clinical review Chronic lymphocytic leukemia

clinicalreview

Standard of care and novel treatments for chronic

lymphocytic leukemia
Amy Hatfield Seung

C
hronic lymphocytic leukemia
(CLL) is a B-cell lineage lym-
phoid malignancy that afflicts
approximately 15,000 individuals
in the United States each year.1 CLL
occurs primarily in middle-aged and
elderly adults, with a median age
at diagnosis of 6570 years.2 While
CLL is generally incurable, some
patients with CLL survive for 10 or
more years.3 Due to its usually in-
dolent course, watchful waiting is
often the best treatment option for
early-stage or asymptomatic disease.
However, more than 50% of patients
with early-stage CLL are at risk for
disease progression. Identification of
patients who are at risk for acceler-
ated CLL progression, and therefore
likely to benefit from early treatment,
is being actively pursued in several
ongoing clinical trials.4 Indeed, it is
challenging to determine whether
early, aggressive treatment of high-
risk patients with CLL will ultimately
result in higher rates of long-term
survival, a longer time to progres-
sion, and long durations of response.
CLL is asymptomatic at diagnosis
in approximately 25% of patients,
whose disease is usually identified
based on the results of labora-
tory tests performed during routine
physical examinations. Symptoms
Purpose. The standard of care and novel
treatments for chronic lymphocytic leuke-
mia (CLL) are reviewed.
Summary. Recent advances in the treat-
ment of CLL have dramatically changed the
therapeutic landscape for both patients
and health care professionals. The major-
ity of conventional first-line therapies are
noncurative and are only used to treat
disease that is symptomatic or progressive
and include chlorambucil, monotherapy
with purine analogues, and combination
chemotherapy. Immunotherapeutic agents
such as rituximab and alemtuzumab may
be indicated in select patient populations.
However, because clinical trials have found
that overall survival does not depend on
the initial therapy, selection of first-line
therapy should be based on patient-
specific factors and the patients goals for
therapy with respect to response, survival,
and symptom palliation. Progression-free
survival time and time to treatment are
critical endpoints for CLL treatment. An
increasingly important endpoint is minimal
residual disease (MRD), as it is considered
of CLL include lymphadenopathy
and organomegaly of the spleen and
liver (Table 1).5-7 About 510% of pa-
tients have constitutional symptoms,
including fevers, night sweats, and
weight loss, at the time of diagnosis.
While infrequent at the time of di-
to be the major cause of relapse in CLL.
Finally, comparison of toxicities between
different therapies is critical in CLL, as it is
in other disease states. Several new agents
are currently being evaluated for use in
CLL, including alvocidib, oblimersen, and
lumiliximab.
Conclusion. Chemotherapy remains the
mainstay of treatment for the majority
of patients with CLL. The introduction of
rituximab, alemtuzumab, and bendamus-
tine has improved the current outlook for
patients with CLL. As overall survival does
not appear to depend on the initial therapy,
treatment should be selected based on
patient-specific factors and goals. Chal-
lenges in CLL include determining when
to initiate therapy, eradicating MRD, and
managing therapeutic resistance.
Index terms: Alemtuzumab; Antineoplas-
tic agents; Bendamustine; Drugs; Flavopiri-
dol; Leukemia; Lumiliximab; Oblimersen;
Resistance; Rituximab; Toxicity
Am J Health-Syst Pharm. 2010; 67:1813-
24
agnosis, dangerous complications of
CLL include infections and autoim-
mune hemolytic anemia. Commonly
observed laboratory test abnormali-
ties in CLL patients are elevated white
blood cell counts, low hemoglobin
levels, and thrombocytopenia.

Amy Hatfield Seung, Pharm.D., BCOP, is Clinical Specialist,
Hematologic Malignancies, and Director, Oncology Pharmacy
Residency, Johns Hopkins Hospital, 600 North Wolfe Street/Carnegie
180, Baltimore, MD 21287 (ahatfie2@jhmi.edu).
The author has declared no potential conflicts of interest.
Copyright 2010, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/10/1101-1813$06.00.
DOI 10.2146/ajhp090147

Am J Health-Syst PharmVol 67 Nov 1, 2010 1813

 clinical review Chronic lymphocytic leukemia
Table 1.
Signs and Symptoms of Chronic Lymphocytic Leukemia5-7,a
Sign or Symptom
Asymptomatic
Symptoms
Lymphadenopathy
Splenomegaly
Hepatomegaly
Constitutional symptomb
Infection
Autoimmune disorder
Abnormal laboratory test values
WBC count of >100,000 cells/mm3 with lymphocytosis
Hemoglobin conc. of <11 g/dL
Platelets count of <100,000 cells/mm3
WBC = white blood cell.
a
Symptoms may include fever, night sweats, and weight loss.
b
CLL staging and prognosis
Two well-accepted staging systems
for CLL are the Rai staging system and
Binet classification (Table 2).8,9 Both
systems differentiate CLL into stages
based on the degree of lymphocytosis,
lymphadenopathy, organomegaly, and
bone marrow failure. While both sys-
tems have different numbers of stages,
it is relatively easy to translate between
the two systems. Despite the utility
of these systems in classifying CLL,
staging is not sufficient for predict-
ing patient prognosis. For example,
some patients with early-stage CLL
have rapidly progressing disease.10,11
Established and exploratory prognos-
tic factors of CLL are summarized in
Table 3.12 Historical prognostic factors
include morphology, bone marrow
histology, lymphocyte doubling time,
and various serum markers, while
biological factors include cytogenetic
abnormalities, cluster of differentia-
tion (CD) 38 expression, mutational
status of the gene controlling the
shape of the variable region of the
heavy chain of the immunoglobulin
(IgVH), and expression of the zeta-
chain (T-cell receptor)-associated
protein kinase 70 kDa (ZAP70) gene
(Figure 1).12
The frequencies of cytogenetic ab-
normalities in CLL patients and asso-
1814 Am J Health-Syst PharmVol 67 Nov 1, 2010
Frequency (% Patients)
2540
5090
2555
1525
510
Infrequent
Infrequent
30
31
16
ciated median survival rates are sum-
marized in Table 4. Both the prognosis
and long-term survival of patients
with cytogenetic abnormalities differ
based solely on karyotype. The most-
favorable chromosomal abnormality
is deletion of the 13q chromosome,
which, in patients with no other ab-
normality, is associated with a good
prognosis, including a median surviv-
al time of 133 months.12,13 In contrast,
patients with deletion of chromo-
some 17p (del 17p), found in fewer
than 10% of patients with CLL, have
a particularly poor prognosis, with a
median survival of 32 months. Several
other cytogenetic abnormalities have
been observed in CLL patients (Table
4). Some patients have multiple chro-
mosomal abnormalities, or complex
cytogenetics, which are thought to be
associated with a poorer prognosis.12,13
CD38 is a cell-surface glycoprotein
that is expressed on some leukemic
cells, particularly in patients with CLL
who experience relatively early dis-
ease progression.14 Patients in whom
CD38 is present on at least 30% of
lymphocytes are considered CD38+
and are expected to have shorter
overall survival and progression-
free survival (PFS) times compared
with patients with CD38 CLL. In
one study, patients with CD38+ CLL
had a 75% chance of disease progres-
sion at a median follow-up time of
90 months, compared with a 13%
chance in CD38 patients.15 Patients
with CD38+ disease also tend to
respond poorly to fludarabine, a cen-
tral chemotherapeutic agent in the
CLL arsenal.16
The absence of IgVH mutations
is also associated with a high risk of
early disease progression in patients
with CLL.17-19 While IgVH mutational
status is an independent prognostic
factor for CLL, IgVH assays are not
widely available; therefore, status is
not routinely tested outside of clini-
cal trials. However, IgVH mutation
status is often gauged in a surrogate
manner: the intracellular signaling
molecule ZAP70 is present in the
majority of patients with CLL who
lack IgVH mutations.20 ZAP70 ex-
pression is highly predictive of both
relatively rapid disease progression
and death.21
Based on prognostic factors, CLL
patients are differentiated into low-,
intermediate-, and high-risk prog-
nostic groups to help direct therapy.
The initial treatment strategy of
early-stage CLL is based on a pa-
tients risk-group assignment (Table
5).3 The differences in both expected
median survival times and expected
median treatment-free intervals
among risk groups are dramatic. For
example, patients in the low- and
intermediate-risk prognostic groups
are expected to have a relatively
long median survival time (>15
and 10 years, respectively). The ex-
pected treatment-free intervals for
these patients are >5 and 34 years,
respectively, and therefore are not
considered to require immediate
treatment. In contrast, high-risk
patients are expected to have a me-
dian survival time of 38 years and
thus have shorter expected median
treatment-free intervals (14 years).
While immediate treatment may
be indicated for these patients, it is
currently recommended only within
a clinical trial setting. Several on-
 clinical review Chronic lymphocytic leukemia

going clinical trials are evaluating

whether treatment of patients with
very-early-stage, asymptomatic CLL
with poor-risk features results in an
overall survival benefit. Patients with
symptomatic disease, which repre-
sents the majority of CLL patients,
have the shortest expected survival
time and are therefore always treated
immediately.3
First-line treatment
Several first-line treatment strate-
gies are currently used in CLL. The
majority of conventional therapies
are noncurative and used only to treat
symptomatic or progressive disease.
Indications for the initiation of CLL
therapy include bone marrow failure,
thrombocytopenia, severe lymphade-
nopathy, a lymphocyte count dou-
bling time of less than six months,
and constitutional symptoms. The
alkylating agent chlorambucil has
been a mainstay of CLL treatment
for several decades.22 Other first-line
strategies include monotherapy with
purine analogues and combination
chemotherapy. In addition to these
treatment options, chemoimmuno-
therapy or the addition of immuno-
therapeutic agents, such as rituximab
and alemtuzumab, may be indicated
for select patient populations. How-
ever, none of the randomized trials
for first-line therapy in CLL have
demonstrated differences in over-
all survival. Therefore, selection of
first-line therapy is usually based
on patient-specific factors (i.e., age,
performance status, comorbidities
[including current infection status],
organ dysfunction [particularly renal
dysfunction, as many CLL agents are
eliminated renally], and eligibility for
stem-cell transplantation [SCT]) and
the patients goals for therapy with
respect to response, survival, and
symptom palliation.
Several endpoints are used to
measure response to therapy in
CLL patients. Overall response rates
(ORRs) are typically used; how-
ever, in CLL, large ORRs usually
Table 2.
Staging Systems of Chronic Lymphocytic Leukemia
Rai Staging System8
Stage 0: Absolute lymphocytosis (lymphocyte
count of >15,000 cells/mm3) without
adenopathy, hepatosplenomegaly, anemia, or
thrombocytopenia
Stage I: Absolute lymphocytosis with
lymphadenopathy without hepatosplenomegaly,
anemia, or thrombocytopenia
Stage II: Absolute lymphocytosis with either
hepatomegaly or splenomegaly, with or without
lymphadenopathy
Stage III: Absolute lymphocytosis and anemia
(hemoglobin conc. of <11 g/dL) with or
without lymphadenopathy, hepatomegaly, or
splenomegaly
Stage IV: Absolute lymphocytosis and
thrombocytopenia (platelet count of <100,000
cells/mm3) with or without lymphadenopathy,
hepatomegaly, splenomegaly, or anemia
Table 3.
Prognostic Factors of Chronic Lymphocytic Leukemia12,a
Factor
Historical
Morphology
Bone marrow histology Nondiffuse pattern
Lymphocyte doubling time
Serum markers
Biological
Cytogenetic abnormalities Normal, del 13q
IgVH mutation status
CD38 expression
ZAP70 expression
a
IgVH = immunoglobulin heavy chain, ZAP70 = zeta-chain (T-cell receptor)-associated protein kinease 70
kDa.
encompass relatively low complete
response rates (CRRs). PFS is a criti-
cal endpoint for CLL treatment, as it
provides information about the du-
ration of response beginning from
initial therapy. Time to treatment,
defined as the time from diagnosis
until treatment is initiated, and time
to next treatment are also useful. An
increasingly important endpoint
in recent years is minimal residual
disease (MRD), which refers to the
Binet Classification9
Clinical stage A: No anemia or
thrombocytopenia and fewer
than three areas of lymphoid
involvement (Rai stages 0II)
Clinical stage B: No anemia or
thrombocytopenia with three
or more areas of lymphoid
involvement (Rai stages I
and II)
Clinical stage C: Anemia,
thrombocytopenia, or both,
regardless of the number
of areas of lymphoid
enlargement (Rai stages III
and IV)
Prognosis
Good Poor
Typical Atypical
Diffuse pattern
<12 mo >12 mo
Normal Elevated
del 11q, del 17q
Mutated Germline
<30% >30%
Low High
small number of leukemic cells
that may remain during and after
treatment in a patients bone mar-
row or peripheral blood despite the
complete disappearance of all other
disease signs and symptoms. As
MRD is considered to be the major
cause of relapse in CLL, much atten-
tion has been focused on how best to
treat MRD.23,24 Finally, comparison of
toxicities between different therapies
is critical in CLL in clinical trials.

Am J Health-Syst PharmVol 67 Nov 1, 2010 1815

 clinical review Chronic lymphocytic leukemia

Figure 1. The promoting roles of antigen stimulation and accessory signals from the mi-
than in the chlorambucil-treated
croenvironment in chronic lymphocytic leukemia (CLL). B cells in patients with CLL who group (20 months versus 14 months,
have unfavorable prognostic markers (left side of figure) are stimulated by the binding p < 0.001); however, no significant
of self-antigens to the B-cell receptor. The dynamic balance of negative and positive difference in overall survival was
signals delivered by the B-cell receptor and the survival signals transduced by IgD and noted. Fludarabine was generally
delivered by other cells, cytokines, and chemokines determine whether the leukemic
cell proliferates or dies by apoptosis. B cells from patients with CLL who have favor-
well tolerated but was associated with
able prognostic markers (right side of figure) are less capable of triggering apoptosis, an increased rate of grade 3 and 4
survival, or proliferation owing to an inability to bind antigen because of changes in the infections. Thus, fludarabine mono-
shape of B-cell receptors, because of V-gene mutations (blue rectangular antigen does therapy appears to be superior to
not fit B-cell receptors, a condition known as clonal ignorance), or because of defective chlorambucil monotherapy as first-
B-cell receptor signaling (despite an adequate fit of green diamond-shaped antigen in
B-cell receptors). This lack of receptor stimulation may be a factor associated with a less
line treatment for CLL. Although the
aggressive form of the disease. Reprinted, with permission, from reference 10. FDA-approved labeling for fludara-
bine only includes the use of the drug
for patients with CLL who have not
responded to or have had disease pro-
gression after treatment with at least
one previous regimen containing an
alkylating agent,28 evidence from this
trial supports the use of fludarabine
as initial therapy. Interestingly, a
third treatment group (n = 123) that
combined fludarabine phosphate (20
mg/m2 i.v. daily for 5 days every 28
days) and chlorambucil (20 mg/m2
orally every 28 days) demonstrated
unacceptable toxicity; therefore,
these two agents are not used to-
gether. Treatment with fludarabine,
as well as other purine analogues, is
associated with an increased risk of
autoimmune hemolytic anemia, a
common complication of CLL itself.
Management of hemolytic anemia
includes treatment with corticoste-
roids, immunoglobulin, rituximab,
and immunosuppressive agents.29,30
The majority of studies of CLL
treatments have been retrospective
and comparative Phase II trials; how-
ever, three large randomized Phase
III studies have compared the combi-
nation of fludarabine and cyclophos-
phamide with fludarabine alone.31-33
While the treatment regimens dif-
Purine analogues. Recently, pu- chlorambucil (40 mg/m2 orally every fered slightly among the studies, the
rine analogues, including fludara- 28 days, n = 181) in patients with general strategy was to administer
bine, cladribine, and pentostatin, untreated CLL, fludarabine-treated fludarabine plus cyclophosphamide
have been increasingly used as first- patients had a 63% ORR and a 20% for 3 days compared with 5 days of
line treatment of CLL.25,26 CRR, compared with a 37% ORR fludarabine monotherapy. Study de-
Fludarabine. In a randomized and a 4% CRR in the chlorambucil- tails and results are provided in Table
study that compared single-agent treated group (p < 0.001 for both 6. Overall, fludarabine plus cyclo-
fludarabine phosphate (25 mg/m2 of comparisons).27 The median time to phosphamide demonstrated ORRs
body surface area i.v. daily for 5 days progression was significantly longer as high as 94% and CRRs as high
every 28 days, n = 170) to single-agent in the fludarabine-treated group as 38%.31-33 Toxicities in all studies

1816 Am J Health-Syst PharmVol 67 Nov 1, 2010


included severe infections; however,
the addition of cyclophosphamide
did not appear to contribute to this
toxicity. Thus, the combination of
fludarabine and cyclophosphamide
appears to be a viable option in the
majority of patients with CLL who
can tolerate it.
Cladribine. Cladribine, a purine
nucleoside analogue that is cell-cycle
nonspecific, has been used in the
treatment of CLL, though it is more
commonly used to treat hairy cell
leukemia. In a Phase III study, inves-
tigators randomized 229 untreated
patients with symptomatic CLL to
receive cladribine (5 mg/m2 i.v. over 2
hours daily for 5 days every 28 days),
fludarabine (25 mg/m2 i.v. daily for
5 days every 28 days), or high-dose
intermittent chlorambucil (10 mg/
m2 orally daily for 10 days every 28
days) repeated for at least three
cycles.32 The ORRs were 75% for
those treated with cladribine, 70%
for fludarabine-treated patients, and
62% for the chlorambucil-treated
group. Cladribine prolonged the me-
dian time to disease progression (25
months), compared with fludarabine
(10 months) and chlorambucil (9
months). Cladribine also prolonged
the median time to second-line
treatment (50 months), compared
with fludarabine (24 months) and
cladribine (21 months). While re-
sponse duration was superior with
cladribine, treatment with the drug
resulted in more neutropenia and
infections than did fludarabine or
chlorambucil therapy.
Robak et al.35 found that cladri-
bine, combined with cyclophos-
phamide in first-line therapy of CLL
patients with 17p13.1 deletion that
causes loss of the TP53 gene encod-
ing for the p53 protein, resulted in
a relatively high response rate. The
investigators retrospectively analyzed
20 patients treated with combina-
tion cladribine (0.12 mg/kg i.v. daily
for 3 days) and cyclophosphamide
(250 mg/m2 i.v daily for 3 days);
cycles were repeated every 28 days
clinical review Chronic lymphocytic leukemia
Table 4.
Cytogenetic Abnormalities in Chronic Lymphocytic Leukemia12,13
Abnormality
Chromosome 13q deletion
Normal
Trisomy 12
Chromosome 11q deletion
Chromosome 17p deletion
Othera
Chromosome 3q deletion, chromosome 6q deletion, trisomy 8q, and t(14q32).
a
Table 5.
Prognostic Risk Groups for Early-Stage Chronic Lymphocytic
Leukemia3
Median Expected
Risk Group Survival (yr)
Low >15
Intermediate 10
High 38
Symptomatic 26
for up to six cycles. Of the 16 patients
(80%) who responded, 50% had a
complete response and 30% had a
partial response. PFS time reached a
median 23 months. While the inves-
tigators concluded that the duration
of response and survival with this
regimen were not adequate, they pos-
tulated that combining the regimen
with p53-independent agents might
improve results.
Pentostatin. Pentostatin, a purine
analogue that specifically inhibits
adenosine deaminase, is also used to
treat CLL. In an early Phase II Cancer
and Leukemia Group B trial in 39 CLL
patients, one third of whom had no
prior treatment for CLL, pentostatin
treatment resulted in a complete re-
sponse in 3% of patients, a partial re-
sponse in 23%, clinical improvement
in 28%, and stable disease in 38%.36
Clinical studies have found that
combinations of these agents are
more effective in creating better
response rates, including complete
responses.37 For example, a combina-
Am J Health-Syst PharmVol 67 Nov 1, 2010
Frequency Median Survival
(% Patients) (mo)
36 133
18 111
14 114
17 79
7 32
8 Not evaluated
Median Expected Immediate
Treatment-Free Treatment
Interval (yr) Required?
>5 No
34 No
14 Unknown
None Yes
tion of pentostatin (2 mg/m2 i.v. for 1
day), cyclophosphamide (600 mg/m2
i.v. for 1 day), and rituximab (375
mg/m2 i.v. for 1 day) repeated every
21 days for six cycles, produced a 63%
complete clinical response in 40 of
64 patients with previously untreated
CLL. Of these patients, 26 (41%) at-
tained a complete response, 14 (22%)
a nodular partial response, and 18
(28%) a partial response, yielding an
overall response rate of 91%.38
Immunotherapeutic agents.
Rituximab. As a single agent, the
anti-CD20 antibody rituximab has
demonstrated modest activity in
first-line treatment of CLL. In a study
of 44 previously untreated CLL pa-
tients, rituximab (375 mg/m2 weekly
for four weeks at 6-month intervals
for up to four courses) resulted in
an ORR of 58% and a two-year esti-
mated PFS rate of 49% at a median
20-month follow-up.39 However, the
CRR remained low (9%), suggesting
limited activity of rituximab mono-
therapy in CLL. In contrast, che-
1817
 clinical review Chronic lymphocytic leukemia

Table 6.
Summary of Phase III Trials Comparing Fludarabine and Fludarabine Plus Cyclophosphamide in
Chronic Lymphocytic Leukemia31-33,a

ORR CRR Median PFS

Ref. Regimen (%) (%) (mo)
29 Fludarabine phosphate 25 mg/m2 i.v. for 5 days (n = 180) 83 7 37
Fludarabine phosphate 30 mg/m2 i.v. for 3 days plus
cyclophosphamide 250 mg/m2 i.v. for 3 days (n = 182) 94 24 48
30 Fludarabine phosphate 25 mg/m2 i.v. for 5 days (n = 137) 60 5 19
Fludarabine phosphate 20 mg/m2 i.v. for 5 days plus
cyclophosphamide 600 mg/m2 i.v. for 1 day (n = 141) 74 23 32
31 Fludarabine phosphate 25 mg/m2 i.v. for 5 days (n =194) 80 15 b
Fludarabine phosphate 25 mg/m2 i.v. plus
cyclophosphamide 250 mg/m2 i.v. for 3 days (n = 196) 94 38 c
Chlorambucil 10 mg/m2 orally for 7 days (n = 387) 72 7 b
a
ORR = overall response rate, CRR = complete response rate, PFS = progression-free survival.
b
Five-year survival rate was 10%.
c
Five-year survival rate was 36%.

moimmunotherapy regimens that
combined rituximab with cyclophos-
phamide and a purine analogue have
yielded excellent results as first-line
treatment of CLL. For example, in a
study of 300 patients with previously
untreated CLL, the combination
of fludarabine (25 mg/m2 i.v. daily
for three days), cyclophosphamide
(250 mg/m2 i.v. daily for three days),
and rituximab (375500 mg/m2 i.v.
on day one), repeated every 28 days
for six cycles, resulted in an ORR of
95%, with a CRR of 72% at a median
follow-up of six years.40,41 Further-
more, fludarabine plus rituximab
demonstrated a 90% ORR and a 47%
CRR in 104 patients with previously
untreated CLL when administered
concurrently, compared with a 77%
ORR and a 28% CRR when ritux-
imab was administered after fluda-
rabine.42 The results of these studies
indicate that rituximab should be
used as initial treatment in CLL in
combination with established che-
motherapy regimens.
Alemtuzumab. Alemtuzumab is
a monoclonal antibody directed
against the CD52 antigen. In an
open-label, randomized trial involv-
ing 297 patients with previously
untreated CLL, alemtuzumab (initial
dose escalation, then 30 mg i.v. 3
times weekly for 12 weeks; n = 149)
was compared with chlorambucil (40
mg/m2 orally once every 28 days for
12 months; n = 148).43 Alemtuzumab
treatment resulted in a significantly
higher ORR (83%) and CRR (24%)
compared with chlorambucil (55%
and 2%, respectively; p < 0.0001 for
both ORR and CRR). Furthermore,
a longer PFS time was observed with
alemtuzumab (14.6 months versus
11.7 months, p = 0.0001). How-
ever, overall survival did not differ
between the two treatment groups.
Adverse-event profiles were similar,
with the exception of a higher rate
of infusion-related and cytomega-
lovirus events with alemtuzumab
and more nausea and vomiting with
chlorambucil. Based on the results
of this study, alemtuzumab was ap-
proved as a single agent for the treat-
ment of B-cell CLL in September of
2007.44
The combination of alemtuz-
umab (initial dose escalation, then
30 mg i.v. three times weekly for four
weeks) and rituximab (375 mg/m2 i.v.
weekly for four weeks) was studied as
early, first-line treatment in high-
risk CLL.45 Of 30 patients, 27 (90%)
responded to therapy, including 11
(37%) complete responses. Response
lasted a median of 14.4 months, and
9 patients required treatment for
progressive disease. These investiga-
tors recommended further studies
to determine whether the early-
treatment strategy decreases morbid-
ity and mortality for high-risk CLL.
Researchers also investigated
the combination of fludarabine
(25 mg/m2 i.v. daily for four days
every 28 days for four months) and
rituximab (375 mg/m2 i.v. weekly
for four weeks), followed by alem-
tuzumab (initial dose escalation,
then 30 mg i.v. three times weekly
for four weeks, beginning five weeks
after the final dose of fludarabine) as
first-line treatment in a Phase II trial
of 41 patients with CLL and small
lymphocytic lymphoma. Alemtu-
zumab was not well tolerated when
it was administered shortly after
the fludarabine and rituximab. The
investigators could not recommend
alemtuzumab as consolidation ther-
apy until the duration of treatment
and the interval after induction are
optimized.46
The German CLL Study Group,
however, found that alemtuzumab
consolidation therapy after first-line
fludarabine with or without cyclo-

1818 Am J Health-Syst PharmVol 67 Nov 1, 2010


phosphamide significantly improved
long-term clinical outcome.47 After
a median follow-up of 48 months,
patients receiving alemtuzumab con-
solidation therapy had a significantly
prolonged progression-free survival
compared with those who had no
further treatment (p = 0.004).
Bendamustine. Bendamustine is a
unique chemotherapeutic agent that,
despite being widely used in Ger-
many for decades for the treatment
of various hematologic malignan-
cies, was only approved in the United
States in 2008 for the treatment of
CLL. Structurally, bendamustine has
a nitrogen mustard residue similar
to that found in cyclophosphamide
and chlorambucil, and it has a benzi-
midazole ring similar to that found
in purine analogues. Preliminary
data revealed that bendamustine
is more stable than other nitrogen
mustards, suggesting that it may have
a longer time of activity in patients.48
Recommended bendamustine hy-
drochloride dosing is 100 mg/m 2
i.v. over 30 minutes on days 1 and 2
every 28 days for six cycles.49 Clinical
trials are currently evaluating ben-
damustine hydrochloride 70 mg/m2
i.v. on days 1 and 2 every four weeks
or when blood counts recover in pa-
tients with progressive CLL.50 As with
many agents, dosage reductions and
delays are recommended for certain
grade 4 and other hematologic tox-
icities.49 No formal studies have been
conducted in patients with impaired
renal or hepatic function.
In an open-label, randomized,
Phase III clinical study that com-
pared bendamustine (100 mg/m2 i.v.
daily for two days) with chlorambucil
(0.8 mg/kg orally daily on days 1 and
15) repeated every four weeks for
six cycles in 319 patients with previ-
ously untreated CLL, patients treated
with bendamustine had an ORR of
68%, compared with 31% for pa-
tients treated with chlorambucil (p <
0.0001), with CRRs of 31% and 2%,
respectively.51 Median PFS times were
21.6 and 8.3 months for patients
clinical review Chronic lymphocytic leukemia
treated with bendamustine and chlo-
rambucil, respectively (p < 0.0001).
No significant differences in overall
survival have been observed to date.
The most commonly observed
nonhematologic toxicities associ-
ated with bendamustine treatment
are fever (similar to that observed
with purine analogues), nausea,
and vomiting.49 Myelosuppression
is also relatively common; in the
aforementioned randomized study,
28% of patients who received ben-
damustine experienced neutropenia
(24% had grade 3 or 4), 23% experi-
enced thrombocytopenia (13% had
grade 3 or 4), and 19% experienced
anemia (3% had grade 3 or 4).51
Hematologic nadirs are expected in
the third week of therapy.51 A small
percentage of patients in clinical tri-
als and described in postmarketing
reports have developed infections,
infusion-related reactions, tumor
lysis syndrome, and rash.49 Premedi-
cation with antiemetics to prevent
vomiting and antihistamine to re-
duce the severity of infusion-related
reactions may be recommended for
some patients.
Treatment considerations. The
optimal duration of first-line CLL
therapy is often not well defined.
Treatment is usually continued until
there is a positive or negative change
in the patients status (i.e., complete
remission, disease progression, or
unacceptable toxicity). Therapy is
also usually terminated if a patients
status reaches a plateau with no
continued improvement (i.e., stable
disease). The utility of consolida-
tion therapy to eradicate MRD after
completion of first-line treatment is
being researched in several ongoing
trials. Thus far, studies that evalu-
ated alemtuzumab or rituximab as a
consolidation therapy for eliminat-
ing MRD revealed that patients free
of MRD after treatment experienced
both a longer remission duration and
a longer survival time.52-54 Toxicities,
including infections, continue to be
problematic in patients who have
Am J Health-Syst PharmVol 67 Nov 1, 2010
received consolidation therapy. The
optimal timing of consolidation
therapy relative to a patients initial
therapy is yet to be determined.
Treatment of recurrent CLL
After recurrence of CLL, the
selection of subsequent treatment
regimens depends on several factors,
including the safety and effective-
ness of previously used regimens.
In general, previous treatment regi-
mens make refractory disease more
difficult to treat. Response rates to
purine analogues after CLL recur-
rence after first-line therapy with an
alkylating agent tend to be higher
and of longer duration.22 The dura-
tion of response to initial therapy
also affects the response to subse-
quent therapies. If the response to
initial therapy lasts for longer than
612 months, patients are com-
monly rechallenged with the initial
regimen. In contrast, a new regimen
is generally used for patients whose
disease quickly progresses. How-
ever, once a patients CLL becomes
refractory to both alkylating agents
and purine analogues, outcomes are
generally poor, as treatment options
are limited, and response durations
are usually less than one year. All of
these patients will eventually suc-
cumb to complications related to
their disease.55
Alemtuzumab monotherapy has
been shown to induce responses in up
to 40% of patients with fludarabine-
refractory CLL.56 However, the re-
sponses have not been durable, and
the median survival has been one to
two years. Nevertheless, in a Phase II
study of subcutaneous alemtuzumab
without dosage escalation, 15 (75%)
of 20 patients with advanced-stage,
relapsed CLL responded to therapy.57
The median time to treatment failure
was 20 months. These investigators
indicated that extended studies of
this regimen are needed to confirm
these results.
Investigators evaluated the ad-
dition of granulocyte-macrophage
1819
 clinical review Chronic lymphocytic leukemia
colony-stimulating factor (GM-CSF)
to rituximab in patients with recur-
rent CLL.58 GM-CSF increases the
surface expression of CD20 on CLL
cells, potentially making them a bet-
ter target for rituximab. The ORR
of patients in this study was 65%,
but the study included patients who
were not previously treated. The
combination was well tolerated, and
investigators are evaluating GM-CSF
with a regimen of fludarabine, cyclo-
phosphamide, and rituximab.58
Treatment regimens that are cur-
rently used or being evaluated in
patients with previously treated CLL
are summarized in the appendix.59-70
SCT
SCT is a treatment option for se-
lect patients with CLL, particularly
those who are younger than 50 years
and are considered to be at high risk
of disease progression.71 Additional
indications for SCT include failure
after first-line fludarabine therapy,
relapse within 12 months of initial
treatment, and presence of del 17p
as detected by fluorescent in situ
hybridization. No prospective stud-
ies have directly compared the safety
and efficacy of autologous, alloge-
neic, and nonmyeloablative regimens
in CLL. While no prospective direct-
comparison trials have compared
standard chemotherapy with SCT,
autologons transplantation was as-
sociated with a potential survival
advantage compared with chemo-
therapy in a retrospective analysis of
107 patients with CLL.72
In addition, a study of 82 patients
with fludarabine-refractory CLL
who received hematopoietic SCT
after nonmyeloablative condition-
ing revealed complete remission in
55% and partial remission in 15% of
patients.73 Patients who underwent
transplantation from unrelated do-
nors achieved a higher CRR. After a
median follow-up time of five years,
the rates of nonrelapse mortality,
progression or relapse, overall sur-
vival, and PFS were 23%, 38%, 50%,
1820 Am J Health-Syst PharmVol 67 Nov 1, 2010
and 39%, respectively. Of the 25 ini-
tial complete responders, 84% were
alive and in complete remission at
the time of the report.
A retrospective study of 50 pa-
tients with advanced CLL compared
reduced-intensity conditioning
(RIC) to full myeloablative condi-
tioning.74 Despite the fact that the
RIC-treated group was older and had
more unrelated donors compared
with the group who received full
conditioning, the five-year overall
survival rate was significantly higher
in the RIC-treated group (63% ver-
sus 18%, respectively; p = 0.006). The
primary reason for inferior survival
rates in the group receiving full con-
ditioning was that transplant-related
mortality was twice as high in these
patients compared with the RIC-
treated group.
Investigational agents
Several new agents are being eval-
uated for use in CLL, including fla-
vopiridol, oblimersen, and lumilix-
imab. Alvocidib, a synthetic flavone,
inhibits multiple cyclin-dependent
kinases and has both antiproliferative
and apoptosis-inducing properties
in human CLL cells.75,76 While early
clinical evaluation of alvocidib in
CLL yielded disappointing results,77,78
a 2007 Phase I clinical trial involving
42 patients with refractory CLL dem-
onstrated better efficacy using an al-
ternative dosing strategy.76 This study
included three treatment groups that
received a 30-minute loading dose
of alvocidib 3040 mg/m2 followed
by a four-hour infusion of alvocidib
3050 mg/m2 once weekly for four
to six weeks. This regimen resulted
in a 45% partial response rate, with
42% of these responses occurring
in patients with high-risk cytoge-
netic traits. Furthermore, alvocidib
resulted in a durable response of
over 12 months. The dose-limiting
toxicity was tumor lysis syndrome,
the rate of which was greatly reduced
after implementation of an aggres-
sive monitoring procedure.76 These
results suggest that further evalua-
tion of alvocidib in CLL should be
conducted.
Oblimersen is an antisense agent
directed against the antiapoptotic
molecule Bcl-2, which is expressed
in virtually all patients with CLL.79
In vitro, oblimersen has been found
to down regulate bcl-2 mRNA and
Bcl-2 protein in concentration- and
time-dependent manners. 80 In a
2007 Phase III study, 241 patients
with relapsed or refractory CLL
previously treated with fludarabine
were randomized to receive either
fludarabine and cyclophosphamide
plus oblimersen or fludarabine plus
cyclophosphamide only.81 The ad-
dition of oblimersen to standard
fludarabine and cyclophosphamide
chemotherapy increased the ORR
from 7% to 17% (p = 0.025) and
tripled the CRR (from 2% to 9%, p =
0.03). Responses were durable and
associated with both an extended
time to progression and survival
time (p < 0.0001). Toxicities attrib-
uted to oblimersen included throm-
bocytopenia, infusion reactions, and
tumor lysis syndrome, whereas no
differences in infection rates were
noted between the two treatment
groups.81 Thus, oblimersen appears
to be active in CLL and is being
studied in combination with other
agents.
Lumiliximab is a chimeric
humanmacaque monoclonal anti-
body directed against CD23, which is
frequently expressed on CLL cells.82
While no responses occurred in a
Phase I evaluation of lumiliximab in
46 patients with relapsed or refrac-
tory CLL, lumiliximab treatment
resulted in a decrease in absolute
lymphocyte counts in 91% of pa-
tients and a reduction in lymphade-
nopathy in 52% of patients.83 The
most commonly observed toxicities
were headache, constipation, nausea,
and cough; grade 3 or 4 neutropenia
and dyspnea were noted in a small
percentage of patients. This agent is
being evaluated in combination with
 clinical review Chronic lymphocytic leukemia

fludarabine, cyclophosphamide, and

rituximab.84
Infection-related risks and
supportive care
Infection-related risks are a major
concern in CLL, including those at-
tributed to treatment and those asso-
ciated with the disease. Lymphopenia
and neutropenia are common in
patients with CLL, leading to a high
risk of recurrent infections, most no-
tably pneumonia.85,86 Patients treated
with different agents are susceptible
to different types of infections (Table
7). As alemtuzumab and purine ana-
logues are associated with the highest
risk of infection, patients receiving
these agents are commonly given
prophylactic antibacterial and anti-
viral agents, often for several months
after therapy has ended.86 In addi-
tion, patients receiving alemtuzumab
should undergo weekly monitoring
with polymerase chain reaction for
cytomegalovirus for the duration of
therapy and for two months after
treatment has stopped.87 Myeloid
growth factors may be used in patients
at risk of developing neutropenia.
While it is not known why hypo-
gammaglobulinemia occurs in 60%
of patients with B-cell CLL, it is ac-
cepted that serum immunoglobulin
G decreases as the disease progresses.
Immune globulin therapy has been
used in CLL to prevent infection. Pa-
tients treated with i.v. immune glob-
ulin have fewer bacterial infections,
but this therapy has not been shown
to decrease the rate of nonbacterial
infections.88 Investigators have also
studied the prophylactic use of low-
dose immune globulin and found
that increased serum immunoglobu-
lin levels do not necessarily correlate
with reduced infections.87
Investigators have considered
vaccination against various infec-
tions in patients with CLL. However,
these patients do not respond well
because their antibody production
is impaired. Protein and conjugate
vaccines may be more effective than
Table 7.
Specific Infections Associated With Therapies for Chronic
Lymphocytic Leukemia86
Therapy
Alemtuzumab Herpes simplex virus, cytomegalovirus, Candida species,
Aspergillus species
Alkylating agents Bacterial
Purine analogues Candida species, Aspergillus species, herpes simplex virus,
Pneumocystis species
Rituximab No significant infections, reactivation of hepatitis B
bacterial polysaccharide vaccines,
and ranitidine may further improve
the benefit of protein and conjugate
vaccines.89 The appropriate vaccina-
tion strategy in patients with CLL
requires further investigation.
Conclusion
Chemotherapy remains the main-
stay of treatment for the majority of
patients with CLL. The introduction
of rituximab, alemtuzumab, and
bendamustine has improved the cur-
rent outlook for patients with CLL.
As overall survival does not appear
to depend on the initial therapy,
treatment should be selected based
on patient-specific factors and goals.
Challenges in CLL include determin-
ing when to initiate therapy, eradicat-
ing MRD, and managing therapeutic
resistance.
Addendum
Since the time of manuscript prep-
aration, FDA approved the marketing
of a new drug, ofatumumab, labeled
for monotherapy in patients with
CLL that is refractory to fludarabine
and alemtuzumab.91-93
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AppendixSelect treatment regimens

for patients with previously treated
chronic lymphocytic leukemia59-70
Fludarabine
Fludarabinecyclophosphamide
Fludarabinecyclophosphamidemitoxantrone
Bendamustinemitoxantrone
Fludarabinecyclophosphamiderituximab
Pentostatincyclophosphamiderituximab
Rituximab, escalated doses or thrice weekly
Bendamustinerituximab
Alemtuzumab
Fludarabinealemtuzumab
Alemtuzumabrituximab
Fludarabinecyclophosphamiderituximab
alemtuzumab

1824 Am J Health-Syst PharmVol 67 Nov 1, 2010

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