Current Treatment Options in Oncology

DOI 10.1007/s11864-013-0229-5

Leukemia (JP Dutcher, Section Editor)

Update on Chronic
Lymphocytic Leukemia:
Overview of New Agents
and Comparative Analysis
Sanford Kempin, MD
Address
Beth Israel Comprehensive Cancer Center, 325 West 15th Street,
New York, NY 10011, USA
Email: skempin@chpnet.org

* Springer Science+Business Media New York 2013

Keywords Chronic lymphocytic leukemia I New agents I Targeted therapy I Immunomodulation

Opinion statement
Treatment options for lymphoproliferative disorders, including chronic lymphocytic
leukemia (CLL), increasingly are based upon molecular targets, taking advantage of
the immense research output over the past several years elaborating genetic abnormal-
ities, downstream signaling, cell-surface immunobiochemistry, and microenvironmen-
tal stimuli. The latter targets have been particularly useful for the treatment of
multiple myeloma, transforming a previously uniformly, fatal disease to one of a more
chronic and potentially curable disorder. Subsequently, new treatment approaches are
less likely to be based on the more classic types of cytocidal therapy, which, although
successful and essential for the more aggressive disorders that are immediately life-
threatening, tend to be less so, with respect to quality of life, risk versus benefit ratio
and overall curability for the indolent diseases. Because the majority of newer agents
are not available to the clinicians practicing in the community, a number of treatment
options developed over the past two decades are capable of significantly improving the
quality of life of patients with advanced CLL. The initial clinical approach to the patient
should be based on performance status, age, comorbidities, and increasingly on prog-
nostic factors elucidated over the past three decades. Initially, both simple laboratory
studies and easily measurable clinical manifestations were used to guide the clinician
(lymphocyte count, anemia, thrombocytopenia, enlarging lymph nodes, splenomegaly,
hepatomegaly), and clinical staging systems were developed. At present a cadre of bi-
ologic factors, including cytogenetic alterations, gene expression profiles with subse-
quent immunoglobulin abnormalities, and expression of CD38 and Zap-70, are now
available and are standard decision-making criteria to treat a patient with CLL. An ini-
tial period of observation allows the clinician along with the patient to gather all the
information necessary to make an informed treatment decision. Frequently, a “watch
and wait” approach, which for CLL does not appear to harm the patient, is the most
 Leukemia (JP Dutcher, Section Editor)

appropriate decision. Complications of CLL, such as autoimmune hemolytic anemia and

idiopathic thrombocytopenic purpura, will lead to treatment at least temporarily in
those patients who might otherwise have not needed therapy. Frontline therapy will
range from easily administrable single-agents to combination chemoimmunotherapy
regimens. Experimental protocols, utilizing “post state of the art” treatments, are
available in the form of research protocols at major treatment centers. At the present
time, it is premature to recommend bone marrow ablative therapy as initial treatment
unless the prognosis appears grave and the patient can withstand the rigors of
this approach.

Introduction
CLL is the most commonly encountered leukemia,
with an incidence in the United States of 22–30 per
100,000 in patients older than age 65 years and a me-
dian age at diagnosis of 72 years [1]. At present, both
internists and hematologists are observing that “rou-
tine” physical evaluations in younger patients often
demonstrates abnormalities of the complete blood
count, particularly the neutrophil/lymphocyte ratio,
which lead to further evaluations and a diagnosis of
a clonal B-cell proliferation.. The clinical manifesta-
tions of CLL range from an asymptomatic patient with
minimal B-cell lymphocytosis to a progressive clinical
picture of enlarging lymph nodes, splenomegaly, ane-
mia, thrombocytopenia, and life-threatening infections.
Historically, the treatment for CLL has been one of
an eradicative approach utilizing agents and proce-
dures with direct cell-kill capacity. Radiation therapy
was the initial therapy of CLL and numerous treatment
modalities were explored, some of which were quite
successful in controlling the disease and normalizing
blood counts [2]. Subsequently, single- and multiple-
agent chemotherapy and more recently combinations
of chemotherapy and monoclonal antibodies have be-
come the standard approaches. With our increasing
ability to understand, at a molecular level, the basic
properties of B cells, such as differentiation, prolifera-
tion, cell death-apoptosis, and crosstalk between other
lymphoid and nonlymphoid cell populations in the
environmental niches, it becomes evident that there
are now an increasing number of targets, leading to
what might now be called “downstream therapeutics,”
taking advantage of the structure and function of
these targets.
During the past 100 years, numerous therapeutic
trials have been reported for the treatment of CLL.
These trials have been used with less than an ideal
appreciation of the heterogeneity and natural history
of the disease. With the application of the Rai clinical
staging system [3], one can begin to appreciate the
benefit, or lack thereof, of these therapeutic interven-
tions. During the past two decades, an increasing
number of prognostic factors not only have opened
the door to understanding the clinical heterogeneity
of the disease but have led to possible therapeutic
implications not previously appreciated. As we have
begun to understand the natural history of CLL, the
need for observation versus treatment has become
the most important determinant in a clinician’s initial
approach to the patient.
Recognized since the modern era of treatment of
the disease were patients who developed a lymphocy-
tosis consistent with CLL but in whom treatment was
unnecessary and survival was similar to an aged-
matched control population. Benign monoclonal lym-
phocytosis (BML) [4] has been studied for the past de-
cade, and although this entity itself may have its own
heterogeneity, the basic mechanisms responsible for
its lack of progression in most patients into a symp-
tomatic disorder have not been elucidated. The impor-
tance of recognizing this population is to prevent the
utilization of unnecessary and even potentially lethal
treatment in the absence of clinical indications.
It is essential that a period of observation be under-
taken before a treatment decision is made unless life-
threatening complications are present. Once clinical
acumen and laboratory parameters lead to a decision
to treat the patient, a variety of options are available.
Risk stratification is helpful when deciding upon a
treatment modality [5••]. These options, depending
upon the clinical situation, may include the use of
alkylating agents alone to the more recent combina-
tion therapies developed over the past two decades
[6, 7, 8••, 9]. Recently, a number of new agents have
demonstrated important clinical efficacy, and some
 Update on Chronic Lymphocytic Leukemia: Overview of New Agents Kempin

have been approved for use in CLL, but it is not yet to cure the disease, this accumulation of new agents
possible to compare their overall efficacy to the more offers the future potential for an” almost” cure (i.e., ty-
standard regimens. However, in view of the fact that rosine kinase inhibitors for the treatment of chronic
less than marrow ablative approaches are not likely myelogenous leukemia) with less morbidity.

Current Treatment Approaches in the Modern Era

Before the introduction of purine nucleoside analogues (PNA), the concept
of cure of CLL was not seriously considered as a therapeutic goal except at
centers devoted to stem cell transplantation. Alkylating agents were success-
ful at controlling clinical manifestations and normalizing blood counts.
However, these treatments appeared to have only modest impact on survival.
Patients inexorably relapsed from what were only partial remissions. Com-
bination chemotherapy, beginning with the introduction of corticosteroids
[10], was developed both in the United States and Europe [11–13], and al-
though significant numbers of complete responders were reported in various
trials, there was no evidence that eradication of the disease had occurred and
patients eventually relapsed. It was clear that to eradicate this disease one had to
be able to demonstrate the absence of minimal residual disease (MRD) if one
were to hope for eradication of the malignant clone(s) of cells and restoration of
normal hematopoiesis [14]. Before the modern era of therapy, this remained an
elusive endpoint, other than in the setting of marrow ablative approaches
[15••]. PNA therapy was introduced in the early 1970s and in combination with
alkylating agents and monoclonal antibodies has become the standard treat-
ment approach. Responses to these combinations in appropriately chosen pa-
tient populations are successful in achieving long-term, disease-free intervals as
well as a survival advantage compared with earlier treatments.

Purine Nucleoside Analogues (Pentostatin, Cladribine, Fludarabine)

Deoxycoformycin (Pentostatin (P); Bedford) was the first purine analogue to
enter clinical trials, and the results as reported by Grever et al. were impressive
[16]. By combining it with an alkylating agent (cyclophosphamide) and a CD-
20 monoclonal antibody (PCR), a particularly effective combination is now in
use as front-line therapy [17, 18]. Cladribine (Leustatin; Janssen Biotech)
demonstrated promising results with complete and partial remissions of 38 %
and 37 % respectively in untreated patients [19]. Grade III and IV toxicities were
significant, and this agent is only rarely used today for this indication.
Fludarabine (Fludara; Genzyme) was initially developed for the treatment of
acute myeloid leukemia. However, at marrow ablative doses this agent was le-
thal. By pharmacokinetic manipulation, Keating et al. [20] were able to establish
a therapeutic dose that was highly effective at inducing remissions. The addition
of an alkylating agent (cyclophosphamide) [21] and a CD-20 monoclonal an-
tibody-rituximab (FCR) [22] has given similar responses to the PCR combina-
tion, and both are now considered frontline therapies. It should not, however,
be forgotten that alkylating agents, as a single modality, in patients in whom
disease “eradication” would appear to be unrealistic, is still a reasonable ap-
proach [23]. Unfortunately, even with such aggressive therapy (PCR, FCR), the
 Leukemia (JP Dutcher, Section Editor)

eradication of the disease, at least at the molecular level, is still not possible and
short- and long-term side effects, such as immunosuppression with resultant
infections [24••] and second malignancies (a complication known to be in-
creased in patients with CLL as a reflection of its natural history) have been
reported [25]. The encumbrance of administration and toxicities of these agents
in combination, however, is likely to decrease, if not abolish their use, as more
directed approaches, taking advantage of the pathophysiology of CLL cells and
their environmental niche, are found to be at least as equally effective and less
toxic. Bendamustine (Treanda; Cephalon) was produced to take advantage of
both the alkylating agent and purine nucleoside properties of a single molecule
[26]. At present, the drug is thought to act predominantly as an alkylating agent.
Both as a single agent and in combination with monoclonal antibodies,
bendamustine has demonstrated significant activity in non-Hodgkin lympho-
ma and CLL [27] and currently is being used as initial therapy and in numerous
clinical trials.

Stem-Cell Transplantation
Stem-cell cell transplantation has been utilized for nearly three decades for
the treatment of CLL and the most recent updates confirm its efficacy in
eradicating the disease [28••]. Previously limited to younger patients with
minimal comorbidities, clinical situations that are unusual in a standard CLL
population, reduced intensity conditioning offers older patients an oppor-
tunity for this approach [28••]. Adoptive immunity utilizing modified T cells
to recognize B-cell antigens is the most intriguing of new therapies and may
ultimately replace our standard treatment regimens [29••].

Monoclonal Antibody Therapy

An ideal therapeutic intervention would consist of targeting a specific molecule,
one found only on the malignant cell. Studies on the immunoglobulin-ex-
pressing B cell demonstrated the feasibility of this approach in non-Hodgkin
lymphoma, and in fact long-term survival was demonstrated [30]. This ap-
proach utilizing unique idiotypes to produce the antibodies, being labor in-
tensive, led investigators to direct efforts toward the production of antibodies
utilizing less specific but more generalized tumor antigens as targets. In CLL,
mainly unconjugated antibodies have been used. Examples of such targets in-
clude CD 20 [31] and CD 52 [32]. The mechanisms of tumor cell destruction
include antibody-dependent cell cytotoxicity (ADCC), complement-dependant
cytotoxicity (CDC), and signaling pathways of apoptosis.
Rituximab (Rituxan; Genentech), the first monoclonal antibody approved
for the treatment of lymphoproliferative disorders, is directed against the CD
20 epitope, important in calcium transport. Since Phase I studies were
completed, there have been numerous reports of its efficacy as a single agent
in CLL [33]. The results were modest compared with its use in non-Hodgkin
lymphomas. Decreased expression of CD 20 was thought to be the pre-
dominant reason for this difference [34]. Modulation of surface CD20 by
bortezomib (Velcade; Millennium), epigenetic alteration of gene expression
and increase in dose may improve its efficacy [35–37]. A significant deter-
minant of its efficacy is related to single nucleotide polymorphisms of
FcgRIIIa and FcgRIIa [38]. The use of rituximab has now become part of the
 Update on Chronic Lymphocytic Leukemia: Overview of New Agents Kempin

standard front-line regimen in CLL after studies showing significant activity

when combined with a purine nucleoside analogue. The German CLL Study
group demonstrated significant benefit compared with fludarabine alone
[39]. The triplet utilizing FCR was more successful than FC [40], thus
establishing the rational for triplet therapy in the frontline or relapse
setting. Rituximab has been found to be useful in treating several com-
plications of CLL (and other lymphomas), including idiopathic throm-
bocytopenic purpura (ITP) [41], autoimmune hemolytic anemia (AIHA)
[42], and red cell aplasia (RCA) [43]. Rituximab maintenance therapy after
maximal initial response has become standard practice for the treatment
of non-Hodgkin lymphoma and has been explored for the treatment of
CLL [44].

Campath-1H
Campath-1H (Alemtuzumab; Genzyme), a monoclonal antibody, is directed
against the CD52 antigen, expressed on lymphocytes, at nearly all stages of
differentiation, as well as granulocytes, eosinophils, monocytes, and mac-
rophages. Significant activity has been well documented [45]. Its mechanism
of action is related to ADCC, CDC, and direct cell death and appears to be
independent of the p53 abnormality noted in resistant CLL [46]. Subcuta-
neous administration has led to a more easily administrable regimen [47].
This represents a reasonable single-agent to treat refractory patients.
Antibacterial and antiviral prophylaxis are used during its administration as
infectious complications, particularly reactivation of CMV may be life-
threatening in this population [24••]. Alemtuzumab has been used along
with a PNA combination [48]. When used as a consolidation program after
maximal efficacy of one of the PNA regimes, significant toxicity was observed
[49, 50]. Consolidation after PCR is still being explored as part of a clinical
trial. Its ability to improve blood and bone marrow involvement has led to
its use as a preparatory regimen for stem-cell transplantation [51].

Ofatumumab (Arzerra; GlaxoSmithKline and Genmab A/S)

This agent, specific for the CD20 molecule but distinct from the epitope
recognized by rituximab, is reported to have more CDC activity than
rituximab [52]. In combination with fludarabine and cyclophosphamide,
it has significant activity in the initial treatment of high-risk patients
[53]. However, its overall efficacy, particularly in patients with the 17p
deletion and bulky disease, is modest.

Other Monoclonal Antibodies and Immunoconjugates

The CD20 molecule is the target for GA101 (obinutuzumab) a type II hu-
manized monoclonal antibody, which differs in its binding properties from
the type I agents, such as rituximab and ofatumumab [54]. The benefits,
relative to rituximab, include lack of internalization as seen with type I agents
and induction of nonapoptotic cell death through lysosomal mediation [55].
A number of monoclonal antibodies are in clinical development, includ-
ing HU1D10, a humanized monoclonal antibody, developed against a var-
iant of an epitope on the HLA-DR B chain [56]. Clinical studies have
demonstrated activity in CLL [57]. Lumiliximab, directed against CD 23, has
 Leukemia (JP Dutcher, Section Editor)

demonstrated activity for inducing ADCC and apoptosis in CLL cells and clinical
trials, particularly in combination with FCR, have been reported recently, with
disappointing results [58]. TRU-016, a modification of a CD 19 antibody has
completed phase 1 clinical trials [59]. Other antibodies being explored include
those targeting CD 19 (XmAb5574) and CD 22 (epratuzumab) [60].
It is unclear at this time whether further attempts at using monoclonal an-
tibodies, as single-treatment modalities, will be undertaken. Rather, their
combinations with other specific targeted therapies may yield significant
advances. Immunoconjugates represent an attempt to improve the thera-
peutic efficacy of monoclonal antibodies. LMB −2, a conjugate utilizing a
pseudomonas exotoxin, directed against CD25 demonstrated significant re-
sponses in CLL [61] as has the anti CD-22 immunotoxin BL-22 [62]. It is not
known whether further immunoconjugates will be developed specifically for
CLL.

Innovative Biologic Therapy

Recent insights into the biology of CLL cells and their interaction with the
microenvironment (mesenchymal stromal cells, monocyte-derived nurse-like
cells, T cells, and matrix) have led to new targets for agents that may be used
singly or added to more standard regimens [63, 64, 65••]. Bone marrow
stromal cells (BMSC) provide both the structural integrity to support CLL cell
growth as well as growth factors. There is a bidirectional cross-link between
BMSCs and CLL cells; the relationship is maintained by chemokine receptors
(CXCR4 and CXCR5) and adhesion molecules (VLA-4). The B-cell receptor
(BCR) is essential to maintain the B-cell clonal expansion through down-
stream interactions with a series of tyrosine kinases, including spleen tyrosine
kinase (Syk) and Bruton tyrosine kinase (BTK) and secretion of cytokines
(CCL3) functioning as chemoattractants for T cells and monocytes [63, 64].

B-Cell Receptor Signaling Pathway and Kinase Inhibitors

Dasatinib (Sprycel; Bristol-Myers Squibb): This broad-spectrum tyrosine
kinase inhibitor, presently used as up-front therapy of chronic myelog-
enous leukemia, demonstrates modest activity in CLL with
myelosuppression as the predominant side-effect [65••, 66••, 67, 68].
Ibrutinib (PCI-32765): This is an irreversible inhibitor of BTK [69••].
This agent also has been found to inhibit microenvironmental stimuli
[70••]. Significant activity has been observed in CLL with an acceptable
side effect profile. Lymphocytosis is a common occurrence in this class
of agents. Studies are ongoing, combining ibrutinib with monoclonal anti-
bodies and bendamustine [71••]. Further combination studies are anticipated.
Fostamatinib (R406 pro-drug): This is a reversible inhibitor of Syk. Modest
activity has been observed in SCLL/CLL with minimal toxicity. Lymphocytosis is
commonly observed [72].
GS-101 (CAL-101): This is a reversible inhibitor of P13KD form of the
p110 catalytic subunit [73]. As a part of the BCR activation sequence,
P13K appears to be constitutively active in CLL. Inhibitors of this group
promote caspase-dependent apoptosis and inhibit the protective nature
of stromal cell (nurse cells) interaction with CLL cells, with downregulation of
chemokines and cytokines. The major side-effects are liver function ab-
 Update on Chronic Lymphocytic Leukemia: Overview of New Agents Kempin

normalities and, as expected, lymphocytosis. This agent has been com-

bined with rituximab and bendamustine with an acceptable side effect
profile [74].

BCL-2 Inhibition
Oblimersen sodium: BCL-2 is universally expressed and upregulated in CLL
cells, possibly related to a deletion of miRNA regulators. Antisense oli-
gonucleotides that bind mRNA, inducing enzymatic cleavage and inhibi-
tion of protein translation, have been developed during the past 20 years
and have been utilized in BCL-2–expressing lymphoid malignancies. The
first to enter clinical trials in CLL was oblimersen sodium, which dem-
onstrated modest activity as a single agent [75]. Myelosuppression was the
major toxicity. First cycle reactions, such as tumor-lysis syndrome, were
reported. This agent has been combined with rituximab and cyclophos-
phamide, demonstrating an increase in the CR/nPR rate [76]. There are
no plans at this time for further development.
ABT-263 (Navitoclax): This agent inhibits BCL-2, BCL-xl, and BCL-w, induc-
ing apoptosis of CLL cells [77]. Responses were seen in fludarabine refractory
patients and this drug is now in clinical trials [78]. Agents in this group of drugs
might sensitize the cells to the apoptotic effects of rituximab [79].
Homoharringtonine: This inhibitor of Mcl-1, a member of the Bcl-2 fam-
ily of antiapoptotic proteins, was developed originally for the treatment of
acute myeloid leukemia and now used for the treatment of CML, has dem-
onstrated significant in vitro activity against CLL cells and will be entering
into clinical trials [80].

Immunomodulation
Lenalidomide (Revlimid; Celgene): The introduction of immunomodulating
drugs (IMiDs) has revolutionized the treatment of multiple myeloma [81]
and improved patients with the myelodysplastic syndrome [82].
Lenalidomide, a thalidomide analogue, apart from its significant activity in
MDS and multiple myeloma, has been shown to decrease the production of
growth factors, which prolong the survival of CLL cells [83]. These include
vascular endothelial growth factor and TNF-a, which may alter the micro-
environment in favor of CLL proliferation. The overall response rate in re-
lapsed or refractory CLL patients was significant, but with no evidence of
specificity for the 17p resistant patients [84••]. Life-threatening tumor flares
and a tumor lysis syndrome were observed at a dose of 25 mg/d for 21 days
[85] and safer schedules are being explored. It is feasible to combine
lenalidomide and monoclonal antibodies [86, 87] and chemotherapy [88];
however, significant toxicity remains a problem and the most appropriate
treatment schedule for lenalidomide has not yet been determined.

Conclusions
The treatment of the symptomatic patient with CLL remains a therapeutic
challenge. The availability of active agents and combinations has improved
the quality of life and for some has resulted in a survival advantage. How-
ever, the “cure” for the disease, defined as best as we can by ablation of clonal
 Leukemia (JP Dutcher, Section Editor)

lymphopoiesis, and normalization of the immune response has not yet been
accomplished. The initiating event in this disease is still mysterious; the
primeval immune dysregulatory event has not been defined, taking into
consideration the numerous genetic abnormalities discovered. The familial
nature of immune disorders seen in this population and its association with
aging favor a still undefined genomic basis. Because normalization of the
immune system is still not possible other than by allogeneic reconstitution,
our present strategies will consist of treating those manifestations of the
disease as described and at the same time exploring new therapeutic strate-
gies. With clinical expertise, the improvement in quality of life of patients
with this disorder should be the most important goal. As reviewed, at least a
number of options are available to patients, and over the next several years
many of the new treatments being explored are likely to become standard.
However, unless combined with basic research programs, the disease is not
likely to be eradicated. The most recent studies of clonal evolution of CLL [89,
90] demonstrate the need for early initial, radical elimination of the malignant
cell before resistance may occur or the need for multiple targeted therapy—ei-
ther upfront or sequentially—an approach that has been highly successful for
the treatment of AIDS.

Conflict of Interest
Sanford Kempin is a consultant for Celgene.

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