2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TREATMENT OF FOLLICULAR LYMPHOMA
mediates the ubiquitation and degradation of proteins, and
is frequently deregulated in lymphomas, including FL. Although
suppression of nuclear factor-kappaB (NF�B) appears
to be the major mechanism of action of bortezomib,
there is also upregulation of proapoptotic factors such as
NOXA and downregulation of antiapoptotic factors. The
increased activity of proapoptotic factors in a disease that
is characterized by universal bcl2 overexpression may be
mechanistically important. The VERTICAL trial (Velcade
in Relapsed or Refractory Follicular Lymphoma) added
four weekly doses of bortezomib to a 35-day cycle of
escalating doses of bendamustine plus rituximab for five
consecutive cycles. 27 Among 63 patients receiving the
highest bendamustine dose level, the overall response
rate was 88% and complete response rate was 53%. Another
trial testing this combination had a slightly different
treatment schedule that used the more standard bortezomib
scheduling of twice-weekly doses. 28 Again, there was an
impressive overall response rate of 83%, and this regimen
is currently undergoing further testing in both relapsed
and front-line settings to determine the incremental benefit
of bortezomib to a bendamustine and rituximab backbone.
Given high patient heterogeneity, it is clear that a subset
of patients stand to benefit a great deal from new agents
used at this point in the overall disease course. However,
short of randomized multiarm trials, the challenge will be to
standardize patients in some way to allow fair comparisons
of different regimens. It is not sufficient to use the number of
prior regimens, because, as discussed earlier, the front-line
regimens vary greatly, and time to relapse and determination
of relative rituximab sensitivity compared with resistance
all influence the likelihood of response to subsequent
therapy. A second-line FLIPI or other biologic tool is greatly
needed. Until these tools are available, this heterogeneous
disease state will remain the most challenging setting in
which to assess relative efficacy of a new therapy, and
incorporation of new agents will be difficult to apply in a
controlled fashion.
Multiply Relapsed and/or Refractory FL: Promising
Agents and Approaches for Chemoresistant and
Rituximab-Resistant Disease
Despite the major positive impact of chemoimmunotherapy,
nearly all patients eventually demonstrate both
chemotherapy and rituximab resistance, making multiply
relapsed FL a disease state of great unmet need. An agent
capable of demonstrating activity in this clinical setting
would quickly have impact and could be moved earlier into
the disease course, as reflected by lenalidomide and bendamustine,
both of which first showed activity in relapsed/
refractory FL. This is currently the disease state in which
gains in knowledge regarding FL pathogenesis have spurred
new and targeted agents with promising clinical validation
ongoing.
Among B-cell malignancies, few potential targets are as
ubiquitous as the B-cell receptor (BCR) and its downstream
signaling cascade. BCR normally responds to antigens by
triggering an internal signal leading to gene transcription
and B-cell activation and proliferation. 29 Malignant B-cell
transformation usually retains the need for an intact and
tonically active BCR, and agents that block its signaling
have shown promising preclinical effects. 30-33 The Tec-
kinase Bruton’s tyrosine kinase (BTK) appears to be required
to form immunoglobulin and to allow B-cell survival
as part of BCR signaling. 34 PCI-32765 is a novel, orally
available, irreversible covalent inhibitor of BTK. Preclinical
studies confirm its selectivity for its target, the ability to
completely halt BCR signaling, and potent activity in B-cell
lymphomas, chronic lymphocytic leukemia models, and autoimmune
models. 35-38 A phase I trial in B-cell non-Hodgkin
lymphoma showed an impressive response rate of 54% in an
intent-to-treat population that included both aggressive and
indolent histologies. 39 Among 16 patients with FL, one-third
had an objective response including three complete responses.
Early results are promising, but it is also clear that
single-agent PCI-32765 primarily leads to partial responses
in FL and its impact on response durability is yet to be
determined. Using this agent in earlier disease states is
worthy of investigation.
Just downstream of BCR signaling is the phosphoinositide
3-kinase (PI3K)/Akt/mammalian target of rapamycin
(mTOR; PAM) axis, which is also emerging as a major
pathogenetic mechanism in FL. The natural function of
PI3K is to transduce external growth signals and modulate
downstream targets that control cellular proliferation,
motility, metabolism and cell growth vs. survival
(reviewed in Courtney, Corcoran, and Engelman 40 ). There
are four PI3K isoforms—alpha, beta, gamma, delta—with
the delta isoform having restricted expression in human
leukocytes. CAL-101 is an orally bioavailable PI3K
inhibitor that is highly selective for the p110 delta isoform. 41
In vitro models show that CAL-101 can block tonic PI3K
signaling with decreased activation of downstream targets,
including Akt. Preliminary data from phase I studies
show promising activity of CAL-101 in B-cell malignancies,
including FL. 42-44 Among 30 patients with indolent
lymphomas, including 17 patients with FL, the single-agent
overall response rate was 63%, with a median PFS exceeding
1 year. The most common grade 3 or 4 event was
transient increase of hepatic enzymes, which occurred in
27% of patients. On the basis of the safety profile and
efficacy, CAL-101 has been added to the backbone of
bendamustine and rituximab in a phase I combination
study (NCT01088048). 45 Preliminary results show excellent
tolerability and an overall response rate of more than 65%
in a group of heavily pretreated patients with indolent
lymphomas.
An important downstream substrate of PI3K and Akt is
the serine/threonine kinase mTOR. The natural functions of
mTOR are to integrate growth signals and nutrient availability
and influence cell growth via control over mRNA
translation. Several preclinical investigations support
the central role of mTOR in FL (reviewed in Smith 46 ).
Single-agent temsirolimus, a rapamycin analog, was tested
in 39 patients with relapsed or refractory FL; more than
half of patients had an objective response, including 25%
complete responses. 47 Nonhematologic toxicities included
metabolic abnormalities (hyperglycemia, hypertriglyceridemia,
hypercholesterolemia), stomatitis, and rash. Combination
studies of temsirolimus plus lenalidomide
(NCT01076543) and everolimus plus lenalidomide
(NCT01075321) are ongoing.
A near-universal feature of FL is BCL2 overexpression,
primarily as a result of the hallmark translocation, t(14;18).
The constitutive expression of the antiapoptotic BCL2 pro-
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