The standard management of low-grade lymphoma
remains controversial. Long-term follow-up studies of patients
treated with conventional regimens have shown that currently
available treatments are not curative.
New Treatment Approaches for Low-Grade Lymphoma
Nucleoside AnalogsNewer chemotherapeutic agents, such as
fludarabine (Fludara) and cladribine (2-chlorodeoxyadenosine
[Leustatin]), have significant single-agent antitumor activity in
low-grade lymphoma and are currently being tested in combination
regimens.[1,2] Because these nucleoside analogs cause significant
myelosuppression and immunosuppression and are associated with an
increased risk of opportunistic infections, their role in the
treatment of low-grade lymphoma remains undefined.
Interferon-AlfaRecently, a meta-analysis of randomized
trials evaluating the role of interferon-alfa (Intron A, Roferon-A)
in the treatment of follicular lymphoma concluded that
interferon-alfa prolonged overall survival in patients receiving more
intensive initial therapy with regimens containing doxorubicin or
mitoxantrone (Novantrone), as compared with patients receiving less-intensive
therapy with single-agent alkylator therapy or CVP
(cyclophosphamide, vincristine, and prednisone). In contrast, the
Southwest Oncology Group (SWOG) reported that the use of
interferon-alfa after inten-sive induction chemotherapy with
ProMACE-MOPP (prednisone, methotrexate, Adriamycin, cyclophosphamide,
etoposide, mechlorethamine, Oncovin, and procarbazine) did not extend
relapse-free or overall survival in patients with advanced low-grade lymphoma.
These conflicting results make it difficult to specify
recommendations regarding the role of interferon-alfa in the
management of low-grade lymphoma.
Stem-Cell TransplantationAutologous stem-cell
transplantation is an effective therapy for relapsed diffuse
aggressive lymphoma and histologically tranformed lymphoma, but
its role in low-grade lymphoma is still under investigation. A number
of phase II trials have demonstrated the feasibility of this
intensified approach in patients with low-grade lymphoma. In the
absence of randomized trials, however, it has been impossible to
demonstrate that autologous stem-cell grafting has curative potential
or prolongs survival in patients with low-grade lymphoma.
Although the acute toxicities of autologous stem-cell transplantation
have been significantly reduced during the 1990s, there is still a
significant risk of long-term complications, such as
treatment-related myelodysplasia and acute leukemia.
Monoclonal Antibody Therapy of Lymphoma
The development of monoclonal antibodies (MoAbs) with defined
specificities to lymphoma-associated antigens represents a revolution
in the treatment of patients with lymphoma. Phase I/II clinical
studies have been conducted using native or modified MoAbs directed
against lineage-specific surface markers, such as CD19, CD20, and
CD22. To enhance cytotoxicity, modified MoAbs, such as
toxin-conjugated or radiolabeled antibodies, have also been designed.
Rituximab (Rituxan) is a genetically engineered, chimeric,
murine/human MoAb that targets the CD20 antigen found on the surface
of most B-cell lymphomas. This product was recently approved by the
FDA for use as a single agent in the treatment of relapsed low-grade
lymphoma. It also is under investigation for use in combination
regimens for follicular, mantle cell, and diffuse aggressive lymphomas.
McLaughlin and colleagues provide an excellent review of the
mechanisms of action and pharmacokinetics of rituximab, as well as
clinical experience with its use in the treatment of B-cell lymphoma.
Because it is a chimeric molecule, rituximab is less immunogenic and
has a longer half-life than murine MoAbs. The authors review
preclinical data demonstrating that rituximab mediates human effector
functions (eg, complement-mediated cell lysis and antibody-dependent
cell-mediated cyto-toxicity) in an antigen-specific manner. In
addition, induction of apoptosis and sensitization of resistant cells
lines by rituximab have been seen in some cell culture models,
providing a rationale for combining rituximab with chemotherapy in
Dosing ScheduleThe weekly schedule of rituximab
administration was based on pharmacokinetic studies. However, it is
unclear from these observations what peak serum rituximab levels are
required to attain a maximum anti-tumor response. Since the half-life
of rituximab is prolonged after each successive dose, would a
decreased frequency of administration after the second or third dose
lead to prolongation of therapeutic serum rituximab levels?
Future studies need to compare the efficacy of four vs eight doses of
rituximab. Similarly, the use of rituximab as an adjuvant or
maintenance therapy needs to be investigated, particularly in
patients with minimal residual disease.
PremedicationThe use of cortico-steroid premedications
prior to rituximab administration was specifically prohibited in all
of the trials reported to date. The primary reason for this exclusion
was to avoid the confounding factor of concurrent corticosteroid
administration in assessing the efficacy of rituximab therapy.
As the authors point out, adverse events occurring in these trials
included hypotension, bronchospasm, chills, and fever, which
developed in 8%, 10%, 32%, and 49% of patients, respectively. Similar
adverse events are being reported as part of post-marketing
surveillance, some of which are considered to be serious and
unlabeled (ie, not listed in the Rituxan package insert). These side
effects may be clinically significant, especially in elderly patients
with compromised cardiopulmonary reserve. In the absence of any
specific data suggesting that corticosteroids are contra-indicated,
it may be prudent to premedicate patients with a dose of
corticosteroid prior to rituximab adminis-tration to avoid important
side effects and hypersensitivity reactions in this generally older
ImmunosuppressionTreatment with rituximab produces
profound B-cell depletion, which persists for at least 6 months and
recovers slowly thereafter. The incidence of serious infections does
not appear to be increased in patients given rituximab.
Recently, Tetreault et al described a patient who developed
Coombs positive hemolytic anemia and immunoblastic peripheral
T-cell lymphoma 18 months after receiving rituximab for low-grade
follicular small cleaved cell lymphoma. This report raises the
possibility that the immune defects resulting from depletion of
CD20-positive cells may be clinically important.
Other available therapies for low-grade lymphoma also produce altered
states of immunity. For example, treatment with nucleoside analogs
often results in profound T-cell depletion, which can lead to the
development of opportunistic infections and immune-mediated
cytopenias. Whether prior, concomitant, or subsequent therapy with
nucleoside analogs increases the risk of infections or complications
of immunodeficiency in patients receiving rituximab remains to be determined.
Patient SelectionAll of the clinical trials of rituximab
conducted to date have enrolled only patients with measurable
disease. However, rituximab is ideally suited for randomized studies
in low-grade lymphoma patients with minimal disease (ie, following
conventional chemotherapy or autologous stem-cell transplantation).
Other promising areas for further investigation of rituximab include:
(1) in vivo purging prior to autologous stem-cell
transplantation, with or without post-transplant rituximab
consolidation; (2) treatment of other subtypes of B-cell lymphoma,
such as small lymphocytic, mantle cell, lymphoplasmacytic, and
marginal zone (eg, mucosa-associated lymphoid tissue [MALT] lymphoma)
histologies; (3) incorporation into front-line chemotherapy regimens
for low-grade and aggressive lymphomas; (4) identification of
patients who are more likely to benefit from an extended course of
therapy, such as those with bone marrow or peripheral blood
involvement; and (5) treatment of elderly patients with comorbid conditions.
Rituximab compares quite favorably with other treatment approaches
available for low-grade lymphoma and provides an alternative to the
use of more toxic interventions, such as nucleoside analogs,
interferon-alfa, and autologous stem-cell transplantation. Although
the development of rituximab represents a major advance in the
treatment of B-cell malignancies, it is not a curative therapy for
recurrent low-grade lymphoma. It is conceivable that the use of
rituximab as a consolidation or maintenance therapy may lead to
prolongation of survival; however, the majority of patients with
recurrent or advanced low-grade lymphoma will die as a consequence of
Alternative treatment strategies are needed, particularly in younger
patients whose lifespan is likely to shortened because of their
low-grade lymphoma. The ability of radioimmunotherapeutic approaches
to selectively target radiation to malignant B-cells may improve the
efficacy of MoAb therapy when administered as front-line or
autologous stem-cell transplantationbased salvage therapy.
Finally, carefully selected patients with low-grade or follicular
lymphoma may be candidates for allogeneic bone marrow
transplantation. This aggressive approach is associated with high
early mortality but a very low rate of relapse, presumably because of
the graft-vs-lymphoma effect seen in this setting.
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