-5% of CLL
patients. A combination of ITP with AIHA referred to as
Evan’s syndrome can be seen in up to 30% of patients with
ITP. The treatment of ITP in CLL is similar to idiopathic
disease with corticosteroids and intravenous immunoglob-
ulin used in first-line therapy. Rituximab frequently is used
in second-line treatment, and splenectomy can be consid-
ered in some patients. The role of thrombopoietic agents in
CLL associated ITP is not well established.
Infectious complications
Infections remain a major cause of morbidity and mortality in
CLL patients. The pathogenesis of infection is multifactorial,
including inherent immune defects related to the primary
disease process and therapy-induced immunosuppression.
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Complications of CLL | 

The early and frequently profound onset defect in humoral Second malignancies
immunity in patients with CLL results in hypogammaglobu-
Second malignancies occur in up to 25% of CLL patients, a
linemia and an increase in risk of serious infections by
rate almost double that seen in the general population.
encapsulated bacteria. The spectrum of infectious complica-
Malignancies with the highest increase in rates are nonmela-
tions of therapy is related to the specific therapeutic agents
noma skin cancer, melanoma, lung, head and neck, prostate,
utilized.
kidney, and lymphoma. The cause of death is related to these
Alkylator-based therapy usually is associated with respi-
second malignancies in 7%-10% of patients. Potential expla-
ratory tract infections that usually are bacterial, caused by
nations for this finding include chronic immunosuppression
common Gram-positive and -negative organisms. Purine
related to the CLL and its therapy, risk factors common to
analogues and alemtuzumab cause quantitative and quali-
both disorders as environmental exposures or heritable fac-
tative T-cell abnormalities. In an intergroup trial, CLL
tors, and detection bias (because of physician visits). In addi-
patients receiving fludarabine had more major and herpes-
tion, EBV-related non-Hodgkin lymphomas have been
virus infections than those receiving chlorambucil; Pneu-
reported following alemtuzumab therapy.
mocystis, Aspergillus, and CMV infections were uncommon.
Therapy-related myelodysplasia and acute myeloid leuke-
Manifestations of herpesvirus infections may be atypical.
mia (t-MDS/AML) have been reported in these patients, often
Risk factors for infection in fludarabine-treated patients
with acquired abnormalities in chromosomes 5 or 7, implicat-
include advanced-stage disease, prior therapy, response to
ing alkylator involvement. These disorders were more com-
therapy, elevated creatinine, hemoglobin <12 g/dL, and
mon in patients receiving initial therapy with concurrent
decreased serum IgG. Treatment with alemtuzumab is
chlorambucil plus fludarabine, than with either single agent, in
complicated by frequent opportunistic infections, with
an intergroup trial. In another prospective trial, the cumulative
CMV reactivation occurring in 10%-25% of patients. Case
incidence rates of these disorders at 7 years with initial single-
reports of the development of progressive multifocal leuco-
agent fludarabine or fludarabine plus cyclophosphamide ther-
encephalopathy following combination CIT also are emerg-
apy were 4.6% and 8.2%, respectively. A 10.8% incidence of
ing. For prevention of infection, the use of immunoglobulin
t-MDS/AML was found in a series of patients receiving fluda-
replacement may reduce the rate of infection, but it does
rabine-based regimens for low-grade lymphoproliferative dis-
not affect survival, and thus routine use is not recom-
orders. Prior cytotoxic therapy, as well as the inclusion of
mended. Standard vaccinations with nonlive vaccines are
mitoxantrone in the combination regimen, increased the risk
recommended, although immune response may be less
of this complication. A paratrabecular pattern of marrow
robust. Prophylactic antimicrobial recommendations are
involvement also has been suggested as a risk factor.
based on the specific therapeutic regimen. With the addi-
tion of cyclophosphamide to fludarabine-based regimens,
Pneumocystis and antiviral prophylaxis generally is utilized. +EYPOINTS
For alemtuzumab, weekly monitoring for CMV reactiva- s !)(!AND)40ARECOMMONCOMPLICATIONSOF#,,ANDNEEDTO
tion by PCR is recommended, as well as Pneumocystis and BEDIFFERENTIATEDFROMOTHERCASESOFCYTOPENIAS
antiviral prophylaxis. Valganciclovir prophylaxis has dem- s 0URINEANALOGUETHERAPYISASSOCIATEDWITHDEVELOPMENTOF
onstrated efficacy in preventing symptomatic CMV reacti- SEVERE!)(!WHICHCANBEFATAL
vation but causes considerable myelosuppression.
Richter transformation
A Richter transformation may develop over time in 3%-5%
MEDIATEDIMMUNEDEFECTS
of CLL patients. The diffuse large B-cell usually (about 70%-
s 02#!IN#,,CANBEASSOCIATEDWITHVIRALINFECTIONSINCLUDING
PARVOVIRUS"
s 4HESPECTRUMOFINFECTIONSOCCURRINGINTREATED#,,PATIENTSIS
INmUENCEDBYTHESPECIlCTHERAPYUTILIZED
s 0URINEANALOGUESANDALEMTUZUMABRESULTINSIGNIlCANT
CELL
s #-6REACTIVATIONISASIGNIlCANTISSUEWITHALEMTUZUMAB
80%) arises from the CLL cells but is a de novo second lym- THERAPYOCCURRINGIN
OFPATIENTS
phoid malignancy in a minority of patients. Recent data s 
OF#,,PATIENTSWILLDEVELOPTRANSFORMATIONTOA
suggest that this transformation may be more common in HIGH
GRADENON
(ODGKINLYMPHOMA2ICHTERTRANSFORMATION 
patients of unmutated IGVH status. Presenting manifesta- MANIFESTEDBYRAPIDLYINCREASINGLYMPHADENOPATHYORHEPATO

tions include fever, rapidly increasing lymphadenopathy or SPLENOMEGALYFEVERANDELEVATED,$(
hepatosplenomegaly, and markedly elevated LDH levels. s 3ECONDMALIGNANCIESINCLUDINGLUNGANDSKINCANCERSARE
Prognosis is poor, with survival generally <6 months, but MORECOMMONIN#,,PATIENTSTHANINTHEGENERALPOPULATION
s 4HERAPY
RELATEDMYELOIDDISORDERSMAYCOMPLICATETHECOURSE
long-term survival is possible with aggressive therapy in
OFPATIENTSRECEIVINGmUDARABINE
BASEDREGIMENS
some patients.

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For personal use only. Copyright © The American Society of Hematology 2013. All rights reserved.
 | Chronic lymphocytic leukemia
Other related lymphoproliferative
disorders
Prolymphocytic leukemia
B-cell prolymphocytic leukemia (B-PLL) is a rare mature
B-cell leukemia characterized by an accumulation of pro-
lymphocytes, typically with the involvement of the periph-
eral blood, bone marrow, and spleen. By definition,
prolymphocytes must compromise more than 55% of blood
lymphocytes. The latter distinction is important, as many
CLL patients may have some prolymphocytes seen on the
peripheral blood smear. The differential diagnosis requires
the exclusion of CLL, myeloid cell leukemia (MCL), and
other lymphomas in the leukemic stage. B-PLL affects pre-
dominantly males with a median age of 65-70 years. Immu-
nophenotype bright-surface immunoglobulin expression
and bright CD20 expression are features that differentiate it
from CLL. CD5 expression is seen in 30% of the cases, and
the disease is typically CD10 negative. FISH for t(11;14)
often is required to differentiate B-PLL from the leukemic
stage of MCL. Patients often present with rapidly progressive
lymphocytosis accompanied by the development of organo-
megaly and presence of systemic symptoms. Optimal treat-
ment is not established. Alemtuzumab has been used with
some success. The disease usually is fatal within several years
from diagnosis.
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