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 specifically reported.
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(Drug information on doxorubicin) HCl, Oncovin, and prednisone(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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.