Role of Interferon-Alfa in NHL: Still Controversial?

The malignant lymphomas are among the most responsive of neoplastic disorders. Objective tumor shrinkage has been seen after therapy with virtually all classes of chemotherapeutic agents, including alkylating agents, antimetabolites, vinca alkaloids, antibiotics, anthracyclines, and topoisomerase inhibitors, as well as corticosteroids and biological agents, such as monoclonal anti–B-cell antibodies and interferon-alfa (Intron A, Roferon-A). Despite use of such a wide variety of active agents, significant prolongation of survival or cure has been seen reliably only in patients with diffuse large cell lymphomas. Even in these patients, increased dose intensity or the addition of more complex regimens has not improved early results.

Histology and Outcome

The influence of histology on outcome in non-Hodgkin’s lymphoma (NHL) was demonstrated in an early trial[1] from the Southeastern Cancer Study Group (SEG). We had noted that carmustine (BCNU) produced a higher than expected response rate than other agents in NHL, especially cyclophosphamide (Cytoxan, Neosar), vincristine (Oncovin), and prednisone (Deltasone) individually or in combination (COP). When BCNU was combined with COP (BCOP), we observed a plateau in the survival curve, suggesting the possibility that some of the patients may have been cured. Patients treated with COP without BCNU showed no such plateau.

This stabilization of the survival curve was seen only in those patients who had been classified as having diffuse “histiocytic” lymphoma, or what today might be called intermediate-grade diffuse large cell lymphoma. Nodular (follicular) or diffuse small cell lymphomas did not show this plateau.

Similar observations had been made when doxorubicin was added to COP in the CHOP regimen. We compared CHOP vs BCOP[2] and once again demonstrated the plateau in survival curves with both regimens in patients with diffuse large cell lymphoma. The higher response rate in the CHOP arm led us to conclude that this combination regimen might be preferable for the treatment of these patients. Subsequent attempts at improving the results in these patients with more intensive therapy[3,4] did not appear to increase the cure rate, nor did any treatment favorably influence survival in patients with small cleaved cell or other follicular lymphomas.

Interferon-Alfa in Follicular Lymphoma

We were fortunate to have participated in some of the earliest trials of interferon-alfa in NHL.[5] As with other agents, interferon-alfa produced responses in all categories of NHL, and we found that patients who did not respond to lower doses of interferon-alfa (5 MU three times per week) might respond to 10 days of 20 MU/d.

As summarized in the article by Haase-Statz and Smalley, many other studies have documented the activity of interferon-alfa in NHL. Of particular interest are the studies in follicular lymphoma, in which interferon-alfa added to an anthracycline-based regimen offered a significant survival advantage over chemotherapy alone. When interferon-alfa was added to less aggressive treatments, such as single alkylating agents, an overall survival advantage was not observed, although there was evidence of an improvement in disease-free survival. Curiously, the efficacy of an intensive combination (ProMace-MOPP) was not improved by the addition of interferon-alfa.

The authors conclude, with considerable justification, that interferon-alfa should be added to an anthracycline-based regimen for the treatment of patients with follicular lymphoma, particularly when the disease is bulky and symptomatic.

Interferon in Other Histologies

The utility of interferon-alfa in other histologic categories of NHL is less clear. Only one study has demonstrated a survival advantage for interferon-alfa–treated patients with diffuse large cell lymphoma; this study utilized a regimen that included cyclophosphamide, mitoxantrone (Novantrone), bleomycin (Blenoxane), dexamethasone, cytarabine (Cytosar-U), and cisplatin (Platinol). Although the use of interferon-alfa during induction chemotherapy with CHOP or subsequently during a maintenance phase deserves exploration, I feel that it is too early to suggest that interferon-alfa be used in patients treated with these regimens outside of a clinical trial setting.

Although responses to interferon-alfa therapy have been seen in other B-cell categories and in cutaneous T-cell lymphomas, it remains to be seen whether its role in these histologies is to provide transient disease control, important though that might be, or whether it might eventually be shown to improve the survival of these patients.

Conclusions

The cure or prolongation of survival of patients with NHL has proven to be an elusive goal. We have a bountiful supply of active therapeutic agents, but responses are often short lived. Although a subset of patients may be cured, the majority are not. In entire histologic categories, the best option is to withhold therapy until the disease becomes symptomatic or quite bulky, at which point therapy usually is palliative in intent. Thus, it is quite gratifying to learn that interferon-alfa has actually changed the long-term outcome of patients with follicular lymphomas, and may eventually be shown to improve the lot of patients who have other histologic types.

References:

1. Durant JR, Gams RA, Bartolucci A, et al: BCNU with and without COP and cycle-active therapy in non-Hodgkin’s lymphomas. Cancer Treat Rep 61:1085, 1977.

2. Gams RA, Rainey M, Dandy M, et al: Phase III study of BCOP vs CHOP in unfavorable categories of malignant lymphoma: A Southeastern Cancer Study Group trial. J Clin Oncol 3(9):1188-1195, 1985.

3. Zuckerman KS, Case DC, Gams RA, et al: Chemotherapy of intermediate-and high-grade non-Hodgkin’s lymphomas with an intensive epirubicin-containing regimen. Blood 82(12):3564-3573, 1993.

4. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002-1006, 1993.

5. Gams RA, Gordon D, Guaspari A, et al: Phase II trial of polyclonal lymphoblastoid interferon (Wellferon) in the management of malignant lymphomas (abstract). Proc Am Soc Clin Oncol 3:65, 1984.