NcXHF

KREM AND GOPAL
TABLE 1. Median Ages of Presentation of iNHL
Subtypes
Disease Median Age (Years) Reference(s)
CLL/SLL 72 12
LPL 60-64 10, 11
MZL 72 12
FL 65 12
Abbreviations: iNHL, indolent B-cell malignancies; CLL, chronic lymphocytic leukemia; SLL,
small lymphocytic lymphoma; LPL, lymphoplasmacytic lymphoma; MZL, marginal-zone
lymphoma; FL, follicular lymphoma.
KEY POINTS
Older patients are more prone to comorbidities, reduced
performance status, and grade 3 or higher toxicities,
making safety and tolerability key considerations in the
choice of treatment for indolent B-cell malignancies.
New anti-CD20 monoclonal antibodies, administered in
combination with chlorambucil, have demonstrated efficacy
in patients with chronic lymphocytic leukemia who are
older or have comorbidities.
The phosphatidyl-3-kinase inhibitor idelalisib and the
Bruton’s tyrosine kinase inhibitor ibrutinib have
demonstrated good efficacy and tolerability in patients
with chronic lymphocytic leukemia, including patients with
high-risk cytogenetics.
mTOR inhibitors, immunomodulatory drugs, and proteasome
inhibitors have efficacy across several indolent B-cell
malignancy histologies but have not resulted in high
tolerability in all patient subtypes.
Immunotherapies such as programmed cell death 1
blockade show promise of efficacy with excellent
tolerability.
dependent cytotoxicity, and apoptosis. 17,18 With the advent of
rituximab, anti-CD20 monoclonal antibody therapy assumed
an essential role in the therapy of the majority of B-cell
malignancies. Novel anti-CD20 agents have been developed
in an effort to build on the progress made in the rituximab
era. There are two recognized classes of anti-CD20 antibodies:
type 1 (ibritumomab, rituximab, and ofatumumab) and
type 2 (obinutuzumab). Type 1 antibodies organize CD20
molecules into “rafts” and exert their effects primarily by
ADCC and complement-dependent cytotoxicity, and less so
by apoptosis. Type 2 antibodies utilize apoptosis to a greater
degree and also exert more potent ADCC as well. 19,20
The radioimmunoconjugate 90 yttrium-ibritumomab-tiuxetan
(YIT) fuses a murine anti-CD20 antibody to a chelator (tiuxetan)
that holds the beta-emitter isotope 90Y. YIT received
initial approval in 2002 for relapsed or refractory low-grade
lymphoma, but recent data show that it has considerable
single-agent effıcacy as initial therapy 21,22 or consolidation
therapy 23 for patients with FL or MZL. The percentage of patients
age 60 or older ranged from 28% to 50% in those studies,
with minimal or no grade 3 to 4 nonhematologic adverse
events. In the randomized consolidation FIT trial, 8% of
patients in the YIT arm experienced grade 3 to 4 infections
versus 2% of patients in the control arm. Thus, radioimmunoconjugate
therapy offers potent single-agent effıcacy coupled
with excellent tolerability, a favorable combination in
older patients.
Ofatumumab was approved by the U.S. Food and Drug
Administration (FDA) in October 2009 as a single agent for
relapsed CLL after a single-arm, phase II study with 59 patients
of median age 64 with relapsed or refractory disease
after fludarabine and alemtuzumab therapy demonstrated a
58% overall response rate (ORR). In the trial, 27 patients were
age 65 or older and 10 patients were age 70 or older. Response
rates were similar for younger and older patients. Grade 3 to
4 infections developed in 12% of patients, 10% of patients
experienced fatal infections, and 64% of patients experienced
infusion reactions. 24
A subsequent open-label trial in the fırst-line setting,
COMPLEMENT-1, randomly assigned 447 patients who
were not candidates for fludarabine-based therapy to receive
ofatumumab and chlorambucil (217 patients) versus chlorambucil
alone (227 patients). The median age was 69, with 69% of
patients age 65 or older, and 72% of patients had at least two
comorbidities including chronic kidney disease; thus, the
trial had excellent applicability to patients with advanced age.
Effıcacy and safety results are summarized in Table 3. Briefly,
fırst-line ofatumumab and chlorambucil achieved a higher
RR and improved progression-free survival (PFS) compared
with chlorambucil alone. 25 It should be noted that the
comparator arm, chlorambucil monotherapy, is commonly
reserved for patients who are candidates for minimally aggressive
therapy, yet still produced substantial rates of
adverse events and severe infections. A Canadian costeffectiveness
analysis of the COMPLEMENT-1 trial demonstrated
an incremental cost-effectiveness ratio of CAD
$68,672 per quality-adjusted life-year (QALY) gained. 26 On April
17, 2014, the results from COMPLEMENT-1 led to the FDA
approval of ofatumumab in combination with chlorambucil
for the front-line treatment of patients with CLL.
Obinutuzumab received FDA approval on November 1,
2013, for the fırst-line treatment of patients with CLL in combination
with chlorambucil, based on results of the openlabel,
phase III CLL11 trial of 781 patients comparing
obinutuzumab and chlorambucil, rituximab and chlorambucil,
and chlorambucil alone. All patients had coexisting
morbidities and a median age of 73. Results are summarized
in Table 3. The obinutuzumab-chlorambucil arm demonstrated
superior PFS, and overall survival favored obinutuzumab/chlorambucil
over chlorambucil alone (RR 0.41;
p 0.002), but did not reach statistical signifıcance for
obinutuzumab/chlorambucil compared with rituximab/
chlorambucil. In the aggregate, hematologic toxicity was
higher in the obinutuzumab/chlorambucil arm versus rituximab/chlorambucil,
emphasizing that the improved PFS was
somewhat counterbalanced by increased toxicity. Of note,
109 of 240 patients in the obinutuzumab plus chlorambucil
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