NcXHF

NEW TARGETED THERAPIES FOR iNHL
New Targeted Therapies for Indolent B-Cell Malignancies in
Older Patients
Maxwell M. Krem, MD, PhD, and Ajay K. Gopal, MD
OVERVIEW
Molecularly targeted agents have become an established component of the treatment of indolent B-cell malignancies (iNHL). iNHL
disproportionately affects older adults, so treatments that have excellent tolerability and efficacy across multiple lines of therapy are
in demand. The numbers and classes of targeted therapies for iNHL have proliferated rapidly in recent years; classes of agents that
show promise for older patients with iNHL include anti-CD20 antibodies, phosphatidyl-3-kinase (PI3K)/Akt/mammalian target of
rapamycin (mTOR) signaling pathway inhibitors, immunomodulators, proteasome inhibitors, epigenetic modulators, and immunotherapies.
Here, we review the proposed mechanisms of action, efficacy, and tolerability of novel agents for iNHL, with an emphasis on their
applicability to older patients.
For slightly more than a decade, targeted therapies have
established a track record of improving outcomes for
older patients with lymphoma. Rituximab was the fırst
widely utilized targeted therapy for B-cell lymphomas and
resulted in survival improvement when combined with standard
chemotherapy for older patients with diffuse large
B-cell lymphoma, 1 chronic lymphocytic leukemia (CLL), 2
and follicular lymphoma (FL). 3-6 The addition of rituximab
to traditional chemotherapy ushered in a new standard of
care for fıt patients with both aggressive and indolent B-cell
non-Hodgkin lymphomas, termed chemoimmunotherapy,
that led to new benchmarks for response rate (RR) and overall
survival. In recent years, targeted therapy options have
multiplied rapidly, which may once again lead to new standards
of care and treatment expectations for B-cell malignancies,
in particular indolent lymphomas. 7,8
Based on 2008 World Health Organization classifıcations,
iNHL comprises the following histologic subtypes: FL; small
lymphocytic lymphoma (SLL)/CLL; lymphoplasmacytic
lymphoma (LPL), which is defıned as Waldenström macroglobulinemia
(WM) when associated with a monoclonal
immunoglobulin M component and bone marrow involvement;
and marginal-zone lymphoma (MZL), which includes
marginal-zone lymphoma of mucosa-associated lymphoid
tissue. 9 iNHL disproportionately affects older populations
(Table 1) and may require multiple treatment courses over
decades, 10-12 so there is a need for effective targeted agents as
either supplements to or replacements for traditional regimens.
An observational study of 1,495 patients with CLL
demonstrated that older age was associated with worse performance
status, a higher comorbidity score, and more advanced
disease at treatment initiation, 13 highlighting the
need for agents that have effıcacy and tolerability in older patients.
Furthermore, age-related host factors reduce treatment
tolerability and increase the risk of grade 3 to 5
toxicities, 14 making adverse effects key considerations.
Both the classes and numbers of targeted therapies have
rapidly proliferated, resulting in an evolving and more complex
treatment landscape. Available classes that have
spawned second-generation agents include monoclonal antibodies,
cell-signaling pathway inhibitors, immunomodulators,
and proteasome inhibitors. Several new classes of agents
are in clinical trials and show promise (Table 2). We will discuss
these classes of agents, their proposed mechanisms of
action, and the clinical data regarding their effıcacy and tolerability
in older patients. Our emphasis will be on those that
are currently marketed, have been studied in older populations,
and have later-phase clinical data.
ANTI-CD20 ANTIBODIES
CD20 is a glycosylated phosphoprotein antigen found on the
surface of B lymphocytes at most stages of B-cell development,
starting at the pro-B-cell phase but ending before differentiation
into plasma cells. Its function is believed to be
optimization of antibody responses, but it has no known natural
ligand. 15,16 Monoclonal antibodies directed against
CD20 neutralize both benign and malignant B cells; anti-
CD20 antibody cytotoxicity mechanisms include antibodydependent
cell-mediated cytotoxicity (ADCC), complement-
From the University of Louisville Brown Cancer Center, Louisville, KY; Fred Hutchinson Cancer Research Center, Seattle, WA.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Maxwell M. Krem, MD, PhD, University of Louisville Brown Cancer Center, 529 South Jackson St., Louisville, KY 40202; email: mkrem@uw.edu.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
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