NcXHF

KREM AND GOPAL
activated protein kinase, and Cullin 4 to function as part of an
E3 ubiquitin ligase complex. 55 CRBN is required for the therapeutic
effect of IMiDs. Its downstream signaling targets include
interferon regulatory factor 4 and tumor necrosis
factor-alpha. 56 Lenalidomide-bound cereblon, in its ubiquitin
ligase function, also targets the Ikaros family zinc fınger
proteins 1 and 3, which are B-cell–specifıc transcription factors,
for degradation. 57
Lenalidomide has shown effıcacy in the treatment of relapsed
or refractory iNHL. In a study of 43 patients of median
age 63 (21% older than 75) with FL, SLL, or MZL, 25 mg lenalidomide
monotherapy administered 3 out of 4 weeks for
up to 52 weeks induced a 23% ORR with a median duration of
response of 16.5 months or greater. 58 Common adverse events
(any grade) included neutropenia (58%), fatigue (51%), thrombocytopenia
(42%), anemia (37%), and diarrhea (33%). Common
grade 3 to 4 toxicities included neutropenia (46%),
thrombocytopenia (19%), anemia (9%), asthenia (5%), and
pneumonia (5%); 67% of patients required dose reductions or
interruptions. Treatment discontinuation because of adverse
events occurred in 19% of patients; there was one treatmentrelated
death. Lenalidomide showed effıcacy in a relatively heavily
pretreated population (median of three prior treatments)
with moderate tolerability, with a study population that included
older patients.
Later-line effıcacy of lenalidomide led to a fırst-line, phase
II trial of lenalidomide and rituximab in 110 patients with
iNHL. Histologic subtypes included FL (50 patients), SLL (30
patients), and MZL (30 patients), with median ages of 56, 59,
and 59, respectively. Treatment with lenalidomide plus rituximab
resulted in an ORR of 90%, a 65% CR rate, and a median
PFS of 54 months. Response rates were similar across subtypes
but highest in patients with FL. The most common grade 3 to 4
AEs included neutropenia (35%), pain or myalgia (9%), rash
(7%), fatigue (5%), thrombosis (5%), and pulmonary symptoms
(5%); 28% of patients required dose reductions. No treatmentrelated
deaths occurred. 59 Thus, the combination of lenalidomide
and rituximab was well tolerated with good effıcacy,
though the median patient ages were younger than those typically
seen for the histologic subtypes treated. Toxicity and dosereduction
or discontinuation rates may be higher in older
patient populations. This approach is under investigation in a
phase III trial that recently completed accrual to evaluate rituximab
and lenalidomide versus rituximab and chemotherapy in
untreated patients with FL.
IMiDs have also demonstrated effıcacy in WM. 60 The combination
of rituximab and lenalidomide induced a 50% ORR
in a trial of 16 patients; 12 had been previously untreated and
four patients had received prior therapy. The median age was 65.
However, 13 out of 16 patients experienced a hematocrit decrease,
resulting in early termination of enrollment; 88% of patients
required treatment discontinuation. The most common
grade 3 to 4 toxicity was neutropenia (31%). 61 Given the concern
for thalidomide and neuropathy in WM patients, and the
unique, idiosyncratic association of lenalidomide with anemia
in WM, IMiD therapy will require further development before
being ready for “prime time” in WM, especially in older patients
who may be more affected by adverse events.
PROTEASOME INHIBITORS
Proteasome inhibitors such as bortezomib and carfılzomib
inhibit the chymotrypsin-like sites of the proteasome’s
20S subunit. That inhibition disrupts protein homeostasis and
protein folding quality control, resulting in proteotoxic stress
and activation of the unfolded protein response, leading to cell
death; cancer cells experience higher toxicity as they are more
susceptible to proteotoxic stress. 62 Bortezomib has been in use
for the treatment of multiple myeloma for more than a decade,
and its use in mantle cell NHL dates back several years, having
received approval for relapsed or refractory disease in 2006 and
approval for fırst-line therapy in October 2014. Bortezomib is
still being studied for use in indolent lymphoma.
Three phase II studies have established effıcacy of bortezomib
in relapsed or refractory iNHL. 63-65 Results varied,
with response rates ranging from 13% to 53%; the study with
the lowest ORR was notable for a 64% stable disease rate. 64
None of the studies reported grade 3 neuropathy higher
than 10%. Notably, Di Bella et al enrolled a cohort of median
age 70, 64 with grade 3 or 4 adverse events including
thrombocytopenia (20%), fatigue (10%), neutropenia
(8.5%), neuropathy (6.8%), and diarrhea (6.8%). 64 Thus,
bortezomib may be a reasonably well-tolerated option
with modest effıcacy in an older population. de Vos et al compared
biweekly (1.3 mg/m 2 on days 1, 4, 8, and 11 of 21-day cycles)
with weekly (1.6 mg/m 2 on days 1, 8, 15, and 22 of 35-day
cycles) bortezomib in combination with rituximab and found
the weekly regimen to be better tolerated, with fewer grade 3 or
higher adverse events, including neuropathy (10% biweekly versus
5% weekly). 65
These initial favorable results led to a randomized, phase
III trial of bortezomib plus rituximab versus rituximab
alone for patients with relapsed or refractory FL. In the
study, 1.6 mg/m 2 of bortezomib was administered intravenously
on days 1, 8, 15, and 22 of 35-day cycles. A total of
676 patients were enrolled with a median age of 57; 28% of
patients were older than age 65. The addition of bortezomib resulted
in a modest increase of PFS from 11 to 13 months. Grade
3 or higher adverse events were higher in the combination arm,
46% compared with 21%. Grade 3 or higher infection (11% vs.
4%), neutropenia (11% vs. 4%), diarrhea (7% vs. 0%), and neuropathy
(3% vs. 1%) favored rituximab alone. The combination
arm experienced 1% possible treatment-related deaths. 66 Given
the higher toxicity of the combination regimen, the modest
2-month improvement in PFS was disappointing.
However, recent data in high-tumor burden iNHL suggest
that combination therapy with bortezomib and rituximab
may still be desirable. A front-line phase II trial with 42
patients of median age 61 with primarily FL received 1.6
mg/m 2 of bortezomib intravenously on days 1, 8, 15, and
22 of 35-day cycles. The ORR was 70% with a CR rate of
e370
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