NOVEL TREATMENTS FOR CHRONIC LYMPHOCYTIC LEUKEMIA

Novel Treatments for Chronic Lymphocytic Leukemia and

Moving Forward
Jennifer R. Brown, MD, PhD, David L. Porter, MD, and Susan M. OBrien, MD
OVERVIEW
The last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These include the antibody
obintutuzumab (GA-101), as well as small-molecule inhibitors of key pathways involved in the pathogenesis of CLL, specically the B-cell
receptor (BCR) pathway (especially Brutons tyrosine kinase [BTK] and P13K), and the antiapoptotic pathway (especially BCL-2). We will
consider each in turn, focusing on the molecules most advanced in clinical development. There has also been extensive development
in rewiring the patients own immune system to treat CLL. This has been done through modifying autologous T cells to express a
chimeric antigen receptor (CAR). Thus far all CAR-T preparations have targeted the CD19 antigen. This is a good rational for B-cell
malignancies as CD19 expression is limited to B-cell malignancies and normal B cells. The in vivo amplication of the transduced T cells
relies on signaling and co-signaling domains and provides signicant killing of CLL cells. As exciting as these novel agents and
approaches are, they obviously beg the question, will chemotherapy as a treatment for CLL soon be obsolete? Although chemotherapy
is associated with known short-term toxicities, it has the advantage of being completed in a short period of time and being relatively
inexpensive in comparison to novel therapies. In addition, long-term follow-up of results with chemoimmunotherapy have now identied
a group of patients whose remissions are maintained for more than 10 years. An important question that will arise going forward is
how to incorporate novel agents without eliminating the long term benets possible with chemoimmunotherapy in a subset of patients
with CLL.

he last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These
include the antibody obinutuzumab (GA-101), as well as
small-molecule inhibitors of key pathways involved in the
pathogenesis of CLL, specifcally the B-cell receptor (BCR)
pathway (especially Brutons tyrosine kinase [BTK] and
PI3K), and the antiapoptotic pathway (especially BCL-2). We
will consider each in turn, focusing on the molecules most
advanced in clinical development.

ANTI-CD20 ANTIBODY: OBINUTUZUMAB

Obinutuzumab (GA101) is a humanized, glycoengineered
type II IgG1 antibody against CD20 which has a different
mechanism of action compared to rituximab or ofatumumab. Obinutuzumab causes more direct cell killing, likely
through a lysosomal mediated mechanism, and confers enhanced antibody-dependent cellular cytotoxicity (ADCC),
with reduced complement dependent cytotoxicity (CDC).1
Obinutuzumab has shown enhanced effcacy in killing CLL
cells in vitro compared to rituximab and ofatumumab. Early
clinical data with obinutuzumab demonstrated very rapid

clearance of B cells from peripheral blood, as well as neutropenia.2

The defnitive registration trial for obinutuzumab was undertaken by the German CLL Study Group in their CLL11
study.3 This trial was performed in 781 previously untreated
patients with CLL and clinically signifcant medical comorbidities and/or reduced renal function. The patients were
randomly assigned 1:2:2 to chlorambucil (clb) alone,
chlorambucil with rituximab (R-clb), or chlorambucil with
obinutuzumab (G-clb). Both R-clb and G-clb treatment resulted in statistically signifcant improvements in overall response rate (ORR) and progression-free survival (PFS)
compared to clb alone (PFS R-clb 16.3 m vs. clb 11.1 m, HR
0.44, p 0.001; G-clb 26.7 m vs. clb 11.1 m, HR 0.18, p
0.001), as well as in complete remissions (CR). Based on these
data, G-clb was approved by the U.S. Food and Drug Administration (FDA) in November 2013 for the initial therapy for
patients with CLL. Updated data on the G-clb arm in comparison to clb alone have also demonstrated an overall survival (OS) beneft favoring G-clb (9% deaths for G-clb vs.
20% deaths for clb; hazard ratio [HR] 0.41; p 0.002).
Likely of greater interest, however, was the direct compar-

From the Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, Boston, MA; Blood and Marrow Transplantation, Hospital of the University of Pennsylvania, Philadelphia, PA;
Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX.
Disclosures of potential conicts of interest are found at the end of this article.
Corresponding author: Susan M. OBrien, MD, Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 428, Houston, TX
77030; email: sobrien@mdanderson.org.
2014 by American Society of Clinical Oncology.

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ison of G-clb to R-clb. The safety of obinutuzumab was

largely similar to rituximab, with the exception of an increased rate of infusion reactions during the frst dose. Neutropenia was similar (33% with G-clb vs. 28% with R-clb).
Infusion reactions may be minimized by dividing the frst
dose (100 mg on day 1, 900 mg on day 2), and by premedicating with methylprednisolone or dexamethasone, diphenhydramine, and acetaminophen. This comparison showed
that G-clb improved ORR, CR, and molecular response compared to R-clb, and resulted in a marked increase in PFS,
from 16.3 months with R-clb to 26.7 months with G-clb.3 The
large difference in PFS between these anti-CD20 antibodies is
impressive, and suggests that the difference in molecular
mechanism between obinutuzumab and rituximab is likely
signifcant in CLL. These results provide the impetus for further studies of obinutuzumab in CLL in relapsed disease or in
combination with other novel agents.

B-CELL RECEPTOR PATHWAY INHIBITION

Although activating somatic mutations in the BCR pathway
are relatively rare in CLL,4 constitutive activation of the pathway is quite common, and kinases within this pathway have
proven to be excellent therapeutic targets in CLL. BTK and
PI3K have been most successfully targeted in the clinic and
will therefore be the focus of this discussion, but inhibitors of
SYK and LYN may follow soon. All inhibitors of this pathway
in the clinic result in an initial redistribution of lymphocytes
into peripheral blood which resolves slowly over time, such
that response criteria have been modifed to include a category PR-L, meaning partial response with ongoing lymphocytosis.5

KEY POINTS
B-cell receptor inhibitors, such as ibrutinib and idelalisib,
result in rapid reduction in lymphadenopathy with a
simultaneous rise in the absolute lymphocyte count which
should not be mistaken for progressive disease.
ABT-199, a novel BCL-2 inhibitor, results in marked efcacy
in patients with relapsed and refractory disease but also
can result in tumor lysis.
All trials with targeted oral agents have thus far been
designed with continuous administration compared with the
short specied number of cycles seen with chemotherapy.
Chimeric antigen receptor (CAR)modied T-cell therapy is
associated with prolonged remissions in patients with
refractory disease; toxicities include a cytokine release
syndrome that may be abrogated by antiinterleukin-6 (IL6) monoclonal antibodies.
Fludarabine/cyclophosphamide/rituximab (FCR) can result in
remissions lasting 10 years in a subset of patients with
mutated IgVH genes and absence of poor cytogenetics such
as 17p deletion or 11q deletion.

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BTK INHIBITION
BTK is a Tec family kinase that functions in signal transduction downstream of the B-cell receptor. Its critical importance is underscored by the fact that mutations of BTK result
in the human disease X-linked agammaglobulinemia, which
is characterized by immunodefciency and an absence of B
cells. The BTK inhibitor ibrutinib has recently shown remarkable effcacy in CLL, and two additional BTK inhibitors
have also now reported clinical data in CLL (Table 1).

Ibrutinib
Ibrutinib is a potent covalent inhibitor that binds irreversibly
to cysteine 481 (Cys481) in BTK. Despite a relatively short
half-life, this irreversible inhibition results in 24-hour target
inhibition, as demonstrated in the phase I study of ibrutinib
in B-cell malignancies.6 Ibrutinib is not a specifc inhibitor
but rather inhibits 19 other kinases at inhibitory concentrations (IC50s) less than 100 nmol/L, including six that share
a cognate cysteine and could potentially also be inhibited
covalently.7 In fact, recent research has demonstrated experimentally that ibrutinib does inhibit interleukin-2 inducible
kinase (ITK), a critical kinase involved in T cell signaling,
covalently.8 The relative signifcance of different targets to
the clinical activity of ibrutinib is unknown, although resistance mutations have been found in which Cys481 is mutated
to Ser, suggesting that BTK is at least a key target.9
In the initial phase I study in B-cell malignancies, promising effcacy signals were seen in multiple diseases including
CLL,6 leading to initiation of the phase Ib/II program. This
phase Ib/II program included cohorts of patients with relapsed refractory CLL treated at 420 mg (51 patients) or 840
mg daily (34 patients) as well as a previously untreated older
cohort treated primarily at 420 mg daily (31 patients); the
results of both have been recently published.10,11 International Workshop on CLL (IWCLL) response rates were 71%
in both cohorts, with an additional 13% in each study having
PR-L. Most impressively, the PFS in the relapsed refractory
cohort is 75% at 26 months,10 and 96% in the untreated cohort at 22 months.11 The relapse rate is higher in those patients with 17p deletion however, with 57% PFS at 26
months.10 Ibrutinib was well-tolerated with the primary potential safety concern being bleeding risk, particularly in the
setting of anticoagulation.
The RESONATE registration trial comparing ibrutinib to
ofatumumab in patients with relapsed CLL was stopped early
in January 2014 as it met its primary PFS endpoint as well as
its secondary OS endpoint. Ibrutinib will likely be approved
by the FDA for relapsed CLL in early 2014. Combination
studies of ibrutinib with rituximab, with bendamustine/
rituximab (BR) and with fludarabine/cyclophosphamide/
rituximab (FCR) have all been reported in abstract form.
Additional registration trials, with ibrutinib given as a single
agent in 17p-deleted CLL and for up-front therapy in elderly
patients, as well as in combination with BR, are ongoing.

NOVEL TREATMENTS FOR CHRONIC LYMPHOCYTIC LEUKEMIA

Table 1. Novel Drugs

Target

Drug

Mechanism

Patients

ORR

PFS

CD20

Obinutuzumab (G)

Type 2 antibody

Untreated elderly
CLL3 (n333 G-clb
vs 330 R-clb),
phase 3

ORR 78% G-clb vs 65%

R-clb, p
CR 21% vs 7%, P

26.7m G-clb vs 15.2m R-clb,

HR 0.39, p0.0001

BTK

Ibrutinib

Covalent kinase inhibitor

(Binds Cys 481)

Rel/refr CLL10 (n85),

phase 2

71% ORR 13% PR-L

75% at 26 months

Untreated elderly
CLL11 (n31),
phase 2

71% ORR 13% PR-L

96% at 22 months

PI3K

BCL-2

CC-292

Covalent kinase inhibitor

(Binds Cys 481)

Rel/refr CLL12 (n84),

phase 1

50% ORR 13% PR-L, at

RP2D 500 mg BID

N.R.

ONO-4059

Covalent kinase inhibitor

(Binds Cys 481)

Rel/refr CLL13 (n19),

phase 1

78% ORR 11% PR-L

N.R.

Idelalisib

Competitive kinase
inhibitor, PI3K

Rel/refr CLL14 (n54),

phase 1

39% ORR 33% PR-L

29m median at RP2D

150 mg BID

Rel/refr CLL16, (n110

Idela-R vs 110
placebo-R), phase 3

ORR 81% Idela-R vs 13%

placebo-R, p

Median not reached, Idela-R

vs 5.5m placebo-R,
HR 0.15, p0.001

IPI-145

Competitive kinase
inhibitor, PI3K and

Rel/refr CLL17 (n47),

phase 1

47% ORR 98% nodal

response rate

N.R.

ABT-199

Small molecule BH3

mimetic

Rel/refr CLL19 (n67),

phase 1

84% ORR
23% CR

N.R.

Abbreviations: Clb, chlorambucil; R, rituximab; ORR, overall response rate; PFS, progression-free survival; HR, hazard ratio; Cys, cysteine; Rel, relapsed; refr, refractory; PR-L, partial response with
lymphocytosis; RP2D, recommended phase II dose; N.R., not reported; PI3K, the delta isoform of phosphatidylinositol 3 kinase; PI3K, the gamma isoform of PI3K; CR, complete response.

OTHER BTK INHIBITORS

Two other covalent inhibitors of BTK that bind to the same
Cys481 residue have reported clinical data. CC-292 is a more
specifc inhibitor of BTK that, unlike ibrutinib, does not inhibit SRC family kinases or ITK. The phase I study of CC-292
in CLL was recently updated12 and the drug has been well
tolerated. The recommended phase II dose is 500 mg twice
daily. At this dose the IWCLL partial remission (PR) rate was
50%, with 13% additional PR-L. Median follow-up is still
short, currently at 7.4 months for this cohort as of December
2013. Combination studies have been initiated. The other
compound is ONO-4059, also a more specifc inhibitor than
ibrutinib. This drug is early in its phase I study, with 19 patients enrolled and no dose-limiting toxicities yet observed.13
IWCLL response rate was 78%, with an additional 11% PR-L.
Longer follow-up will be required to clarify how the activity
of either of these drugs compares to that of ibrutinib.

PI3K INHIBITORS
Idelalisib
The frst PI3K inhibitor to be tested in CLL was idelalisib
(formerly known as CAL-101 or GS-1101). Idelalisib is a potent specifc inhibitor of the delta isoform of PI3 kinase,
which appears to have its most critical function in B cells.
Idelalisib was studied in a large phase I study in hematologic
malignancies which included 54 patients with CLL who had
been heavily pretreated, with a median of fve prior regimens,
and 70% of whom had refractory disease. The nodal response
rate was 81%, IWCLL PR rate was 39%, and PR-L rate was
33%. The PFS in the entire study population was 17.1

months, but for those treated at the recommended phase II

dose of 150 mg twice daily or higher, the median PFS was 29
months.14 A phase II study of idelalisib with rituximab in 64
previously untreated CLL patients showed a 97% ORR with
19% complete remissions and 93% PFS at 24 months.15 In
this study, the nine patients with 17p deletion all experienced
a response, including three with complete remissions, and
none have experienced disease progression to date. The primary toxicities with idelalisib have included increase in hepatic transaminases, usually readily manageable by
interrupting the drug, and diarrhea including colitis in a subset of patients.
The frst registration trial of idelalisib, in which idelalisib
with rituximab was compared to placebo with rituximab in
patients with CLL and signifcant medical comorbidities
whose disease relapsed within 24 months of prior therapy,
was stopped early for effcacy, and presented at the American
Society of Hematology meeting in December 2013.16 110 patients were enrolled on each arm, and 44% had high-risk 17p
deletion. With idelalisib, the ORR was 81% and the hazard
ratio for PFS was 0.15 (p 0.0001). Overall survival was also
signifcantly improved in the idelalisib arm, with three deaths
on that arm compared with nine on the placebo arm (HR
0.28, p 0.02). These results have been submitted for FDA
consideration, and two other registration trials in relapsed
CLL are ongoing.

IPI-145
IPI-145 is the other PI3K inhibitor advanced in clinical trials
in CLL and is a potent inhibitor of the delta as well as the
gamma isoforms. The effect of gamma inhibition is unclear,
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FIG 1. The chimeric antigen receptor consists of the single chain variable fragment of an antibody (scFv) that recognizes the CD19
protein on B cells and leukemia cells coupled to the CD3 zeta activation domain and co-stimulatory domains from CD28 and/or 4-1BB.
This combines the MHC independent recognition of a tumor antigen with the activating potential of the T-cell receptor, allowing for
redirection of T cells to leukemia. Inset shows normal T cell:APC interaction through T cell receptor/CD3 recognition of an antigen and
co-stimulation through CD28 or CD137 (41BB). In the foreground a T cell comes into contact with a CD19 tumor cell at white box. In
the background, magnied illustration of T cell interaction with CD19 on tumor cell through a CAR molecule containing the scFv antiCD19 recognition fragment and internal costimulation domains. Most modern constructs include the CD3z stimulatory domain (rst
generation CARs) with the addition of 4-1BB or CD28 (second generation CARs). CARs are now being tested that contain all 3
stimulatory domains (3rd generation). Sue Seif. Reproduced with permission from Sue Seif and Stephan Grupp.

as gamma is expressed in CLL cells as well as T cells and

neutrophils, with the potential to increase effcacy or toxicity. Dose escalation of IPI-145 has been completed with a
maximum tolerated dose of 75 mg twice daily.17 In CLL,
however, the dose selected to move forward is 25 mg twice
daily, since this dose achieves full delta inhibition, has a similarly high response rate, and may show less toxicity. At the
most recent report, 47 patients with relapsed refractory CLL
have been treated, with a 98% nodal response rate and 47%
IWCLL ORR. Follow-up is still quite short, at 5.2 months as
of December 2013, suggesting many patients may have persistent lymphocytosis at this point. A registration trial comparing IPI-145 to ofatumumab in relapsed refractory CLL
has been initiated.

BCL-2 INHIBITION: ABT-199

BCL-2 is nearly universally overexpressed in CLL, making it
an excellent therapeutic target. The frst-generation clinical
inhibitor ABT-263 had a 35% response rate in heavily pretreated patients with CLL but dosing was limited by thrombocytopenia that resulted from on-target inhibition of
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BCL-XL in platelets.18 ABT-199 is a second-generation inhibitor that is highly selective for BCL-2 and is currently
completing its phase I study.19 Thrombocytopenia has not
been a problem on this study, in which the primary toxicity
has been tumor lysis syndrome. The dose-escalation schema
has been revised twice to manage the tumor lysis and currently the drug is slowly escalated weekly over 4 weeks, initially in the hospital, to the planned maximum dose in CLL,
which is 400 mg daily. ABT-199 has been very effective, with
88% nodal response, 100% lymphocyte response, and 89%
bone marrow response, generally soon after therapy initiation. The ORR is 84% with 23% complete remissions, including some patients negative for minimal residual disease.
Forty-three of 67 patients remain on study at a median of 11
months as of December 2013. Registration trials are planned
for this drug but may be delayed as the extent of required
monitoring is clarifed.

THE USE OF CHIMERIC ANTIGEN

RECEPTORMODIFIED T CELLS TO TREAT CLL
Patients with multiply relapsed and/or refractory CLL have a
poor prognosis with few effective treatment options. Autol-

NOVEL TREATMENTS FOR CHRONIC LYMPHOCYTIC LEUKEMIA

ogous T cells engineered to express a chimeric antigen receptor (CAR) have shown recent success in the treatment of
advanced CLL by combining the specifcity of antibodydirected targeting with the extensive in vivo amplifcation
and cell-mediated killing characteristic of cellular therapy.
The long-term persistence of this genetically engineered biologic agent can then provide ongoing tumor control and
vaccine-like protection against recurrence.
A CAR is composed of a targeting domain, a hinge region
for flexibility, a transmembrane domain, and intracellular
signaling components. The targeting domain is typically derived from a single-chain variable fragment (scFv) of an antibody recognizing a cell-surface antigen of choice (CARs
typically cannot recognize intracellular antigens). The signaling domain is critical for optimal function of the CAR and
generally includes the CD3 chain alone (frst-generation
CAR) or a signaling domain plus a costimulatory domain
such as CD28 or 4 1BB (CD137; second-generation CAR).20
Second-generation CAR-modifed T cells are more potent
than frst-generation CARs. Third-generation CARs incorporating more than one costimulatory molecule are in early
stages of clinical testing.21 A schematic of this approach is
shown in Figure 1.
CD19 is an excellent tumor target for CAR therapy; expression is limited to B-cell malignancies, normal B cells, and a
small population of other immune cells. It is not expressed on
hematopoietic stem cells or other normal tissue.22 Although
effective anti-CD19 directed therapy therefore also targets
normal B cells, it is not expected to induce marrow aplasia.
Previous limitations to effective cellular therapy included
lack of specifcity of T cells, inability to generate suffcient
numbers of cells for clinical application, minimal in vivo expansion, and poor persistence. Improved technology for introduction of new genetic material, and for T-cell expansion,
means that large numbers of modifed T cells can now be generated in 10 to 14 days. Most CAR trials have expanded T cells
in high numbers by exposure to anti-CD3/anti-CD28 coated
beads that can be removed before infusion.23 Several methods exist for the stable introduction of a CAR into T cells, but
most studies have used lentiviral or retroviral transduction
with effciencies consistently greater than 20%. After transduction and integration, CAR-modifed T cells are expanded
ex vivo over approximately 2 weeks. Using these techniques,
recent trials have shown that after intravenous infusion,
CAR-modifed T cells can undergo remarkable in vivo proliferation and persist for long periods of time, overcoming
some of the previous barriers to successful cellular immunotherapy. Typically patients receive lymphodepleting chemotherapy before CAR cell infusion with the intent of
promoting homeostatic proliferation and expansion of the
infused CAR-modifed T cells. It remains unknown, however, whether pre-infusion chemotherapy is actually necessary in all patients.
At the University of Pennsylvania (UPenn), autologous T
cells modifed with a CAR directed against CD19 that contains the CD3/4 1BB signaling domains (termed CTL019
cells) were used to treat patients with relapsed and refractory

CLL. It was initially reported that CTL019 cells could undergo massive in vivo proliferation, result in delayed tumor
lysis, and induce potent antitumor responses.24,25 The clinical trial that included 14 patients with relapsed and refractory
CLL has been completed26; a schematic of the trials is shown
in Fig. 2. Patients were heavily pretreated with a median of
four prior regimens. Similar to other trials using anti-CD19
CAR, all patients received lymphodepleting chemotherapy
before CTL019 cell infusion. Patients received a median of
7.5 x 108 total cells (range: 1.7 to 50 x 108), corresponding to
1.4 x 108 (range: 0.14 to 5.9) genetically modifed cells. In
many cases, these cells were capable of undergoing dramatic
proliferation with more than a 3-log increase in vivo and
demonstrated long-term persistence. Four patients (29%)
achieved a CR and 4 (29%) achieved a PR for an overall response rate of 57%. CAR-modifed T cells have been detected
by flow cytometry beyond 3 years after infusion in some patients, correlating with a similar remission duration of more
than 3 years. There was no correlation between response and
cell dose administered, patient age, prior therapy, or cytogenetic risk profle. To better defne the activity of CTL019 cells
and determine the contribution of the cell dose, a randomized phase II study comparing two different doses of CTL019
cells is being performed. Although still in progress, an early
analysis on the frst 18 patients treated has not identifed a
signifcant dose:response or dose:toxicity relationship.27 This
is a surprising and important fnding and differs from results
seen with standard drugs that are not self-replicating; response and toxicity are more likely determined by the number of cells generated by in vivo proliferation and expansion
rather than by the dose infused.
Several other studies using gene-modifed T cells to target
CD19 have been reported and have been recently summarized.28 Using an anti-CD19 CAR containing the CD28 costimulatory domain and retroviral transduction, the group at
Memorial Sloan Kettering Cancer Center have reported
modest activity in at least one of eight patients with CLL.29
Remissions in patients with CLL have been shown by the
group at the National Cancer Institute as well, using a more
intensive lymphodepleting chemotherapy regimen and an
anti-CD19 CAR containing the CD28 costimulatory domain.30 Interestingly, this group has also shown that donorderived CAR-modifed T cells can be used to treat relapsed
CLL after allogeneic stem cell transplantation without induction of graft-versus-host disease.31 The major differences between these trials and the studies done at the University of
Pennsylvania are the use of retroviral-mediated introduction
of the CAR construct and the inclusion of the CD28 costimulatory domain rather than 4-1BB. The design of the
clinical trials are otherwise quite similar. Whether these differences account for the variations differences in activity and
outcome is not known at this time.

TOXICITY
A number of toxicities can be anticipated with anti-CD19
CAR T-cell therapy. B-cell aplasia is an expected on-target
complication resulting in prolonged hypogammaglobulineasco.org/edbook | 2014 ASCO EDUCATIONAL BOOK

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FIG 2. Overview of CTL019 therapy. (1) Leukapheresis: the patients own T cells are harvested; (2) T cells are activated ex vivo
expansion on antibody-coated beads and genetically transduced ex vivo with a construct encoding the anti-CD19 chimeric antigen
receptor; (3) CTL019 cells undergo ex vivo expansion on antibody-coated beads; (4) patients receive a preparative lymphodepleting
regimen before T-cell infusion; (5) CTL019 cells are reinfused into the patient where they undergo in vivo expansion and target CD19
cells for destruction. They remain persistent in the body to guard against residual or recurring disease.

mia. Indeed, B-cell aplasia can be considered a biomarker for

ongoing CAR T-cell activity. Hypogammaglobulinemia is
usually managed with regular immunoglobulin repletion;
whether immunoglobulin repletion is in fact necessary to
prevent infections is not known and will need to be studied in
future trials.
The development of a delayed tumor lysis syndrome
(TLS) is a testament to the proliferative capacity and potency
of CAR T cells and has been seen in several CAR studies.25,31
TLS typically develops at the height of T-cell proliferation
and is associated with a cytokine release syndrome that requires careful monitoring during the frst several weeks
after infusion; a xanthine oxidase inhibitor has been administered for several weeks after T-cell infusion to prevent
complications from TLS. Once established, management of
TLS is generally successful with standard supportive care
measures.
Patients with a disease response almost all develop a cytokine release syndrome (CRS). This is one of the more unique
complications of CAR T-cell therapy and has been reported
in varying degrees of severity in most CAR T-cell trials. The
CRS is manifested by symptoms that can include high fevers,
rigors, anorexia, nausea, myalgias, and arthralgias, and progress to hypotension, capillary leak with pulmonary infltrates,
and hypoxia. This is believed to be related to cytokine production from the rapidly expanding T cells, though cytokines
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can also be produced by activated macrophages and/or

dying tumor cells. The CRS has also been associated with a
macrophage activation syndrome (MAS) associated with
hemophagocytosis, cytopenias, hypofbrinogenemia, and
marked elevations and ferritin.32 In particular, very high levels of interleukin-6 (IL-6) and interferon gamma have been
noted during the CRS. This led to interventions using the
IL-6 receptor antagonist tocilizumab, which has consistently
led to rapid improvement in the clinical and biochemical abnormalities associated with CRS and MAS.32 In the UPenn
experience, the CRS has not been particularly responsive to
corticosteroids, although others have reported successful
treatment of a similar CRS with high doses of corticosteroids.33 It is not yet known whether blockade of cytokines
with anticytokine therapy such as tocilizumab or corticosteroids affects the antitumor response. Therefore, intervention
for severe CRS has been effective, but the most appropriate
timing of intervention remains unknown. Treating patients
with lower tumor burdens may produce a less-intense cytokine reaction,33 lending support to using this approach before the disease becomes refractory and patients have
extensive disease.
There are other theoretical risks to consider when using
integrating retroviral or lentiviral vectors, transposons, and
electroporation to introduce new genetic material into the T
cell. For instance, random integration could result in inser-

NOVEL TREATMENTS FOR CHRONIC LYMPHOCYTIC LEUKEMIA

tional mutagenesis and induction of T-cell lymphoproliferative disorders. This risk appears to be low based on the longterm follow-up of patients with human immunodefciency
virus (HIV) treated with a CD4 CAR, where there have been
no cases of genotoxicity in more than 540 patient-years of
observation.34 In addition, the development of replicationcompetent virus is also highly unlikely as supported by extensive follow-up from 29 different clinical trials.35
More than 40 patients with CLL have been treated at
UPenn and many patients have been treated at other centers.
To date, the majority of clinical trials have included patients
with advanced and heavily pretreated CLL. In a short period
of time, investigations have developed a better understanding of the potential activity, anticipated short-term toxicities, and outcomes using autologous T cells genetically
modifed with an anti-CD19 CAR. It is reasonable to now
consider testing this approach earlier in the course of disease
(when toxicity may be minimized and before exposure to purine analogs and other chemotherapy agents with the potential for long-term marrow damage and other toxicity) or
perhaps at the time of minimal residual disease.36 Moving
forward, CARs directed against other CLL-specifc antigens
will be tested and it will be exciting to test CAR-modifed T
cells in combination with other novel agents or immune
modulators that may augment or regulate the activity of CAR
T cells.

FUTURE PLANS
The advent of tyrosine kinase inhibitors (TKIs) as well as new
monoclonal antibodies in the treatment of CLL have raised
the question of whether chemoimmunotherapy, the current
of standard of care, will soon become a thing of the past. Although these novel agents vary in terms of their side effects,
the one thing that they have in common is the lack of myelosuppression. This is a marked contrast to chemoimmunotherapy such as FCR where the primary initial complication
is myelosuppression and associated infections. Obinutuzumab, the new anti-CD20 monoclonal antibody, recently
received FDA approval for initial use in CLL in combination
with chlorambucil. It is likely that ibrutinib and idelalisib will
both be approved by the FDA this year for patients who with
relapsed CLL, and ABT-199 following on thereafter. Although the initial label for these drugs will be in relapsed disease, there are front-line trials ongoing, and planned, to allow
for expansion of the label to previously untreated patients. In
addition, since off-label use of agents is common in the
United States, particularly when there is published data available, this is likely to occur. This raises the question of whether
chemotherapy-free regimens should be initiated in the near
future, or whether there is still a role for regimens such as
FCR.
The use of FCR as initial therapy for patients with CLL resulted in a median PFS of approximately 5 years in the German CLL 8 trial in which patients were randomly assigned
between FC and FCR.37 Phase II data from the MD Anderson
Cancer Center single-center experience suggested a PFS of

approximately 6 to 7 years.38 This longer PFS was likely seen

based on extensive local experience with this regimen and the
more extensive use of growth factor support to facilitate completion of six cycles; growth factor support has not routinely
been used in the German CLL trials. The only front-line data
currently available for the new agent involves the use of ibrutinib in treatment-nave patients older than age 65.11 This
group was specifcally targeted since there is widespread
agreement in the CLL community that the myelosuppression
and infections associated with chemoimmunotherapy are
more problematic in older patients or those with signifcant
comorbidities. In that trial with ibrutinib the median PFS has
not been reached, and only one patient has experienced relapsed disease with a median follow-up of 30 months.39 However, it is important to note that this experience is based on
analysis of only 31 patients; although this early data is impressive, there is no 5-year follow-up to offer a comparison to
front-line chemoimmunotherapy. Nevertheless, the relative
ease of administration of this agent in a patient population
which is less able to complete a full course of chemoimmunotherapy suggests that there will be rapid adoption of TKIs
in this population.
The other population in which chemoimmunotherapy is
relatively ineffective are patients with 17p deletion. It is well
known that these patients have a poor disease response to
chemotherapy-based regimens, partly related to the absence
of p53. The median PFS of patients with 17p deletions treated
with FCR as front-line therapy was approximately 12 months
in the MD Anderson Cancer Center analysis38 and identical
in the German CLL 8 trial.37 Clearly, a 12-month PFS in a
front-line population is poor, and this is another group that
will rapidly be treated with novel agents rather than chemoimmunotherapy. Data from the ibrutinib trial in patients
with relapsed and refractory CLL indicated that the median
PFS of patients relapsed/refractory disease with 17p deletion
was 2 years, signifcantly longer than the front-line PFS seen
with chemoimmunotherapy.
Recent data from long-term follow-up of a cohort of 300
patients from MD Anderson Cancer Center presented at the
iwCLL meeting in 2013 showed that approximately 30% of
these patients were still in remission at 10 to 14 years from the
start of chemotherapy. Although 30% is a minority of patients, if this group could be reliably identifed, then perhaps
in those patients continued use of chemoimmunotherapy in
some form is a strategy that should be retained. An analysis of
prognostic factors suggested that such patients can be identifed, they were patients who did not have a 17p or 11q deletion, had a mutated IgVH gene and frequently had trisomy 12
or 13q deletion. In fact, when the PFS analysis was limited
only to patients with a mutated IgVH gene, 60% were still in
remission at 10 years.
However, late complications of chemoimmunotherapy
have been recognized, and there may be some that have not
yet been reported. A serious, albeit infrequent, complication
is the development of treatment-related myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (AML).38
This is a devastating phenomenon because treatment outasco.org/edbook | 2014 ASCO EDUCATIONAL BOOK

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BROWN, PORTER, AND OBRIEN

comes are poor for these secondary malignancies, and survivals are generally short. This raises the question of whether
the use of novel antibodies such as obinutuzumab or oral inhibitors in combination with chemotherapy may allow the
duration of the regimen (usually six cycles/6 months) to be
shortened and produce the same or better outcomes with
limited exposure to chemotherapy.
The low CR rate seen even in the trial in patients receiving
front-line treatment may suggest that 10-year remissions are
unlikely to occur with single-agent TKIs. However, given the
short follow-up in the front-line population and the continued evolution of responses over time, it is possible that in that
group CR rates will increase beyond the currently seen 13%.
Although responses may continue to improve in the relapsed/refractory population, clearly the constant decline in
the PFS and OS curves in these patients suggests that the
competing risk of resistance will likely not result in a large
increase in the CR rate. Data showing that mutations in both
BTK and PLC gamma may occur in resistant disease recapitulate fndings seen with TKIs in the setting of chronic myelogenous leukemia, namely that specifc targeting of kinases
inevitably results in a proportion of patients developing resistance through mutations of the target.40
One obvious question is whether new TKIs or BCL-2 inhibitors can be combined with each other or with novel antibodies such as obinutuzumab. At this time there is no
clinical trial data to answer this, but there is a reasonable rationale for combining various agents. There is some data

evaluating TKIs in combination with antibodies, clearly

showing that the use of rituximab or ofatumumab results in
faster responses because of the abrogation of lymphocytosis
seen with single-agent TKIs. However, current data, admittedly with very short follow-up, suggest the CR rates are not
increased and PFS may not be signifcantly enhanced in this
setting.41 Combining oral targeted agents is a very attractive
concept but raises an important and ever more present issue
in cancer therapeutics, which is the cost of drugs. These novel
agents are likely to be very expensive and combining them
outside of a clinical trial may be prohibitory. In addition, because of the current reimbursement schema for oral therapeutics requiring a copay (which varies signifcantly from
insurance to insurance), even when these drugs are covered
by insurance the concomitant copay may make use of the
agent impossible in a given patient. Taking a lesson from HIV
drugs would suggest that if such combinations could be
achieved in a single pill this strategy would be more practical
in the long run.
Currently, it is very exciting to have these novel, relatively
nontoxic, oral agents available that are not myelosuppressive
and can be easily administered. Although chemotherapy is
associated with the short-term complications of myelosuppression and infection as well as the low risk of late t-MDS or
t-AML, the therapy is inexpensive and treatment is fnished
after 6 months. The rapidly rising cost of cancer care suggests
that this is something that will have to be factored into the
algorithm moving forward.

Disclosures of Potential Conicts of Interest

Relationships are considered self-held and compensated unless otherwise noted. Relationships marked L indicate leadership positions. Relationships marked I are those held by an immediate
family member; those marked B are held by the author and an immediate family member. Relationships marked U are uncompensated.

Employment or Leadership Position: David L. Porter, Genentech/Roche (I). Consultant or Advisory Role: Jennifer R. Brown, Boehringer Ingelheim;
Celgene; Emergent; Genentech; Novartis; Onyx; Pharmacyclics; Sano; Vertex. Susan M. OBrien, Amgen; Celgene; Emergent BioSolutions; Genentech; Genmab;
Gilead Sciences; GlaxoSmithKline; Innity; Lilly; MorphoSys; Pharmacyclics; Sunesis Pharmaceuticals; Talon Therapeutics; Teva. Stock Ownership: None.
Honoraria: None. Research Funding: Jennifer R. Brown, Celgene; Genzyme.Susan M. OBrien, ARIAD; Bayer; Biogen Idec; Bristol-Myers Squibb; Calistoga
Pharmaceuticals; Emergent BioSolutions; Gemin X; Genentech; Genta; Gilead Sciences; Hana BioSciences; Innity; Lilly; MorphoSys; Novartis; Pharmacyclics;
Talon Therapeutics. David L. Porter, Novartis. Expert Testimony: None. Other Remuneration: None.

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