Interferon-alpha is a naturally occurring
protein with antiviral and anti-proliferative properties. Clinical
studies using the relatively pure, naturally occurring
interferon-alpha product in patients with non-Hodgkins lymphoma
(NHL) were initiated in the 1970s and suggested potential therapeutic
value.[1,2] The number and size of clinical studies evaluating this
agent increased significantly in the 1980s following the development
of recombinant technology that allowed for the pure, relatively
rapid, and substantially increased production of therapeutic
quantities of the protein (interferon-alfa [Intron A, Roferon-A]).
The therapeutic administration of interferon-alfa has been shown to
be safe and tolerable, although it produces, in a dose-related
fashion, flu-like symptoms and myelosuppression that can be
bothersome to the patient. Interferon-alfa has been shown to be
therapeutically efficacious in patients with NHL, particularly
follicular lymphoma and cutaneous T-cell disorders, but its role in
the treatment of these malignancies has not been established. This
agent may be effective in other varieties of NHL as well, but its use
has not been widely studied in most other NHL subtypes.
Controversy therefore exists as to the value of interferon-alfa in
the overall therapeutic approach to NHLs. Studies are difficult to
compare because of differences in the chemotherapy regimens, the
included NHL subtypes, the definition of disease types, and
interferon-alfa schedules and doses.
The classification of the NHLs has evolved over the years. Introduced
in the 1960s, the Rappaport classification is histologically
oriented. The Kiel and updated Kiel classifications, devised in
the 1970s and 80s, are histologically and immunologically
oriented[4,5] and are widely used throughout Europe.
The International Working Formulation (IWF) incorporated clinical
parameters in addition to histologic criteria and by doing so
attempted to achieve a common ground for clinicians and pathologists
and to consolidate the existing systems. The IWF introduced the
concepts of low-grade and intermediate-grade
into its classification; both are clinically based terms that take
into consideration the natural history of the disease and the likely
response to treatment as available in the 1970s.
The IWF is used extensively in North America. Because the Kiel and
IWF classifications are based on different variables, it is difficult
to interpret and compare the outcomes of clinical trials based on one
or the other system. Also, although most of the randomized trials
evaluating the use of interferon-alfa have used the IWF as the basis
for eligibility, the concepts of low- and intermediate-grade lymphoma
may no longer be useful as the primary basis for defining treatment
of this clinically broad, histologically diverse group of disorders.
Lastly, treatment (both cytotoxic and biological) has evolved since
the IWF was defined, and treatment approaches need to be reevaluated
in light of current knowledge.
Revised European-American Lymphoma Classification
In 1994, the Revised European-American Lymphoma (REAL) classification
was introduced to address newer knowledge about and better
understanding of NHL. It uses known mol-
ecular characteristics, phenotype, morphology, and clinical aspects
of the various lymphomas. This classification places the three
follicular lymphomasfollicular small-cleaved cell, follicular
mixed cell, and follicular large-cell lymphomainto one
category. Previously, in the IWF classification, follicular large
cell had been classified as an intermediate-grade lymphoma.
In addition, currently recognized subtypes, such as mantle cell
lymphoma, had not been defined in the early 1980s, and these subtypes
were scattered throughout the low- and intermediate-grade disorders
in the IWF. Mantle cell lymphoma and other subtypes, including
monocytoid lymphomas and marginal zone B-cell lymphomas, are
well-defined entities in the REAL classification and have been
separated from the follicular lymphomas.
The follicular lymphomas, as defined in the REAL classification,
appear to be a relatively homogeneous group of disorders involving
the malignant transformation of a relatively mature B-cell. It may no
longer be justified to separate them clinically and therapeutically
into low- and intermediate-grade lymphomas. These disorders share
a unique, but not universally demonstrable, chromosome abnormality.
Subsequent, mainly retrospective, evaluations have agreed that the
REAL classification offers significant promise as a means of defining
lymphoma subtypes that are pathologically consistent and
prognostically useful.[8-11] However, it should be recognized that
since all of the clinical studies to date have been based on either
the Kiel or IWF system, the results of these studies may be biased,
either positively or negatively, by the inclusion of disease types
that are recognized as independent disorders by the REAL classification.
In this article, we will attempt to add REAL classification terms to
study descriptions, where appropriate. However, it is often
impossible to retrospectively apply these terms, as disease
histologies varied within the respective studies and were not always
Follicular lymphoma, as defined by the REAL classification, is the
second most commonly occurring B-cell lymphoma. The disorder has
a B-cell immunophenotype, a t(14;18) chromosome translocation, and a
follicular growth pattern.
Follicular lymphoma is usually indolent in nature, with a median
survival of 5 years; although some patients live 10 years or more,
all patients eventually die of their disease. There appears to be no
plateau on the survival curves of any of the three follicular
subtypes. This suggests the current inability to achieve a cure, at
least with the cytotoxic drug combination CHOP (cyclophosphamide,
doxorubicin HCl, Oncovin, and prednisone).
Initial studies with recombinant interferon-alfa as a single agent in
the mid-1980s confirmed that this agent had antiproliferative and
antitumor effects against both low- and intermediate-grade lymphomas;
an objective response rate of 30% to 50% (depending on the degree of
previous treatment) was achieved in early phase II studies.[13-16] At
about the same time, in vivo studies performed in mice carrying human
cell lines suggested that there might be a synergistic
antiproliferative effect between interferon-alfa and the cytotoxic
agents cyclophosphamide (Cytoxan, Neosar) and doxorubicin.
Clinical trials incorporating the combination of interferon-alfa and
cytotoxic agents then commenced.
To date, several cytotoxic agents have been shown to be efficacious
in the treatment of follicular NHL. Single-agent therapy with an
alkylating agent, either cyclophosphamide or chlorambucil (Leukeran),
controls symptoms and shrinks bothersome lymphadenopathy but has not
been shown to prolong survival.
Many treating physicians add vin-cristine (Oncovin) and prednisone to
single-agent alkylating therapy (eg, cyclophosphamide) since these
two agents have independent antitumor activity and do not add
marrow-suppressing effects. Although the resulting
combinationCOPincreases complete response rate and
prolongs time to progression, it does not affect overall survival.[18,19]
Watch-and-Wait ApproachThis inability to
beneficially influence overall survival with either single-agent
alkylator or COP therapy led, in the mid-1980s, to a conservative
therapeutic approach, at least with regard to patients with the low-grade
disorders. The concept of watch and wait emerged as a
reasonable approach to managing early, basically asymptomatic
disease. The Stanford group demonstrated that withholding treatment
in the early stages of the low-grade lymphomas did not
have a detrimental effect on survival; on the contrary, initiating
therapy early, prior to the development of symptoms, failed to
improve a patients survival.
Patients presenting with follicular mixed lymphoma, a
low-grade lymphoma in the IWF classification, or with
follicular large-cell lymphoma, an intermediate-grade
lymphoma, usually receive moderately aggressive combination cytotoxic
therapy once the diagnosis has been established. It is generally
accepted, although it has never been proven, that patients with these
two subtypes do better with more aggressive therapy.
CHOPInitial reports that these subtypes might be curable
with combination chemotherapy have not been confirmed. Recent
retrospective evaluations do not demonstrate a plateau in the
survival curves of patients treated with CHOP, suggesting that this
therapeutic approach is not curative. Likewise, still more aggressive
chemotherapy approaches have not improved on the survival results
achieved with CHOP. The CHOP regimen, which includes the addition
of doxorubicin (60 mg/m²) to COP, is probably the most common
chemotherapeutic combination used for clinically or histologically
aggressive low- or intermediate-grade lymphoma. It is cycled every 21
days for 6 to 8 months.
Studies comparing the relative merits of CHOP with COP or
single-agent therapy have never been performed. Thus, it has never
been shown that CHOP has a beneficial effect on survival and, if so,
in which clinical or histologic subtype.
New Agents and CombinationsRecently, newer agents and
combinations using them have become available. The purine analogs
fludarabine (Fludara) and cladribine (Leustatin) have each been shown
to be efficacious, but their effect on survival has not been determined.
Combination approaches, including alternating triple
therapy (ATT), which includes steroids and interferon-alfa plus
up to nine cytotoxic chemotherapeutic agents that are cycled based on
the Goldie-Coldman hypothesis, can eliminate the malignant clone (as
manifested by the translocated chromosome marker) in a high
percentage of a small group of patients with low-grade lymphoma.
A combination using fludarabine and mitoxantrone (Novantrone), an
anthracycline, plus dexamethasone (FMD) has also been evaluated in
patients with refractory or relapsed disease and has generated
interest and excitement.
In addition to defining appropriate cytotoxic chemotherapeutic
approaches for patients with follicular lymphoma, the place of the
biological agents, including interferon-alfa and the recently
introduced monoclonal antibody, rituximab (Rituxan), needs to be
defined. To date, it has not been possible to consider cure in these
disorders, although the elimination of the translocated chromosome by
rituximab plus CHOP, ATT, and high-dose chemotherapy followed by
the administration of a purged bone marrow transplant
may offer such a possibility. Studies of new approaches to the
treatment of the two common histologic subtypes, follicular lymphoma
and diffuse large-cell lymphoma, using biological agents and a
variety of new and old cytotoxic drugs are warranted.
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