MTD | 113-070A | Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia

Since CLL remains incurable with
standard therapies due to
development of disease refractoriness,
continued research is needed to
develop improved treatment
outcomes for patients with CLL.
Gracia Dayton. City Snails. Watercolor on paper, 13⬙ × 22⬙.
Treatment of Relapsed or Refractory
Chronic Lymphocytic Leukemia
Marays Veliz, MD, and Javier Pinilla-Ibarz, MD, PhD
Background: Recent advances in the treatment of chronic lymphocytic leukemia (CLL) have moved beyond
the traditional use of alkylating agents and purine analogs into regimens combining these two chemotherapy
classes with monoclonal antibodies.
Methods: This article reviews treatments options for patients with relapsed or refractory CLL.
Results: Several studies have investigated novel agents in treating patients with 17p deletion, TP53 mutation,
and fludarabine-refractory CLL, as well as patients with suboptimal response to intense treatment. These
investigational agents include rituximab, alemtuzumab, ofatumumab, bendamustine, high-dose methylprednisolone,
lenalidomide, lumiliximab, cyclin-dependent kinase inhibitors, small modular immunopharmaceuticals, Bcl-2
inhibitors, and histone deacetylase inhibitors. While these newer drugs and combination therapies have shown
promise as treatment options for CLL, additional studies are needed to determine the immunosuppression, toxicities,
and infections associated with their use.
Conclusions: Despite improvement in initial overall response rates, most patients relapse and require further
treatment. CLL remains incurable with standard therapies due to development of disease refractoriness. As such,
novel approaches such as those noted above warrant continued research to improve outcomes for patients with CLL.
Introduction
Although recent advances in first-line therapy of chronic
lymphocytic leukemia (CLL) have prolonged the duration of first remission, patients eventually experience
disease progression, with limited therapeutic options.1,2
In general, patients with asymptomatic relapsed disease should be followed expectantly, and indications
From the Department of Malignant Hematology at the H. Lee Moffitt
Cancer Center & Research Institute, Tampa, Florida.
Submitted May 20, 2011; accepted October 3, 2011.
Address correspondence to Javier Pinilla-Ibarz, MD, PhD, Department
of Malignant Hematology, Moffitt Cancer Center, 12902 Magnolia
Drive, Tampa, FL 33612. E-mail: Javier.Pinilla@moffitt.org
Dr Veliz reports no significant relationship with the companies/
organizations whose products or services may be referenced in this
article. Dr Pinilla-Ibarz receives honoraria from GlaxoSmithKline
Corp, Genentech Inc, and Cephalon Inc.
January 2012, Vol. 19, No. 1
for reinitiation of treatment should follow the same
guidelines of the National Cancer Institute (NCI) and
the International Workshop on Chronic Lymphocytic
Leukemia (IWCLL) for these patients as for previously
untreated patients.3,4
Treatment selection of relapsed disease depends on
a variety of factors, including patient age, performance
status, duration of response to initial therapy, type of
prior therapy, disease-related manifestations, and genetic
abnormalities within the CLL cells. In most cases, firstline therapy can be repeated if the duration of response
has lasted more than 1 year. On the other hand, treatment decisions are more challenging in patients with
therapy-refractory disease or with the 17p deletion and
TP53 mutation. Fluorescence in situ hybridization (FISH)
imaging should be performed in all patients to determine cytogenetic abnormalities before making treatment
Cancer Control 37
decisions since many patients with relapsed CLL often
acquire high-risk chromosomal abnormalities such as
del11(11q12) and del17(17p13). These abnormalities
result in resistance to most conventional chemotherapies
used in the treatment of CLL. Among patients with highrisk prognostic factors, a subgroup of very high-risk CLL
patients can be identified, with median survival below
24 to 36 months at the treatment time point. Based on
this definition, patients with 17p deletion (5% to 8%),
TP53 mutation (4% to 5%), and fludarabine-refractory
CLL (5%), as well as patients with suboptimal response
to intense treatment, belong in this group.5 Fludarabinerefractory disease is defined as CLL that does not respond
to fludarabine or that recurs within 6 months of treatment with a fludarabine-containing regimen. In contrast
to the encouraging clinical outcomes of patients with
fludarabine-sensitive disease, the prognosis of patients
with fludarabine-refractory CLL is poor, with a median
survival of less than 1 year.6,7 A single-institution report
of 99 patients with CLL refractory to fludarabine and
alemtuzumab showed an overall response (OR) rate of
23% to salvage therapy other than stem cell transplantation (SCT), with no complete responses (CRs) and an
overall survival (OS) of 9 months.7 Thus, new agents are
needed for the treatment of these patients, particularly
for those with high-risk cytogenetic abnormalities such
as 17p deletion, for which allogeneic SCT remains the
only therapy that offers a prolonged progression-free
survival (PFS). This review focuses on treatments options
for patients with relapsed or refractory CLL.
Outcomes With Salvage Chemotherapy
Resistance to purine analogs is emerging as a major challenge in the management of patients with CLL. Most of
these patients have already been exposed to and have
become refractory to alkylating agents. The response
rate to fludarabine alone in relapsed CLL ranges from
45% to 65%, and it is even lower in patients refractory to
initial therapy (20%).8-13 In a retrospective review of 147
patients with CLL who were refractory to fludarabine or
had a remission of less than 6 months in duration after
a fludarabine-containing regimen, the OR rate was 22%
to the first salvage regimen, with a median survival of 10
months.6 The response rate was highest in the group
receiving combination therapy with a purine analog and
alkylating agent (37%; 16 of 43 patients). The response
rates for alkylating agent-refractory, alkylating agent-naive, and alkylating agent-sensitive CLL were 18%, 22%,
and 40%, respectively, with respective survival rates of 8
months, 10 months, and 14 months. As expected, survival
was longer in responders than in nonresponders. Among
patients treated with a second salvage regimen, the best
response rates were noted in those who underwent SCT
(6 of 9 patients responded) and in those who received
alemtuzumab (4 of 6 patients responded).6 In patients
with fludarabine-refractory CLL, the response rate to
38 Cancer Control
the combination of fludarabine and cyclophosphamide
therapy was 39% (3% CR).14
In a study including 88 patients with CLL, the response rate to the combination of fludarabine and mitoxantrone was 50% in those with fludarabine-sensitive relapsed CLL and 25% in those with fludarabine-refractory
disease, but overall the combination of these agents did
not show a significant advantage over fludarabine alone.15
The combination of fludarabine, cyclophosphamide, and
mitoxantrone (FCM) in 60 patients with relapsed or refractory CLL induced a response in 78% with a CR rate of
50%, including 17% achieving negative minimal residual
disease (MRD), and a partial response (PR) rate of 28%.
The median duration of response was 19 months.16 Similar results were reported in a smaller study that included
29 patients with relapsed or refractory CLL who achieved
a response rate of 78% (32% CR, 25% nodular PR, 21%
PR), a median duration of response of 19 months, and a
median survival of 42 months.17
Rituximab as a Single Agent
Rituximab, a chimeric murine/human monoclonal antibody directed against CD20, has revolutionized the
approach to patients with various B-cell malignancies,
including CLL, because of its activity, its non–cross-resistance with chemotherapy, and its favorable safety profile.18 In a pivotal phase II study, 50% of patients affected
by follicular lymphoma achieved at least a PR.19 However,
an OR rate of 13% (all PRs) was observed in patients with
relapsed or refractory small lymphocytic lymphoma (SLL)
or CLL. Similar modest results have been reported in
other small trials in which rituximab was administered as
a single agent, with poor OR rates ranging from 6% to 35%
(PRs) in the treatment of relapsed CLL.20-24 Single-agent
rituximab has inferior clinical activity in CLL where it is
less effective for clearing disease from the bone marrow
and has a short response duration.24
Attempts to enhance the efficacy of rituximab have
included increasing either the dose or the dose density
of its administration, which has improved the benefit
of rituximab in CLL but neither with success. A study
of single-agent rituximab using a thrice-weekly dosing
schedule in 33 previously treated or untreated patients
reported a 45% OR rate, including 42% PRs and an overall
median duration of response of 10 months.25 Thirteen
patients experienced transient hypoxemia, hypotension,
or dyspnea, and 1 patient discontinued therapy because
of infusion-related toxicity despite a schedule of steppedup dosing. Moreover, the median time to progression
(TTP) was only 6 months. A group from the MD Anderson
Cancer Center escalated the rituximab dose from 350
mg/m2 to 2,250 mg/m2 in 40 previously treated CLL cases
and in 10 other patients with mature B-cell leukemias
with improved response.26 The OR rate was 40% (36%
in CLL, all PRs), and response was correlated with dose:
22% for patients treated at a dose of 500 mg/m2 to 825
January 2012, Vol. 19, No. 1
mg/m2, 43% at a dose of 1,000 mg/m2 to 1,500 mg/m2, and
75% for those treated at the highest dose of 2,250 mg/
m2. Benefit was predominantly in the blood and nodal
compartment, with response duration approaching that
achieved in follicular lymphoma.
Chemoimmunotherapy
The combination of fludarabine, cyclophosphamide, and
rituximab (FCR) was developed based on in vitro and
in vivo data indicating complementary activity with the
combination. In vitro, fludarabine inhibits repair of cyclophosphamide-induced DNA interstrand cross links.27
Fludarabine combined with cyclophosphamide (FC) increased the remission rate and duration compared with
single-agent fludarabine in previously treated patients
with CLL.14,28 Exposure of fludarabine and rituximab in
the human B-cell non-Hodgkin lymphoma (NHL) cell line
produced a synergistic effect. Fludarabine downmodulated the membrane expression of complement inhibitory
proteins CD46, CD55, and CD59 on B-cell CLL cells without significantly altering CD20 levels, thereby potentially
making these cells more susceptible to rituximab-induced
complement-dependent cytotoxicity.29 Furthermore, in
vitro studies have shown that rituximab sensitizes NHL
to chemotherapeutic drugs through downregulation of
antiapoptotic IL-10 autocrine/paracrine loops and bcl2, making CLL B cells potentially more vulnerable to
fludarabine-induced apoptosis.30
The efficacy, toxicity, and tolerability of chemoimmunotherapy with FCR were evaluated in previously treated
patients with CLL. In one study, 177 patients received
fludarabine 25 mg/m2 per day on days 2–4 of cycle 1 and
on days 1–3 of cycles 2 to 6, cyclophosphamide 250 mg/
m2 per day on days 2–4 of cycle 1 and on days 1–3 of
cycles 2 to 6, and rituximab 375 mg/m2 on day 1 of cycle
1 and 500 mg/m2 on day 1 of cycles 2–6.31 Cycles were
repeated every 4 weeks. Of the 82% of patients who had
previously received fludarabine, 21% were fludarabinerefractory. Among the 177 patients, 3%, 47%, and 50%
of patients had low-risk, intermediate-risk, and high-risk
disease, respectively. The 6 intended courses of treatment
were administered to only 46% of patients. The OR rate
was 73% (25% CR, 16% nodular PR, and 32% PR). Twelve
(32%) of 37 CRs tested achieved molecular remission in
bone marrow. The median TTP for patients achieving a
CR, nodular PR, and PR was 39, 33, and 15 months, respectively. The estimated median survival for all patients
was 42 months. Moreover, the estimated median survival
for CRs and nodular PRs had not been reached but was
estimated to be ≥ 45 and 30 months, respectively. The
estimated median survival was 39 months for PRs and
11 months for nonresponders. The most common toxicities were neutropenia (grade 3/4 in 81% of patients),
thrombocytopenia (grade 3/4 in 34%), anemia (grade 3/4
in 24%), fever of unknown origin (31%), major infections
(16%), and minor infections (18%).
January 2012, Vol. 19, No. 1
The Rituximab in the Study of Relapsed Chronic
Lymphocytic Leukemia (REACH) study was an international, randomized, phase III trial initiated to directly
compare FCR with FC alone in 552 patients with previously treated CLL.32 Patients on both arms of the study
received fludarabine 25 mg/m2 per day and cyclophosphamide 250 mg/m2 per day for 3 days, repeated every
28 days for a total of 6 cycles. Patients were randomly
assigned to receive rituximab 375 mg/m2 on day 1 of
the first cycle and 500 mg/m2 on day 1 of subsequent
cycles. Approximately 18% of patients on both arms had
prior fludarabine exposure, 26% were alkylator-refractory,
and 55% had alkylator-sensitive disease. After a median
follow-up of 25 months, rituximab significantly improved
median PFS (20.6 months for FC vs 30.6 months for FCR;
hazard ratio = 0.65, P < .001), OR rate (58% for FC vs 70%
for FCR; P = .0034), CR rate (13% for FC vs 24.3% for FCR;
P < .001), median duration of response (27.7 months for
FC vs 39.6 for FCR; P = .025), and time to new CLL treatment (34.3 months for FC vs not reached for FCR; P =
.0024). Median OS was 52 months for the FC group but
was not reached for the FCR group, although this was not
statistically significant. Grade 3/4 adverse events were
higher in the FCR group, with slightly more neutropenia
and thrombocytopenia and a similar incidence of grade
3/4 infections to FC. Fatal adverse events were also slightly
higher with FCR (14% vs 10% with FC). The results of
this trial demonstrate that FCR is an active regimen for
treatment of relapsed or refractory CLL. However, FCR
is not without significant toxicity in this setting, and its
use is most appropriate for fit patients in whom prolongation of PFS is a goal.
The introduction of three structurally similar purine analogs — fludarabine,33,34 cladribine,35,36 and pentostatin37,38 — in the late 1980s and early 1990s vitalized the development of new treatments for patients
with CLL. Of these agents, fludarabine has been the
most widely studied, but pentostatin appears to be the
least myelosuppressive.39 Based on the encouraging
results obtained with the combination of pentostatin
and cyclophosphamide in heavily pretreated patients
with CLL,40 rituximab was added to this regimen. In
this study, 46 patients with previously treated CLL or
other low-grade B-cell malignancies received pentostatin
4 mg/m2, cyclophosphamide 600 mg/m2, and rituximab
375 mg/m2 (PCR), administered in 6 cycles at 3-week
intervals.41 For CLL patients, the OR rate was 75% and
the CR rate was 25%. A response was seen in 75% of the
fludarabine-refractory patients. The median duration of
response was 25 months, and median time to treatment
failure was 40 months. The median OS was 44 months.
Myelosuppression was the most common side effect,
with grade 3/4 infections developing in 28% of patients.
The PCR regimen may be used as an alternative to FCR
in relapsed or refractory CLL. Moreover, the combination
of rituximab, cladribine, and cyclophosphamide (RCC)
Cancer Control 39
was administered to 28 patients with recurrent or refractory CLL. The regimen showed an OR rate of 78% in
these heavily pretreated patients; however, these were
mostly PRs, with a CR rate of only 7%. The median PFS
of responders was 12 months.42
A randomized, two-stage, phase II trial of FCM vs FCM
plus rituximab (FCM-R) was conducted in 52 patients
with relapsed CLL, 26 in each arm.43 Responses were
assessed according to the 2008 IWCLL criteria. The OR
rates were 58% in the FCM arm and 65% in the FCM-R
arm, and the respective CR rates were 15% and 42%. The
toxicity of both regimens was acceptable. The addition
of rituximab to FCM improved the response rates in relapsed CLL, resulting in more complete remissions and
without additional safety concerns. Efficacy and safety
should be fully tested in a randomized phase III trial.
Based on preclinical data demonstrating synergistic cytotoxicity between cisplatin and the nucleoside
analogs cytarabine (Ara-C)44 and fludarabine,45-47 the
combination regimen of oxaliplatin, a third-generation
platinum compound, with fludarabine, Ara-C, and rituximab (OFAR1) was administered to 50 patients with
Richter syndrome or fludarabine-refractory CLL in a
phase I/II clinical trial.48 The regimen consisted of increasing doses of oxaliplatin (17.5, 20, or 25 mg/m2 per
day) on days 1 to 4 (phase I), fludarabine 30 mg/m2 on
days 2 to 3, Ara-C 1 g/m2 on days 2 to 3, rituximab 375
mg/m2 on day 3 of cycle 1 and on day 1 of subsequent
cycles, and pegfilgrastim 6 mg on day 6, every 4 weeks for
a maximum of 6 courses. A total of 92% of patients had
previously received a fludarabine-based regimen, including FCR and FCR plus alemtuzumab. OR rates were 50%
in patients with Richter syndrome, 33% in patients with
fludarabine-refractory CLL, and 50% among 14 patients
who were ≥ 70 years of age. Responses were also encouraging in patients with high-risk cytogenetics, including 35% of patients with 17p deletion and 29% of those
with 11q deletion. The median response duration was
10 months. Toxicities were mainly hematologic, and prolonged myelosuppression was not observed. Moreover,
the regimen was well tolerated in patients who were
≥ 70 years of age. To enhance the response rate with a
decrease in myelosuppression that were observed with
OFAR1, a separate phase I/II clinical trial of 102 patients
with Richter syndrome or fludarabine refractory CLL was
conducted in which the daily dose of oxaliplatin was
increased from 25 to 30 mg, the daily dose of Ara-C was
decreased from 1 g/m2 to 0.5 g/m2, and the fludarabine
and Ara-C were given on days 2–3 (level 1), days 2–4
(level 2), or days 2–5 (level 3) every 4 weeks (OFAR2).49
In patients with CLL, the OR rate was 55% with OFAR2
vs 33% with OFAR1, and the median survival was 21.4
months with OFAR2 vs 13.8 months with OFAR1. Although the number of patients was small, OFAR1 was associated with a trend toward superior clinical outcomes
in patients with Richter syndrome compared to OFAR2,
40 Cancer Control
and OFAR2 was associated with a trend towards superior
clinical outcomes compared to OFAR1 in patients with
relapsed/refractory CLL. OFAR is highly active and could
be considered an option in heavily pretreated patients
with fludarabine-refractory CLL.
Alemtuzumab
Alemtuzumab, a humanized IgG1γ monoclonal antibody
directed against CD52, has shown notable activity as
monotherapy for CLL. Although its detailed mechanism
of action is not completely clear, the binding of alemtuzumab to CD52 on target cells may cause cell death by
three different mechanisms: complement-dependent
cytotoxicity,50 antibody-dependent cellular cytotoxicity
(ADCC),51 and apoptosis.52 It has also been shown to induce caspase-independent cell death in human CLL cells
through a lipid raft-dependent mechanism. Additionally,
unlike rituximab, it has also been shown to induce cell
death in vitro in CLL cells through a mechanism that is
independent of p53 status and caspase activation.53 This
unique mechanism of action has made alemtuzumab a
potential option for patients with the high-risk cytogenetic marker del(17p13.1/TP53) mutation.
Alemtuzumab was initially approved in 2001 under
accelerated approval following the pivotal multicenter,
international phase II trial (CAM211) of single-agent
alemtuzumab in 93 patients with relapsed or refractory
B-cell CLL who were previously exposed to alkylating
agents and had failed fludarabine therapy.54 In this trial,
the alemtuzumab dose was increased gradually to a target 30 mg given intravenously 3 times per week for a
maximum of 12 weeks. The OR rate was 33% (2% CR,
31% PR), and the median duration of response was 8.7
months. The median OS was 16 months (32 months
for responders). In this group of patients with essentially no treatment options, serious infections occurred
in 27%. Two studies, however, showed that the infection risk of salvage treatment other than alemtuzumab
was even higher.7 Among 147 fludarabine-refractory
patients receiving salvage treatment, the risk of major
infection with fludarabine-alkylator combinations and
anthracycline-containing regimens were 26% and 47%
per course, respectively.6 In a smaller series of similar
patients receiving a variety of salvage therapies, major
infections occurred in 89% of patients, with a risk of
hospital admission for infection estimated at 17% per
month.55 Against this background, it became evident
that the safety profile of alemtuzumab was comparatively
favorable.7 The efficacy and safety of alemtuzumab led
to its subsequent approval and widespread use in the
treatment of fludarabine-refractory CLL.
According to the results of a phase II study conducted by the German CLL Study Group, the subcutaneous administration of alemtuzumab appears to be as
efficient as the intravenous route and may result in a
marked reduction of the “first-dose” flu-like reactions that
January 2012, Vol. 19, No. 1
frequently occur after intravenous administration.56 The
study included 103 patients with fludarabine-refractory
CLL who received alemtuzumab subcutaneously in a
dose-escalation schedule up to 30 mg 3 times weekly
for up to 12 weeks. The OR rate was 34% (4% CR, 30%
PR). The median PFS was 7.7 months, and the median
OS was 19.1 months. For those with 17p deletion, the
OR rate was 39%, the median PFS was 5.8 months, and
the median OS was 18.3 months. A higher response
rate of 75% was reported in a smaller phase II trial of
subcutaneous alemtuzumab using the full 30-mg dose
without the traditional dose escalation period in weeks
1 and 2.57 However, in this small study of 20 patients,
only those with good performance status were recruited,
and none of them had bulky lymphadenopathy (> 5
cm), which may account for the higher response rate
observed in this trial.
More encouraging results were seen with lower
doses of subcutaneous alemtuzumab (10 mg 3 times
per week for 18 weeks) administered to 49 patients with
pretreated CLL.58 The OR rate was 53% (27% CR). Among
patients with an unfavorable karyotype, 45% responded,
including 60% of those with the 17p aberration. After a
median follow-up of 25 months, the median overall time
to disease progression was 8 months (responders 12
months, nonresponders 4 months), and the median OS
was 30 months. Grade 4 neutropenia was observed in
17%, and cytomegalovirus (CMV) reactivation occurred
in 24% of the patients, with no CMV disease. This study
confirms that low-dose subcutaneous alemtuzumab is
effective in poor prognosis CLL and has a particularly
favorable toxicity profile. These results led to the initiation of the ongoing registration trial for subcutaneous
alemtuzumab (NCT00328198, clinicaltrials.gov).
To assess the possibility of enhancing the therapeutic efficacy and eradicating MRD, alemtuzumab has
been combined with fludarabine by several investigators.
Following the promising results in a small study that
included 6 patients who were refractory to both drugs
when administered as single agents,59 a larger phase II
trial studying the combination was conducted and enrolled 36 patients with relapsed or refractory CLL.60 After
an initial dose escalation of alemtuzumab over 3 days,
alemtuzumab 30 mg plus fludarabine 30 mg/m2 were
administered on 3 consecutive days. Treatment was repeated after 28 days for up to 6 cycles. The OR rate was
83% (30% CR), the median OS was 35.6 months, and the
median TTP was 12.9 months. The median OS for those
achieving a CR had not been reached, and the median TTP
was calculated as 21.9 months. Grade 3/4 toxicity was
mainly hematologic (neutropenia 26%, leukopenia 44%,
and thrombocytopenia 30%) and infectious (5% grade
3/4). Two patients with progressive disease developed
fungal pneumonias, and 1 died of Escherichia coli sepsis. Only 2 subclinical CMV reactivations occurred, despite 80% of patients being CMV IgG-positive at baseline.
January 2012, Vol. 19, No. 1
This study suggested that the fludarabine/alemtuzumab
combination may improve outcome for patients with
relapsed or refractory CLL. To validate these observations, a phase III multicenter, open-label, randomized
study was conducted to compare the efficacy and safety
of the combination vs fludarabine alone as second-line
therapy for patients with relapsed or refractory CLL.61
The study randomized 335 patients and demonstrated
a significantly higher OR rate (84.8% vs 67.9%), CR rate
(30.4% vs 16.4%), and median PFS of (29.6 months vs
20.7 months) with the combination therapy vs fludarabine alone. Adverse events included cytopenias and
infections and were similar for both arms. Infections
including CMV occurred in 47% of patients receiving the
combination and in 35% of those receiving fludarabine
alone, respectively.
Following the impressive results of the fludarabine/
alemtuzumab combination, a multicenter phase II trial
combining fludarabine, cyclophosphamide, and alemtuzumab (FCCam) was conducted.62 Fludarabine 25 mg/
m2 and cyclophosphamide 200 mg/m2, both administered
intravenously, plus alemtuzumab 30 mg administered
subcutaneously were given on days 1–3 and repeated on
day 29 for up to 6 cycles to 56 patients with relapsed or
genetic high-risk CLL. The respective OR and CR rates
were 68% and 22%. Another phase II study including 43
patients with relapsed or refractory CLL was recently
presented that evaluated oral fludarabine 40 mg/m2 per
day and oral cyclophosphamide 250 mg/m2 per day immediately followed by alemtuzumab 10 mg given subcutaneously per day on days 1–3.63 A 2-day escalation of
alemtuzumab was administered prior to the first cycle,
and the dose was increased from 10 mg to 20 mg after
the first cohort of 10 treated patients. The combination was repeated on day 29 for up to 6 cycles. A total
of 93% of patients had previously been treated with a
fludarabine-containing regimen, and 19% had previously
received alemtuzumab. Most patients had poor prognostic factors, including 54% of patients with del(11q) or
del(17p), with 28% showing 17p as the sole aberration
and 68% with unmutated IgVH. The OR rate was 67%
(30% CR, including MRD negativity in 6 patients). After
a median follow-up of 16.7 months, the median PFS was
24.4 months. Grade 3/4 neutropenia was observed in
66% of the administered courses, symptomatic CMV reactivation occurred in 8 cases, and no CMV disease was
recorded. Twelve major infections occurred, including
hepatitis B virus reactivation (1 patient), pneumonia (8
episodes), and sepsis (3 episodes). Although no head-tohead comparison has been reported in the relapsed or
refractory setting, results from a phase III trial comparing
FCR to FCCam in the upfront setting showed an unfavorable safety profile, with decreased clinical benefit for the
FCCam combination.64
In an attempt to further improve the efficacy of FCR,
investigators at the MD Anderson Cancer Center added
Cancer Control 41
alemtuzumab to the combination (CFAR).65 The regimen
consisted of cyclophosphamide 250 mg/m2 on days 3–5,
fludarabine 25 mg/m2 on days 3–5, alemtuzumab 30 mg
given intravenously on days 1, 3, and 5, and rituximab
375 mg/m2 to 500 mg/m2 on day 2, every 28 days for
up to a total of 6 courses.65 The results of a long-term
follow-up of 80 patients who received CFAR as salvage
therapy were recently presented. The median number
of prior treatments was 3 (ranging from 1 to 14), with
75% of patient having received prior fludarabine combined with an alkylating agent (including FCR 56%), and
39% of patients were refractory to fludarabine. Of 79
patients assessed for response, there were 21 CRs (27%),
3 nodular PRs (4%), and 29 PRs (37%), for an OR rate of
67%. The median OS and TTF were 16.6 and 10.6 months,
respectively, for all patients. For those achieving a CR, the
median OS (50+ months) and TTF (28+ months) had not
been reached. Grade 3/4 hematologic toxicity included
neutropenia (62% of courses), thrombocytopenia (34%),
and anemia (16%). Grade 3/4 infectious complications
included pneumonia (n = 7) and sepsis (n = 3). Other
effects included minor infections (n = 32), CMV reactivation (n = 13), and other herpes virus infections (n = 5).
Although this study demonstrated feasibility and included
heavily pretreated patients, whether CFAR provides any
additional benefit over FCR in the relapsed or refractory
setting remains unclear.
The combination of alemtuzumab with rituximab
has also been evaluated by several phase I/II trials in
relapsed or refractory CLL. The OR rate has ranged from
8% to 61%, with a CR rate ranging from 0% to 18%.66-69
Overall, the combination was active with an acceptable
safety profile in these small trials, and further exploration
is recommended. Another promising approach is the
combination of high-dose methylprednisolone (HDMP)
with alemtuzumab, especially for patients with p53 defects. A phase II trial studied a regimen of up to 4 28-day
cycles, each cycle consisting of intravenous methylprednisolone 1 g/m2 on days 1–5 and alemtuzumab 30 mg
3 times weekly on days 1–28 after an initial week of
dose escalation.70 Alemtuzumab was given intravenously
during cycle 1 and subcutaneously thereafter. Preliminary results on the 5 patients (3 previously treated) with
clinically aggressive CLL with bulky lymphadenopathy
showed that all 5 patients responded to therapy. Three
patients achieved a CR, 1 a nodular PR, and 1 a PR. Toxicity was significant but appeared to be manageable with
appropriate antimicrobial prophylaxis and surveillance.
This regimen will be further evaluated within the NCRI
UKCLL06 trial.
In summary, alemtuzumab monotherapy has resulted in OR rates ranging from 33% to 53% and a median
duration of response of 8.7 to 15.4 months in patients
with relapsed or refractory CLL.54,56,71-73 The drug has
effectively eradicated disease from the blood, bone marrow, and spleen, but it has been relatively ineffective at
42 Cancer Control
treating bulky lymphadenopathy, specifically if greater
than 5 cm.54,74 The reason for this differential response
is not clear, although it has been postulated to be related to poor bioavailability of the drug in bulky sites,
thus causing a low saturation of the binding sites on the
surface of the neoplastic cells. Moreover, there may be
variability in the immune effector mechanisms in lymph
nodes compared with other sites.75 Alemtuzumab has
also demonstrated notable efficacy in treating CLL with
17p deletions or TP53 mutations, possibly due to the
fact that it is not dependent on p53 for its antitumor
activity.73,76 Furthermore, a recent retrospective study
confirmed the efficacy of alemtuzumab monotherapy in
105 pretreated (otherwise unselected) patients with CLL.
The OR rate was 49% (all PRs) for 35 patients with 17p
deletion. Interestingly, in this 17p deletion subgroup, the
OR rate was only 29% if less than a 500-mg cumulative
dose was given, and it was 62% if more than a 500-mg
cumulative dose was given. Alemtuzumab has been associated with significant infectious complications, including opportunistic infections with Pneumocystis jirovecii
and CMV. Though investigators are testing alemtuzumab
both in combination with rituximab and other therapies
and as consolidation to eradicate MRD, at this time alemtuzumab should not be used in either manner outside of
a well-designed clinical trial.
Ofatumumab
Ofatumumab, newly approved by the US Food and Drug
Administration (FDA), is an IgG1κ, fully humanized CD20
monoclonal antibody that targets an epitope distinct
from the epitope recognized by rituximab. Its ADCC is
similar to that of rituximab. However, ofatumumab delivers stronger complement-dependent cytotoxicity in in
vitro models, even in malignant B cells with low CD20
expression levels,77,78 and it has shown a slower off-rate
and more stable CD20 binding.77 Laboratory studies
have shown ofatumumab to be effective at inducing lysis
of several B-cell lines as well as killing fresh B-CLL cells
resistant to rituximab.77-79
A phase I/II dose-escalating study evaluating ofatumumab in patients with relapsed and refractory CLL was
initiated at 12 sites in the United States and Europe. This
study evaluated 33 patients in 3 different dosing cohorts.80
The majority of patients (27 of 33) received a total of 4
doses administered once weekly. The response rate for
the cohort receiving an initial dose of 500 mg followed
by three 2,000-mg doses was 50%, with partial remission
observed in 13 of 26 patients. The drug was well tolerated, with the majority of adverse events being related
to infusion reactions and grade 1/2 infections. Another
single-arm phase II study currently recruiting patients is
investigating the effects of ofatumumab retreatment and
maintenance in CLL patients who received the monoclonal antibody in a previous study (Hx-CD20-406). Patients
will receive 8 weekly infusions (300 mg, then 7 × 2,000January 2012, Vol. 19, No. 1
mg doses), followed by 2,000-mg doses once monthly
for 2 years. The study is expected to enroll 25 patients,
and primary outcome measures should be reported after
January 2012 (NCT00802737, clinicaltrials.gov).
Another larger study was conducted to evaluate patients with CLL refractory to alemtuzumab and fludarabine.81 The interim analysis of this pivotal international
study evaluated 138 patients, with 59 who were refractory
to fludarabine and alemtuzumab (FA-ref) and 79 who were
refractory to fludarabine but did not receive treatment
with alemtuzumab due to bulky disease (BF-ref). Ofatumumab was administered as 8 weekly infusions followed
by 4 monthly infusions. The first infusion was given at a
dose of 300 mg, and the subsequent infusions were given
at a dose of 2,000 mg. The OR rates were 58% and 47% in
the FA-ref and BF-ref groups, respectively. All of these were
PRs, with the exception of 1 CR. Complete resolution
of constitutional symptoms and improved performance
status occurred in 57% of patients in the FA-ref arm and
in 48% of patients the BF-ref arm. The response was also
significant in those who received prior rituximab therapy
(OR rate 54% in the FA-ref arm and 44% in the BF-ref
arm) as well as those who received prior treatment with
the combination of fludarabine, cyclophosphamide, and
rituximab (OR rates of 50% and 44% in the FA-ref and BFref groups, respectively). Furthermore, ofatumumab was
also active in those with 17p deletion, with a response
rate of 41% in the FA-ref group, although the response
rate was 14% in the BF-ref group with 17p deletion. The
median time to response was 1.8 months, and the median
duration of response was 7.1 months in the FA-ref group
and 5.6 months in the BF-ref group. The median PFS and
OS survival times were 5.7 and 13.7 months in the FA-ref
group, respectively, and 5.9 and 15.4 months in the BFref group. The most common adverse events occurring
during treatment were infections (67%), infusion-related
reactions (64% of patients in the FA-ref group and 61%
of patients in the BF-ref group), nearly all of which were
grade 1 or 2. These reactions predominantly occurred
during the first and second infusions and subsided during
the course of treatment: cough (18%), diarrhea (16%),
anemia (16%), fatigue (15%), fever (15%), neutropenia
(15%), dyspnea (13%), nausea (11%), and rash (10%). This
study led to accelerated approval of ofatumumab in October 2009 by the FDA for patients with CLL refractory
to fludarabine and alemtuzumab. The final results for the
primary endpoint of this study in 206 enrolled patients
were updated at the 2010 annual meeting of the American
Society of Hematology.82 The OR rate by an independent
endpoint review committee evaluation was 51% for the
FA-ref group and 44% for the BF-ref group. Two patients
in the BF-ref group achieved a CR. The median duration
of response was 5.7 months in the FA-ref group and 6
months in the BF-ref group. The median PFS was 5.5
months in both groups; the median OS was 14.2 months
for the FA-ref group and 17.4 months for the BF-ref group.
January 2012, Vol. 19, No. 1
Bendamustine
Bendamustine is a unique alkylating agent that was first
synthesized in the early 1960s in the former East German
Democratic Republic. Its structure has similarities to
both alkylating agents and antimetabolites.83 However,
bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of
action include activation of DNA-damage stress response,
inhibition of mitotic checkpoints, and induction of mitotic catastrophe. It induces many proapoptotic genes,
thereby restoring p53/tumor suppressor gene function
and causing a strong activation of intrinsic apoptosis. In
addition, unlike other alkylators, bendamustine activates
a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism.83 It also causes
DNA double-strand breaks, but these are more extensive
and durable than those produced by other alkylating
agents. Moreover, bendamustine showed incomplete
cross-resistance with other alkylating agents such as
cyclophosphamide due to a substance-specific interaction between bendamustine and DNA.84 For more than
30 years, bendamustine was used in East Germany to
treat patients with NHL, CLL, multiple myeloma, Hodgkin
lymphoma, and carcinoma of the breast. Following the
German reunification, many new studies were initiated
to better define the value of this drug in treating these
conditions.85
Several small studies using different dosing schedules have demonstrated the clinical activity of bendamustine as a single agent in the treatment of relapsed
CLL or alkylating agent-refractory CLL.86-90 These studies
have reported an OR rate between 56% and 93% and
a CR rate between 7% and 29%. While doses of 100
mg/m2 for monotherapy and 90 mg/m2 in combination
with rituximab are used to treat newly diagnosed CLL,
dose-escalation trials in the relapsed or refractory setting
suggest that these doses cause significant myelosuppression.86-90 Therefore, a lower dose of 70 mg/m2 on days
1 and 2 every 4 weeks should be used in pretreated
patients, especially in those who have received fludarabine.88 Bendamustine appears to be a good choice for
second-line therapy due to its efficacy in pretreated CLL
patients and its lack of significant cross-resistance with
other alkylating agents or fludarabine.
Based on preclinical data showing that the addition
of rituximab in vitro reduced the dose of bendamustine
required to induce apoptosis in ex vivo B-CLL cells,91 the
combination of these two agents was studied.92-94 The
German CLL Study Group conducted a multicenter phase
II trial of bendamustine in combination with rituximab
in patients with relapsed CLL.92 The study enrolled 81
patients who received bendamustine 70 mg/m2 on days
1 and 2 and rituximab 375 mg/m2 for cycle 1, then 500
mg/m2 for subsequent cycles. Cycles were given every
28 days for up to 6 courses. In the 62 patients who were
included in the response assessment, the OR rate was
Cancer Control 43
77.4% and the CR rate was 14.5%. The OR rate was 92.3%
for the subset with del(11q), 100% for trisomy 12, 44.4%
for del(17p), and 74.4% for unmutated IgVH, suggesting
that bendamustine may be active in high-risk relapsed
CLL. Major toxicities included myelosuppression and
infections. Grade 3/4 neutropenia was seen in 12%, and
treatment-related mortality was reported at 3.7%.
Bendamustine has also been investigated in combination with other agents. A phase I/II study of bendamustine in escalating doses of 80 mg/m2 to 240 mg/m2 per
cycle divided over 2 to 3 days, combined with mitoxantrone on day 1 in doses ranging from 8 mg/m2 to 10 mg/
m2, was conducted in 22 patients with advanced CLL.95
Treatment was repeated every 29 days for up to 6 cycles.
The OR rate was 86% (27% CR). The median TTP was
10 months and median OS was 39 months. The recommended dose for further studies was bendamustine 150
mg/m2 combined with mitoxantrone 10 mg/m2. At the
recommended doses, 7 of the 8 patients had grade 3/4
neutropenia, with 2 developing infections.
In a pilot single-institution phase I/II study, bendamustine was combined with mitoxantrone and rituximab
in 54 patients with B-cell malignancies, including 21 with
CLL.96 Bendamustine (BM) was given at 80 mg/m2 for 2
days, mitoxantrone (M) 10 mg/m2 on day 1, and rituximab
375 mg/m2 on days 8, 15, 22, and 29. Cycle 2 was started
on day 36 and subsequent cycles of bendamustine were
administered every 28 days. Treatment was discontinued
once a CR or PR was achieved. Seventy-two percent
of patients received only 2 cycles of therapy as they
achieved a response. CLL patients had an OR rate of
95% (23% CR), and median TTP was 17 months. Toxicity
was mainly hematologic in 43% of the patients, mostly
grade 3/4 leukopenia and thrombocytopenia. Similar
results were recently reported in a second study by the
same group, using bendamustine combined with mitoxantrone and rituximab in 39 patients with relapsed or
refractory CLL.97 In the absence of larger studies, this
regimen should not be considered at this time outside
of clinical trials.
Preliminary results of a phase II trial of bendamustine
combined with alemtuzumab in the relapsed-refractory
setting were recently reported.98 The protocol combined
4 cycles of bendamustine (70 mg/m2 given intravenously
on days 1 and 2, every 4 weeks) with continuous alemtuzumab (30 mg administered subcutaneously 3 times per
week for 16 weeks). All patients had at least one highrisk feature from CD38, FISH, or IgVH mutation status.
Results available from 7 patients showed 3 CRs, 2 PRs, and
1 stable disease for an OR rate of 71%. Toxicities were
mostly hematologic and infectious, but the regimen was
considered feasible and the study currently continues to
recruit patients.
Despite extensive use with bendamustine for more
than 40 years, a number of questions remain unanswered, such as the optimal dose and schedule. More44 Cancer Control
over, bendamustine has some benefit over other agents
used in CLL. For instance, bendamustine does not seem
to be associated with autoimmune phenomenon, while
fludarabine does appear to have an association. In fact,
resolution of autoimmune phenomenon has been reported with bendamustine use in 2 patients, while no
further episodes occurred in 7 patients with a prior
history of autoimmune disorder.86 Bendamustine seems
to be a reasonable alternative for patients not suitable
for fludarabine-based therapies due to either infectious
risk or autoimmune phenomenon. Bendamustine also
provides a reasonable option for patients not considered appropriate candidates for alemtuzumab because
of recurrent infections or bulky lymphadenopathy. In
addition, while clinicians tend to consider chlorambucil
as initial therapy in elderly patients, the superiority of
bendamustine over chlorambucil with no significant
difference in the rate of grade 3/4 infections provides
further rationale for its use.85
High-Dose Methylprednisolone
A number of prior studies suggest that high-dose corticosteroids are an active treatment in patients with relapsed/refractory CLL, including those with unfavorable
cytogenetic characteristics.99-101 Glucocorticoids are of
interest in the treatment of high-risk CLL because they
can kill lymphoid cells by a p53-independent mechanism and appear to be active in patients with 17p13.1
deletions.101 Glucocorticoids also effectively reduce
bulky lymphadenopathy and cause less myelosuppression than alkylating agents and purine nucleosides
produce.100 These characteristics make it possible to
administer high-dose corticosteroid therapy to patients
with cytopenias and to those in whom myelosuppression
should be avoided.102 Results of a phase II study combining rituximab, an anti-CD20 monoclonal antibody, with
HDMP as a salvage regimen for the treatment of patients
with fludarabine-refractory CLL showed an OR rate of
93%, with a CR rate of 36%.103 Fourteen patients were
treated with 3 cycles of rituximab 375 mg/m2 weekly
for 4 weeks in combination with HDMP 1 g/m2 daily for
5 days. All patients were refractory to fludarabine, and
86% had high-risk disease according to the modified Rai
classification. The median TTP was 15 months, and the
median time to next treatment was 22 months. Median
survival had not been reached after a median follow-up
of 40 months. The regimen was well tolerated, and serious adverse events were rare. All patients were able to
complete the scheduled treatment without delays or
dosage reductions.103 The CR and OR rates reported
with the HDMP/rituximab combination are higher than
those reported for each agent alone in patients with
relapsed/refractory disease25,26,100,101 and higher than
those reported for FC, FCR, or FCM.14,16,31 In addition,
the response rates observed for the HDMP/rituximab
combination are higher than those noted for alemtuJanuary 2012, Vol. 19, No. 1
zumab in patients with fludarabine-refractory disease,
for which OR rates are approximately 30% and CRs are
uncommon.54,56 Another recent report from the same
group showed a similar efficacy in the front-line setting:
a 96% OR rate, with a CR rate of 32% using a reduced
number of days of corticosteroids.104 Although a larger
single-institution review of 37 patients who were treated
with the same HDMP/rituximab combination reported
a lower OR rate of 78% (22% CR), a high response rate
was seen for those with high-risk cytogenetic abnormalities, including OR rates of 55.6% and 66.7% for those
with del(17p) and del(11q), respectively.102 The HDMP/
rituximab combination is an active regimen in patients
with relapsed, refractory, and cytogenetically high-risk
CLL. Further evaluation of this regimen in controlled
trials appears warranted.
A study of the combination of HDMP and ofatumumab was recently reported in patients with CLL who were
not considered good candidates for chemotherapy due
to comorbidities, poor performance status, or profound
cytopenias or due to refractory status to fludarabine
and/or alemtuzumab.105 Eight patients with progressive,
symptomatic CLL were treated with HDMP 1 g/m2 given
intravenously daily × 3 every 28 days for 3 consecutive
cycles and ofatumumab 300 mg as the initial dose, followed by 11 doses of 2,000 mg over a 6-month period.
The median age was 69 years, and the median number of
prior treatments was 4.5, including 4 patients who had
previously received HDMP and rituximab and 2 patients
who underwent matched unrelated-donor SCT. All patients had been previously treated with rituximab, 75%
of the patients failed or were intolerant to fludarabine
and/or alemtuzumab, and 75% had high-risk prognostic
markers including unfavorable cytogenetics, unmutated
IgVH region genes, or high expression levels of ZAP70.
Most of the patients had bulky disease and splenomegaly.
All patients completed the planned therapy with no
major side effects or toxicities. No evidence of marrow
suppression was seen, and even patients with pancytopenia improved their peripheral blood counts with
this salvage regimen. Among the 8 patients, the OR rate
was 50% (4 PRs), 2 patients had stable disease, and the
remainder showed progressive disease. These data suggest that the combination of HDMP and ofatumumab
is a safe and effective salvage regimen for high-risk CLL
patients who otherwise are not candidates for additional
treatment. Additional clinical studies of this combination are warranted.
Emerging Therapies and
Investigational Agents
Lenalidomide
The immunomodulatory agent lenalidomide has demonstrated activity in CLL, and a discussion of this drug is
included elsewhere in this issue (Carbadillo E, Veliz M,
Komrokji R, et al; pp 54-67).
January 2012, Vol. 19, No. 1
Lumiliximab
The success of the monoclonal antibodies rituximab and
alemtuzumab in CLL suggests that cell surface antigens
are promising targets for the treatment of CLL. CLL cells
exhibit high expression of CD23, while non-CLL cells
only minimally express this antigen. As such, CD23 has
become a potential target for directed therapy. Lumiliximab is a macaque-human primatized monoclonal antibody that targets the CD23 antigen.106 In a phase I trial,
investigators found that lumiliximab was well tolerated,
but its efficacy was limited to reduction of lymphadenopathy and lymphocytosis, with no documented CRs or
PRs.106 Since preclinical data suggested an enhancement
of the antitumor effect when lumiliximab was combined
with rituximab or fludarabine, investigators tested the
safety and efficacy of the combination of FCR with lumiliximab for treatment of relapsed CLL.107 In this phase
I/II trial, the toxicity of the combination appeared no
different from that which was previously reported with
FCR in treatment of relapsed CLL. FCR plus lumiliximab
resulted in an OR rate of 65% and a CR rate of 52%. Results from a phase III study comparing FCR to FCR plus
lumiliximab in relapsed CLL did not confirm a benefit in
terms of improved response rate of PFS with the addition
of lumiliximab to FCR.75
GA101
GA101 is the first humanized and glycoengineered type
II monoclonal anti-CD20 antibody to enter clinical trials.
It binds CD20 in a different orientation than rituximab
and over a larger surface area.108 In preclinical in vivo
lymphoma models, GA101 has shown superior efficacy109
as well as increased ADCC and strongly enhanced direct
cell death compared with rituximab110 and ofatumumab.111 A phase I study of GA101 was initiated in 13 patients
with relapsed or refractory disease.110 The OR rate was
62% (1 CRi, 7 PRs, and 5 stable disease) with no clear
dose relationship established. The drug was relatively
well tolerated, with the most common grade 3/4 toxicity being transient neutropenia in 9 patients. Additional
phase II/III studies are underway with this antibody as a
single agent and in various combinations. Other newer
anti-CD20 monoclonal antibodies such as veltuzumab,
AME-133v, and TRU-015 are being investigated in earlyphase clinical trials in patients with NHL or CLL.
Cyclin-Dependent Kinase Inhibitors
Flavopiridol
Flavopiridol (Alvocidib), a broad cyclin-dependent kinase (CDK) inhibitor, induces apoptosis of CLL cells in
vitro112 and is not dependent on p53 for its activity.113 In
initial phase I studies using a continuous-infusion dosing
schedule in a variety of malignancies, no clinical activity
was observed.114,115 Detailed pharmacokinetic modeling led to the development of a novel dosing schedule designed to achieve target drug concentrations in
Cancer Control 45
vivo.116 Following initial phase I studies showing that a
30-minute intravenous bolus followed by 4-hour continuous intravenous infusion schedule was clinically active
with a dose-limiting toxicity (DLT) of acute tumor lysis
syndrome requiring hemodialysis,114,115 a phase II trial
was conducted to evaluate flavopiridol as a single agent
for the treatment of 64 patients with relapsed CLL. The
OR rate was 53% (1.6% CR, 5% nodular PR, and 47%
PR).117 Patients with genetically high-risk disease, including patients with del(17p) and del(11q), also had
significant OR rates (57% and 50%, respectively). Patients
with bulky lymphadenopathy had an OR rate of 51%.
With the implementation of a standardized protocol to
prevent severe tumor lysis syndrome, flavopiridol was
administered safely. Adverse effects included cytopenias, diarrhea, nausea and vomiting, transaminitis, acute
tumor lysis syndrome, and cytokine release syndrome
(fever, flushing tachycardia, nausea). The interim results
of a multicenter, international phase II clinical trial of
flavopiridol among patients with fludarabine-refractory
CLL or prolymphocytic leukemia arising from CLL was
recently reported.118 Patients received a bolus dose of
30 mg/m2 given over 30 minutes followed by a continuous infusion of 30 mg/m2 over 4 hours. If no tumor lysis
syndrome was observed with the first dose, subsequent
doses were administered with a continuous infusion of
50 mg/m2 over 4 hours. Flavopiridol was given once
weekly for 4 weeks, followed by a 2-week break, for up to
6 cycles (24 total doses). Of the planned 165 patients, 68
patients completed at least 2 cycles of therapy and were
evaluated for efficacy and safety. A significant number of
patients had high-risk cytogenetics, including 30% with
del(17p13.1) and 36% with del(11q22.3). Using NCI
1996 criteria, the OR rate was 31%, and all responses were
partial. The objective response rate was 25% for patients
with del(17p13.1), 30% for those with del(11q22.3), and
39% for those with bulky lymphadenopathy. The most
frequent serious adverse events were infections (32%),
tumor lysis syndrome (19%), diarrhea (17%), and febrile
neutropenia (15%). Flavopiridol has demonstrated activity in relapsed CLL with high-risk cytogenetics and
bulky lymphadenopathy,119 but further study is needed
to establish its ultimate role in treating CLL.
SNS-032
Based on the results with flavopiridol, several CDK inhibitors are undergoing clinical study. The MD Anderson
Cancer Center has an ongoing phase I study of SNS-032, a
selective inhibitor of CDK 2, 7, and 9, which are involved
in cell cycle regulation and regulate RNA polymerase
II-dependent transcription. To date, 17 patients with
CLL have been treated with total doses of 15 to 100
mg/m2 infusions. Although no drug-related DLTs were
observed with in the cohort receiving 50 mg/m2, tumor
lysis syndrome was noted in all CLL patients treated at
a dose of 75 mg/m2, and 1 patient experienced a DLT of
46 Cancer Control
vascular leak syndrome. One patient treated at a dose
of 100 mg/m2 experienced tumor lysis syndrome and a
DLT of transaminitis, but no objective responses have
been observed.120
Dinaciclib
Dinaciclib (SCH 727965) is a selective CDK 1, 2, 5, and
9 inhibitor that appears to have a better therapeutic
window than flavopiridol has121 and is being investigated
in a phase I trial in patients with relapsed or refractory
CLL. Preliminary results from this study included 8 PRs
among 23 evaluable patients. Further study of this agent
in CLL is warranted.122
Small Modular Immunopharmaceuticals
In CLL, a small modular immunopharmaceutical (SMIP)
has been developed to target CD37, an antigen that is
involved in the regulation of B-cell function but is not
required for B-cell development. CD37 is a heavily glycosylated cell surface protein expressed constitutively at
high levels on normal and transformed B cells across a
wide range of maturational stages.123 TRU-016 is a novel
humanized anti-CD37 SMIP protein, which is a singlechain Fv-Fc fusion protein representing a structural modification of a CD37 antibody that lacks the CH1 domain.123
In vitro studies with the chimeric version of TRU-016
demonstrated that it was a potent inducer of apoptosis
and ADCC against CLL cells.124 In a phase I study in 57
patients with advanced CLL and SLL, TRU-016 was well
tolerated.123 The median number of prior treatments was
4. In this study, 59% of patients were refractory to their
prior therapy and 57% had high-risk genomic features.
Seven PRs were reported, including 2 PRs in patients
with del(17p13.1). The OR rate for patients with 1 or
2 prior therapies was 44% (7 out of 16), all PRs, and the
median reduction in peripheral lymphocytes was 92%.
No responses were obtained in 41 patients who had 3
or more prior therapies, although a median reduction in
lymphocytes of 67% was reported. There were no serious
adverse events or DLTs at the highest dose of 20 mg/kg,
so a maximum tolerated dose was not reached. Given
the demonstrated single-agent clinical activity of TRU-016
and the its synergistic or additive impact with multiple
agents in preclinical models, further dose escalation and
combination drug trials of TRU-016 have been initiated.
Bcl-2 Inhibitors
Bcl-2, an antiapoptotic protein, is overexpressed in CLL
cells and results in resistance to chemotherapy.125 Antisense oligonucleotides that bind mRNA can target specific proteins and induce enzymatic cleavage of the message, thereby preventing protein translation.126
Oblimersen
Oblimersen, an antisense oligonucleotide, downregulates
the Bcl-2 protein and potentiates the cytotoxic activity
January 2012, Vol. 19, No. 1
of commonly used CLL agents including fludarabine,
rituximab, and alemtuzumab.127 Clinically, oblimersen
displayed modest single-agent activity in a phase I/II trial
in relapsed/refractory CLL.128 A randomized phase III trial
was conducted to compare FC to FC plus oblimersen in
241 patients with relapsed or refractory CLL.127 Twenty
patients (17%) in the FC/oblimersen group and 8 patients
(7%) in the FC-only group achieved a CR or a nodular
PR. TTP and survival were both prolonged in patients
who achieved a CR or a nodular PR (P < .0001). A 5-year
follow-up of these patients demonstrated a significant
survival benefit for those who had fludarabine-sensitive
disease or who achieved a CR or a PR with FC plus oblimersen.129 Adverse effects of oblimersen included nausea,
thrombocytopenia, tumor lysis syndrome (rare), and cytokine release reactions (rare). Oblimersen remains an
investigational drug.
Navitoclax
Navitoclax (ABT-263), a novel, orally bioavailable, small
molecule binds with high affinity to Bcl-2, BclXL, and BclW,
promoting apoptosis. A phase I trial demonstrated that
oral navitoclax monotherapy was well tolerated and had
antitumor activity in patients with CLL with thrombocytopenia as the DLT.136 An international phase I doseescalation study has been initiated to evaluate the safety
and pharmacokinetics of oral navitoclax in combination
with FCR or with bendamustine/rituximab in patients
with relapsed/refractory CLL.137 Accrual on this trial is
ongoing, but preliminary responses in the bendamustine/rituximab arm are encouraging among 4 assessable
patients who received 2 cycles: 1 CRi in a patient with
del(17p), 2 unconfirmed CRs, and 1 PR in a patient with
del(17p). Data are limited in the FCR portion of the study.
SPC2996
Gossypol
Gossypol (AT-101), an orally active cottonseed extract
derivative, acts as a BH3-mimetic, binding to the BH3
pocket of the Bcl-2 family antiapoptotic proteins (Bcl-2,
BclXL, BclW, and Mcl).130,131 Gossypol induces apoptosis
of CLL cells and overcomes microenvironment-mediated
resistance while sparing normal stromal cells.132 It also
enhances the cytotoxicity of rituximab for CLL cells in
vitro.133 Preliminary results of an ongoing phase II study
of gossypol combined with rituximab in patients with
relapsed or refractory CLL demonstrated a PR in 5 of 12
patients (42%). Patients received a regimen of 30 mg daily
for 3 out of every 4 weeks, with rituximab, 375 mg/m2
for 12 doses (total dose = 4,500 mg/m2) on days 1, 3, 5,
8, 15, 22, 29, 31, 33, 40, 57, 59, and 61.134 Intermittent
administration of gossypol with a “pulse” dose regimen
appeared to be associated with an increased proapoptotic
effect in vivo and higher plasma concentrations, as well
as reduced toxicity, when compared with daily dosing.
The most frequent toxicities were gastrointestinal effects,
fatigue, and neutropenia.
Obatoclax
Obatoclax mesylate (GX15-070) is a synthetic small molecule pan–Bcl-2 antagonist with in vitro activity against
CLL cells. In a phase I trial, obatoclax was administered
to patients with advanced CLL at doses ranging from 3.5
mg/m2 to 14 mg/m2 as a 1-hour infusion and from 20 mg/
m2 to 40 mg/m2 as a 3-hour infusion every 3 weeks.135
Although the clinical activity of this agent was limited
(4% PR; 1 of 26 patients), patients with anemia (3 of
11 patients) or thrombocytopenia (4 of 14 patients)
experienced improvements in hemoglobin and platelet
counts. Dose-limiting reactions were neurologic (somnolence, euphoria, ataxia) and were associated with the
infusion. Further evaluation in less heavily pretreated
patients and in combination with other therapeutic
agents is warranted.
January 2012, Vol. 19, No. 1
SPC2996 is a recently developed specific Bcl-2 mRNA
antagonist.138 Patients with relapsed CLL were treated
with a maximum of 6 doses of SPC2996 (0.2 mg/kg to 6
mg/kg) in a multicenter phase I trial.139 SPC2996 caused
a 50% reduction of circulating lymphocytes in 5 of 18
patients (28%), which was found to be independent of
its immunostimulatory and anti–Bcl-2 effects. Further
studies with this agent are warranted.
Kinase-Targeted Therapy
Unlike chronic myeloid leukemia, where a genetic lesion
results in the production of Bcr-Abl tyrosine kinase, CLL
does not have a distinct genetic lesion associated with
pathophysiology or biology of the disease. However,
in recent years, a few kinases have been identified that,
in comparison with normal lymphocytes, are overexpressed, constitutively active, or activated by microenvironment factors in pathogenic CLL cells.140 Selective
small-molecule inhibitors of these kinases are currently
being tested in early-phase clinical trials in patients with
relapsed or refractory CLL, thus opening a new pharmacopoeia for CLL where nucleoside analogs, alkylating
agents, and monoclonal antibodies have long been the
mainstay of therapy.
CAL-101
In CLL, the PI3K pathway is constitutively activated
and dependent on PI3Kδ. CAL-101 is an isoform-selective
inhibitor of PI3Kδ that inhibits PI3K signaling and induces apoptosis of CLL cells in vitro. A phase I study of
CAL-101 in 37 patients with relapsed or refractory CLL
was recently reported.141 Most patients had refractory
disease (65%), bulky lymphadenopathy (81%), and adverse cytogenetics of del(17p), del(11q), or both (63%).
The median number of prior therapies was 5. CAL-101
was administered orally once or twice per day continuously in 28-day cycles for up to 12 cycles. Symptomatic
adverse events were infrequent and not clearly related
Cancer Control 47
to the study drug. CAL-101 reduced lymphadenopathy
in all of the patients, and 91% achieved a lymph node
response (≥ 50% reduction in target nodal lesions). A
transient increase in peripheral absolute lymphocyte
counts of > 50% from baseline was observed in 60% of
patients, which suggested drug-mediated lymphocyte
redistribution. The OR rate was 33% (all PRs) and the median duration of response had not been reached; 75% of
patients with CLL-related thrombocytopenia had either
an improvement to > 100,000/µL or a > 50% increase
from baseline. These results support further evaluation
of CAL-101 alone and in combination with other agents.
Another phase I trial studied CAL-101 in combination
with rituximab and/or bendamustine in patients with
heavily pretreated relapsed or refractory B-cell indolent
NHL and CLL.142 All patients received CAL-101 100 mg
orally twice per day in 28-day cycles for up to 12 cycles.
Patients also received rituximab 375 mg/m2 administered weekly for 8 weeks, starting on day 1 of cycle 1, or
bendamustine 90 mg/m2 administered on days 1 and 2
of each cycle for 6 cycles. Preliminary clinical response
assessments available from 3 patients with CLL showed
a PR in 2 of 3 patients. Enrollment is ongoing and dose
escalation of CAL-101 is planned.
Fostamatinib
B-cell antigen receptor signaling is increasingly recognized as a key factor in promoting clonal expansion in
various B-cell malignancies, including CLL. Engagement
of the B-cell antigen receptor activates Syk (spleen tyrosine kinase), which leads to a number of downstream
events that promote cell survival and growth. Therefore,
inhibition of Syk represents a novel therapeutic approach
in CLL.143 A multicenter phase I/II clinical trial of fostamatinib disodium (R788), the first clinically available
oral Syk inhibitor, in patients with recurrent B-cell NHL
was reported.144 The 11 patients with SLL/CLL enrolled
in the study achieved an OR rate of 55% (all PRs) and a
PFS of 6.4 months. Common toxicities included diarrhea,
fatigue, cytopenias, hypertension, and nausea. Preclinical studies of other Syk inhibitors such as R406 and two
highly selective Syk inhibitors (P142-76 and P505-15)
and a multikinase inhibitor (P420-89) demonstrated responses in CLL cells supporting the clinical development
of these promising new agents in patients with CLL and
other selected B-cell malignancies.143,145
PCI-32765
One of the downstream kinases activated by Syk is Bruton tyrosine kinase (BTK), which is an intermediary enzyme in the B-cell antigen receptor signaling pathway. It
is a cytoplasmic enzyme that is essential in B-lymphocyte
development, survival, and signaling. PCI-32765 is a potent, selective, irreversible, and orally bioavailable small
molecule inhibitor of BTK that has preclinical activity in
B-cell malignancies.146 A phase I trial of PCI-32765 was
48 Cancer Control
conducted in patients with CLL/SLL who had relapsed
or refractory disease after more than one prior treatment
regimen.147 The study included a second phase IB section
that included a cohort of patients aged ≥ 65 years with
CLL/SLL who required treatment and were “treatmentnaive.” The drug was well tolerated, with infrequent grade
3 toxicities. Of the 30 patients enrolled in the study, 14
were evaluable for response. The OR rate was 64% (1
CR, 8 PRs, and 4 stable disease). Both studies are ongoing
and open to enrollment. A similar response rate (60% OR
rate, 6% CR) and safety profile were seen in a separate
phase I trial of PCI-32765 in various B-cell malignancies
that included 15 patients with CLL.148
Dasatinib
Preclinical studies have shown that CLL cells overexpress
Lyn kinase (an Src-family kinase). In vitro inhibition of
Lyn kinase leads to apoptosis of the CLL cells. A phase
I clinical trial of single-agent dasatinib, a Lyn inhibitor,
showed a 20% OR rate and reported myelosuppression
as the major toxicity.149 Another phase II study of dasatinib monotherapy showed a lack of efficacy in heavily
pretreated CLL patients, with an OR rate of 6% and a high
incidence of neutropenia.150 Phase I clinical trials of dasatinib in combination with rituximab or lenalidomide
are currently ongoing.
Heat Shock Protein 90 Inhibitors
The zeta-associated protein of 70 kDa (ZAP70) is expressed in patients with aggressive CLL. Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that
is necessary for the expression and activity of the tyrosine
kinase ZAP70, which is expressed aberrantly in 45% of
patients with CLL. ZAP70+ CLL cells expressed activated
Hsp90 with high binding affinity for Hsp90 inhibitors.
Treatment with Hsp90 inhibitors such as 17-AAG and
17-DMAG induced ZAP70 degradation and apoptosis in
CLL cells but not in T cells, and it also impaired B-cell
receptor signaling in leukemia cells.151 Hsp inhibitors
are currently being investigated in a phase I clinical trial
in relapsed CLL (NCT01126502, clinicaltrials.gov).
Histone Deacetylase Inhibitors
Several studies have demonstrated that histone deacetylase (HDAC) inhibitors, including depsipeptide (a potent
inhibitor of class I HDAC enzymes), MS-275 (a selective
class I HDAC inhibitor), and valproic acid (a nonselective
HDAC inhibitor), can alter histone modifications in CLL
and lead to selective cytotoxicity of CLL cells.152-154 In
vitro studies have shown that valproic acid restores the
apoptotic pathways in CLL cells and thus their ability
to undergo apoptosis.155 A phase I clinical trial of depsipeptide included 10 patients with CLL treated with
depsipeptide 13 mg/m2 given intravenously on days 1,
8, and 15.154 The most common toxicities were progressive fatigue, nausea, and other constitutional symptoms
January 2012, Vol. 19, No. 1
that prevented repeated dosing. Several patients had
evidence of antitumor activity following treatment, but
no PRs or CRs were noted by NCI criteria. Depsipeptide
effectively inhibited HDAC in vivo in patients with CLL,
but this schedule of administration was limited by progressive constitutional symptoms. Future studies with
depsipeptide should examine alternative administration
schedules. Another phase I trial studied belinostat, a
novel HDAC inhibitor, in patients with advanced hematologic malignancies refractory to standard therapy or
for whom no standard therapy exists.156 No responses
were noted in these heavily pretreated patients. However,
disease stabilization was observed in several patients including the 2 patients with CLL enrolled in the study.
MGCD0103 is an orally available, aminophenylbenzamide
small-molecule HDAC inhibitor that selectively targets
class I (HDAC isotypes 1, 2, and 3) and class IV (HDAC isotype 11) enzymes. A phase II clinical trial was performed,
starting at a dose of 85 mg/day and administered 3 times
per week.157 Twenty-one patients with relapsed or refractory CLL received a median of 2 cycles of MGCD0103
(range, 0–12). All patients had previously received fludarabine, 33% were fludarabine-refractory, and 71% had
del(11q22.3) or del(17p13.1). No responses according to
NCI 1996 criteria were observed. Grade 3/4 toxicity consisted of infections, thrombocytopenia, anemia, diarrhea,
and fatigue. Future investigations in CLL should focus on
broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated
with this class of drugs. Several phase I and II studies
are currently ongoing with various HDAC inhibitors as a
single agent or in combination with other agents in CLL.
Conclusions
Treatment strategies in CLL, as a disease of the elderly,
should remain highly individualized. The watch-and-wait
approach remains standard for asymptomatic patients.
Patients who relapse after a disease-free period of over
1 year (or 2 years following chemoimmunotherapy) are
considered to be treatment-sensitive and may receive
the same regimen used for initial treatment.158 Those
who relapse within 6 months of completing an initial
fludarabine-containing regimen or who progress during
therapy are considered fludarabine-refractory.159 Additionally, since more effective regimens tend to be more
toxic, it is important to assess the health status of the
patient and define the goals of therapy before making
treatment decisions. The goal of therapy in older patients
with multiple comorbidities may focus on palliation of
symptoms, while in fit or younger patients who can tolerate more intense regimens, the goal of therapy may be to
maximize their likelihood of long-term survival, with the
ultimate goal in high-risk patients of providing allogeneic
stem cell transplantation. Options for refractory patients
include alemtuzumab with or without rituximab (although not for bulky lymphadenopathy), bendamustine
January 2012, Vol. 19, No. 1
with or without rituximab, and high-dose corticosteroids
with rituximab, ofatumumab, and combination regimens.
Alemtuzumab and high-dose corticosteroids are associated with significant toxicity and prolonged immunosuppression. Since CLL itself causes immune dysregulation,
serious and life-threatening infections often occur after
utilizing immunosuppressive agents. Guidelines for the
use of alemtuzumab include a mandatory weekly standardized, qualitative polymerase chain reaction assay to
test for reactivation of CMV, cotrimoxazole prophylaxis
to prevent Pneumocystis jirovecii infection, and acyclovir prophylaxis to protect against herpes viruses.160
If CMV infection is noted, pre-emptive therapy should
be initiated with ganciclovir or foscarnet, and treatment
with alemtuzumab should be interrupted.160 Finally, the
activity of novel targeted agents, although still in early
stages of clinical investigation, has shown potential to
change the future treatment of CLL, for which allogeneic
SCT remains the only potentially curative therapy. Continued advances in the research of CLL and enrollment
of patients in clinical trials will aid in the pursuit of a
future cure for CLL.
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