Original Article
Recombinant Interferon Alfa-2b Combined with a Regimen Containing Doxorubicin in Patients with Advanced Follicular Lymphoma
N Engl J Med 1993; 329:1608-1614November 25, 1993
- Abstract
Background
Interferon alfa and cytotoxic drugs have synergistic effects in patients with non-Hodgkin's lymphoma. In 1986, we designed a clinical trial to evaluate the benefit of concomitant administration of recombinant interferon alfa with a regimen containing doxorubicin in patients with follicular non-Hodgkin's lymphoma.
Methods
The trial involved 242 patients with advanced low-grade follicular non-Hodgkin's lymphoma selected on the basis of clinical, radiographic, and biologic criteria. All patients were treated with a regimen consisting of cyclophosphamide, doxorubicin, teniposide, and prednisone (CHVP), given monthly for six cycles and then every two months for one year. After randomization, 123 patients also received interferon alfa-2b at a dosage of 5 million units three times weekly for 18 months. The remaining 119 patients received chemotherapy alone.
Results
As compared with the patients treated with CHVP only, the patients treated with CHVP plus interferon alfa had a higher overall rate of response (85 percent vs. 69 percent, P = 0.006), a longer median event-free survival (34 months vs. 19 months, P<0.001), and a higher rate of survival at 3 years (86 percent vs. 69 percent, P = 0.02). Granulocyte toxicity was greater in the patients treated with CHVP plus interferon alfa than in those treated with CHVP alone. There were no treatment-related deaths. Interferon alfa had to be stopped because of toxic effects (fatigue and hepatitis) in 13 patients (11 percent).
Conclusions
The addition of interferon alfa to a regimen containing doxorubicin increased the rate of response, event-free survival, and overall survival in patients with advanced follicular non-Hodgkin's lymphoma, without serious toxicity, although some patients were unable to tolerate the side effects.
Media in This Article
Figure 1
Treatment Protocols for CHVP and CHVP plus Interferon Alfa.Figure 2
Estimated Event-free Survival According to Treatment Group.Article Activity
- Article
Follicular lymphomas are the commonest subgroup of non-Hodgkin's lymphomas, accounting for 25 to 40 percent of cases1,2. Low-grade follicular non-Hodgkin's lymphoma has an indolent course, and patients survive for a median of 7 to 10 years, but most ultimately die of the disease3. Nevertheless, the natural history of the disease varies. Some patients have a small tumor burden and slow progression of disease4,5. In contrast, other patients have a more aggressive course and die within three to five years after diagnosis. Features suggestive of an adverse prognosis at diagnosis include older age,6-9 male sex,6,8 systemic symptoms,9,10 bone marrow involvement,8,9,11,12 advanced Ann Arbor stage,6,10-12 more than one extranodal site of involvement,8,12 poor performance-status score,6 a high serum lactate dehydrogenase concentration,12 and a large tumor mass8,12. The optimal care of patients with these features remains controversial.
Interferon alfa is active in patients with low-grade non-Hodgkin's lymphoma, with a response rate of 50 percent in patients pretreated with combination chemotherapy13,14. Moreover, interferon alfa and some cytotoxic drugs (e.g., cyclophosphamide, doxorubicin, and vinca alkaloids) have synergistic or additive effects in vitro15. These results prompted a multicenter cooperative group in France and Belgium, the Groupe d'Etude des Lymphomes de l'Adulte, to conduct a trial in patients with follicular non-Hodgkin's lymphoma who had a large tumor burden in order to compare a chemotherapy regimen containing doxorubicin with one containing doxorubicin and interferon alfa-2b.
Methods
Eligibility Criteria
This study was an open phase 3 trial with 31 participating medical centers, initiated in October 1986. All previously untreated patients were eligible for the study if they had small-cell (fewer than 5 percent large noncleaved cells) or mixed-cell (5 to 50 percent large noncleaved cells) follicular non-Hodgkin's lymphoma confirmed by nodal biopsy, were less than 70 years of age, had measurable disease, and were classified as being in Ann Arbor stage II, III, or IV with a large tumor burden. Patients were considered to have a large tumor burden if they had at least one of the following, as determined by an analysis of the literature and a previous study9: any nodal or extranodal tumor mass with a diameter of more than 7 cm; involvement of at least three nodal sites, each of which had a diameter of more than 3 cm; systemic symptoms; substantial splenic enlargement; serous effusion, orbital or epidural involvement, or ureteral compression (alone or in combination); and leukemia. Patients were not included if they had antibodies to the human immunodeficiency virus, a previous cancer, cardiac disease, uncontrolled diabetes mellitus, or liver or kidney failure. When the initial examining pathologist suggested a diagnosis of low-grade follicular non-Hodgkin's lymphoma, all the slides were reexamined by two hematopathologists. In the event of discordant results, other pathologists studied the slides to reach a consensus. This study protocol was approved by an ethics committee, and all patients gave informed consent.
Staging and Initial Treatment
The extent of disease was determined by a standardized staging evaluation including computed tomography of the chest and abdomen and bone marrow biopsy. Performance status was graded with the Zubrod scale16.
All patients received the same chemotherapy regimen, consisting of cyclophosphamide at a dose of 600 mg per square meter of body-surface area, doxorubicin at a dose of 25 mg per square meter, and teniposide (VM-26) at a dose of 60 mg per square meter, all given intravenously on day 1, and prednisone at a daily dose of 40 mg per square meter, given orally on days 1 to 5 (CHVP). Treatment consisted of an induction phase of six cycles administered monthly followed by a maintenance phase for patients who responded and those with stable disease, consisting of one cycle every two months for one year. Before chemotherapy began, the patients were randomly assigned to receive either chemotherapy alone or chemotherapy plus concomitant subcutaneous interferon alfa-2b (Intron-A, Schering-Plough) at a dose of 5 million units three times weekly for 18 months (Figure 1Figure 1
Treatment Protocols for CHVP and CHVP plus Interferon Alfa.).In the group given CHVP, treatment was delayed if the polymorphonuclear-leukocyte count was below 1500 per cubic millimeter or if the platelet count was below 75,000 per cubic millimeter. In the group given CHVP plus interferon alfa, the same rules were applied, and treatment with interferon alfa was briefly suspended if the polymorphonuclear-leukocyte count fell below 1000 per cubic millimeter or reduced by half if the count was between 1000 and 1500 per cubic millimeter. Interferon alfa was stopped if the serum aspartate aminotransferase concentration exceeded five times the upper limit of normal or if the serum creatinine concentration exceeded 20 mg per liter (1768 μmol per liter).
Determination of Response to Treatment
All initial sites of disease were reassessed after six cycles of chemotherapy and every six months thereafter. A complete remission was defined as the disappearance of all clinical evidence of disease and the normalization of all laboratory values, radiographic findings, and bone marrow-biopsy findings. A partial remission was defined as a reduction of more than 50 percent in the largest diameter of each measurable site of disease. The disease was considered stable if tumor regression was less than 50 percent. Progression was defined as an increase in tumor size of more than 25 percent or evidence of a new site of involvement. Therapies for patients with relapsing or progressive disease were chosen at the discretion of the investigator.
Statistical Analysis
The study was a prospective, randomized, unblinded trial. The primary study objective was to compare event-free survival in the two treatment groups. For ethical reasons a first interim analysis was planned after the enrollment of 200 patients. The period of event-free survival was calculated from the time of randomization to death (regardless of cause), progression or recurrence, or the last day of follow-up.
The first interim analysis of the results in the patients who had completed induction chemotherapy was performed in January 1992. There was a significant difference in event-free and overall survival between the two groups. Recruitment to the trial was therefore stopped. The data reported here refer to patients who were followed for an additional 12 months.
All analyses were performed on an intention-to-treat basis. The characteristics of the patients before treatment and their response rates were compared with the chi-square test. Logistic-regression analysis was used to determine which variables predicted a response to treatment.
Survival was calculated with the product-limit method, and differences between the two survival curves were tested for significance with the log-rank test17. Proportional-hazards analysis was used to determine which variables were associated with survival and to assess the effect of treatment after adjustment for other factors18. Test statistics for the comparison of major treatment end points were regarded as significant if the two-sided P value was 0.02 or less. Two-sided P values of 0.05 or less were considered to indicate statistical significance for prognostic factors.
Results
Patients' Characteristics
From October 1986 to June 1991, 273 patients entered the trial (134 were treated with CHVP and 139 were treated with CHVP plus interferon alfa). On review of the pathological results, the diagnosis of low-grade follicular non-Hodgkin's lymphoma was not confirmed in 26 patients (13 patients in each group). Five other patients were not included in the analysis: three did not meet the eligibility criteria, and two had incomplete study data. The analysis, therefore, included 242 patients (119 in the group given CHVP and 123 in the group given CHVP plus interferon alfa). The clinical characteristics of the patients in the two treatment groups were similar (Table 1Table 1
Clinical Characteristics of the Patients with Low-Grade Follicular Non-Hodgkin's Lymphoma and Large Tumor Burdens, According to Treatment Group.).Response to Treatment
At the end of the first six cycles of chemotherapy, 69 of the 119 patients (58 percent) treated with CHVP and 93 of the 123 patients (76 percent) treated with CHVP plus interferon alfa had responded to therapy (P = 0.004) (Table 2Table 2
Response to Induction Treatment of Patients with Low-Grade Follicular Non-Hodgkin's Lymphoma and Large Tumor Burdens, According to Treatment Group.). The difference in the rates of complete remission between groups (13 percent in the group given CHVP vs. 20 percent in the group given CHVP plus interferon alfa) was not statistically significant (P = 0.1). Among the patients who had not responded after six cycles, a further 13 patients treated with CHVP and 11 treated with CHVP plus interferon alfa had responses during maintenance treatment. Overall, therefore, 82 patients given CHVP (69 percent) and 104 patients given CHVP plus interferon alfa (85 percent) responded to therapy (P = 0.006). Sixteen of the 69 patients who had a response to CHVP after the first six cycles and 4 of the 93 who had a response to CHVP plus interferon alfa relapsed during the maintenance phase.Several factors determined at the time of diagnosis were evaluated as possible prognostic indicators of the maximal response to therapy. The response rates associated with each of these factors are shown in Table 3Table 3
Overall Response to Treatment, Event-free Survival, and Overall Survival, According to the Patients' Characteristics.. Statistically significant factors negatively associated with responses were treatment with CHVP (P = 0.003), an erythrocyte sedimentation rate exceeding 30 mm per hour (P = 0.02), and the presence of more than one criterion for a large tumor burden (P = 0.05).The median follow-up was 35 months (range, 18 to 70). The median event-free survival for all patients was 28 months. There was a significant difference in the median event-free survival between the two treatment groups: 19 months in the patients treated with CHVP (95 percent confidence interval, 17 to 23 months) and 34 months in the patients treated with CHVP plus interferon alfa (95 percent confidence interval, 31 to 39 months; P<0.001) (Figure 2Figure 2
Estimated Event-free Survival According to Treatment Group.). The following factors adversely affected event-free survival according to univariate analysis: treatment with CHVP (P<0.001), a serum albumin concentration of ≤ 35 g per liter (P = 0.002), the involvement of three or more nodes measuring more than 3 cm in diameter (P = 0.003), and an erythrocyte sedimentation rate exceeding 30 mm per hour (P = 0.009).At the time the study was stopped on December 31, 1992, 65 patients had died: 39 in the group given CHVP (34 of non-Hodgkin's lymphoma, 14 [41 percent] with a premortem diagnosis of histologic transformation) and 26 in the group given CHVP plus interferon alfa (22 of non-Hodgkin's lymphoma, 12 [55 percent] with a premortem diagnosis of histologic transformation). The actuarial median survival was not reached for either of these groups. As shown in Figure 3Figure 3
Estimated Overall Survival According to Treatment Group., the overall survival at three years was significantly higher in the patients treated with CHVP plus interferon alfa (86 percent; 95 percent confidence interval, 83 to 89 percent) than in those treated with CHVP (69 percent; 95 percent confidence interval, 64 to 74 percent; P = 0.02). The difference in survival rates at three years was also statistically significant when deaths unrelated to non-Hodgkin's lymphoma were not taken into account (P = 0.02) or when all the 273 patients who entered the study were included in the analysis (P = 0.02) (data not shown).Univariate analysis showed that the presence of systemic symptoms (P = 0.001) and treatment with CHVP alone (P = 0.02) adversely affected survival (Table 3). These factors and those with a P value of less than 0.1 -- the presence of a bulky tumor (P = 0.06), bone marrow involvement (P = 0.06), and an erythrocyte sedimentation rate exceeding 30 mm per hour (P = 0.06) -- were included in a multivariate regression analysis. The following factors retained their negative influence on survival: treatment with CHVP alone (P = 0.001), the presence of systemic symptoms (P = 0.03), and bone marrow involvement (P = 0.06).
Hematologic Toxicity
During the induction phase, 666 cycles were evaluated in the 119 patients treated with CHVP and 727 cycles in the 123 patients treated with CHVP plus interferon alfa. During the maintenance phase, 465 cycles were evaluated in 101 patients treated with CHVP (i.e., patients with a response or stable disease after the induction) and 579 cycles in 111 patients treated with CHVP plus interferon alfa.
During the induction phase, neutropenia of World Health Organization (WHO) grade 3 or higher occurred in 2 percent of cycles in the CHVP group as compared with 12 percent of the cycles in the group treated with CHVP plus interferon alfa (P<0.001). Neutropenia occurred at some time in 6 patients in the group given CHVP (5 percent) and in 37 patients in the group given CHVP plus interferon alfa (30 percent, P<0.001). There were 2 infections involving neutropenia of WHO grade ≥ 3 in the former group and 11 in the latter group (P<0.001). During the maintenance phase, neutropenia of WHO grade ≥ 3 occurred in 1 percent of CHVP cycles (5 percent of patients) and 6 percent of cycles with CHVP plus interferon alfa (24 percent of patients, P = 0.03). During the induction phase, thrombocytopenia of WHO grade ≥ 3 occurred in seven patients in the group given CHVP plus interferon alfa (6 percent) as opposed to one patient in the group given CHVP (1 percent, P = 0.01), without hemorrhagic complication. No patient had anemia of WHO grade ≥ 3.
Nonhematologic Toxicity
Two patients had transient vascular collapse during treatment with teniposide. Doxorubicin was stopped because of cardiac toxicity in one patient in each treatment group.
Tolerance of Interferon Alfa
Treatment with interferon alfa was stopped in 13 patients (11 percent) because of adverse reactions: severe fatigue in 7 patients, liver injury in 3 patients, and pulmonary embolism, pulmonary edema, and psychiatric disorder in 1 patient each. A further four patients declined to continue treatment with interferon alfa. The dose of interferon alfa had to be decreased in 19 other patients. A total of 87 of the 123 patients (71 percent) received the combined treatment as scheduled.
Discussion
We tested the possible benefits of adding interferon alfa to a regimen containing doxorubicin in a homogeneous group of patients with follicular non-Hodgkin's lymphoma and a large tumor burden. The chemotherapy regimen chosen was characterized by a low dose of doxorubicin and long-term treatment (total, 18 months). This method was selected for two reasons. First, it was similar in design to the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen that appeared promising in patients with advanced chronic lymphocytic leukemia19. Second, low doses of doxorubicin and cyclophosphamide could be given concomitantly with interferon alfa without prohibitive hematologic toxicity. We selected low doses of interferon alfa (5 million units three times weekly) to avoid intolerable toxicity and to obtain an acceptable rate of compliance.
The overall rate of response in the patients treated with CHVP plus interferon alfa was significantly higher than that in the patients treated with CHVP alone. The rates of complete remission (13 percent at the end of induction treatment in the group given CHVP and 20 percent in the group given CHVP plus interferon alfa) were lower than those reported for other patients treated with CHOP regimens5,8,20. There are several possible explanations for the discrepancy. Our patients were selected on the basis of their large tumor burdens, the criteria chosen to define complete remission were more strict than in other studies,5 and patients with even minimal residual radiographic abnormalities or bone marrow infiltration were rated as having a partial response. Some patients who had no response after induction treatment had a response during the maintenance phase. Finally, in some studies, therapy included irradiation of bulky tumors8. In patients with low-grade non-Hodgkin's lymphomas, the response rate is probably less relevant in evaluating the efficacy of a treatment than is the length of time to treatment failure or the overall survival rate.
The first interim analysis demonstrated that patients treated with CHVP plus interferon alfa had a significantly longer event-free survival than those treated with CHVP alone; therefore, further accrual of patients was stopped. Furthermore, overall survival analysis showed a significant difference between the two treatment groups, with a three-year survival rate of 86 percent in the patients treated with CHVP plus interferon alfa as compared with a rate of 69 percent in the patients treated with CHVP (P = 0.02).
There are few reports of concomitant treatment of low-grade non-Hodgkin's lymphomas with chemotherapy plus interferon alfa. A preliminary analysis in one randomized study showed no difference in the overall rates of response between patients treated with chlorambucil alone and those treated with chlorambucil plus interferon alfa, but there was a significant prolongation of remission in the latter group (P<0.015)21. Smalley et al.22 reported the results of an Eastern Cooperative Oncology Group trial involving 249 patients with prognostically unfavorable low-grade or intermediate-grade non-Hodgkin's lymphoma. There was no difference in response rates but a significantly longer median time to treatment failure in the patients treated with a CHOP-like regimen plus interferon alfa than in the patients treated with the CHOP-like regimen alone. Although there was no significant difference in overall survival, treatment with interferon alfa was a significant favorable prognostic factor in the multivariate analysis. It must be emphasized that the median event-free survival in our study and the median time to treatment failure in the Eastern Cooperative Oncology Group study22 were both 19 months in the chemotherapy groups and were 34 and 30 months, respectively, in the groups receiving chemotherapy plus interferon alpha. Several studies have focused on the use of interferon alfa in maintenance therapy. In one, the drug led to a longer remission in patients who had responded to a regimen consisting of CHOP and bleomycin than in historical controls23. The first interim analysis in another study showed that maintenance treatment with interferon alfa-2a after initial treatment with cyclophosphamide, vincristine, and prednisone significantly increased progression-free survival (P = 0.02) but had no influence on overall survival24.
These results demonstrate the beneficial effects of adding interferon alfa to a CHOP-like regimen in patients with advanced low-grade follicular non-Hodgkin's lymphoma. The increase in response rates together with the prolongation of event-free survival improved survival. This treatment needs to be compared with that involving such new and promising drugs as fludarabine and 2-chlorodeoxyadenosine.
Supported by grants from the Association Claude Bernard, Schering-Plough France, Laboratoire Roger Bellon, and Pharmacia Fine Chemicals.
We are indebted to the following clinicians and pathologists, who actively participated in the study: C. Allard, M.F. d'Agay, J. d'Anjou, J. Benevent, F. Berger, A. Blanc, D. Bordessoule, R. Bouabdallah, J.C. Brouet, S. Castaigne, T. Caulet, J.P. Clauvel, L. Degos, A. Delannoy, M. Divine, C. Doyen, P. Dubigeon, C. Duval, J.P. Fermand, A. Ferrant, M. Ffrench, J. Gabarre, F. Gaillard, F. Galateau, C. Garnier, P. Gaulard, J. Hamels, J.L. Harousseau, A. Herrera, G. Laurent, C. Lavignac, G. Lepeu, J.P. Marolleau, C. Martin, C. Marty-Double, G. Merignargues, J.L. Michaux, N. Mielpied, P. Mineur, H. Noel, E. Oksenhendler, B. Pignon, G. Pinon-Netter, J.F. Ramee, M. Raphael, M. Raymond-Gelle, O. Reman, M. Renoux, J.F. Rossi, F. Rumilly, G. Salles, B. Schwed, C. Sebban, J. Simony-Lafontaine, I. Tabah, B. Taine, G. Tertian, A. Thyss, H. Tilly, and P. Travade; and to C. Barli, N. Canuel, V. Ribondin, M. Storez, and particularly S. Houga for their technical assistance and assistance in the preparation of the manuscript.
Source Information
From the Departments of Hematology (P.S.-C., P.B., C.G.) and Biostatistics and Medical Information Systems (E.L.), Hopital Saint-Louis, Paris; the Department of Pathology, Hopital Necker, Paris (N.B., M.P.); Hopital Henri Mondor, Creteil, France (F.R., C.H.); Centre Hospitalo-Universitaire de Caen, Caen, France (M.L.); Universite Catholique de Louvain, Louvain, Belgium (A.B.); Centre Hospitalier Lyon-Sud, Pierre Benite, France (B.C.); and Schering-Plough, Levallois, France (Y.P.).
Address reprint requests to Dr. Solal-Celigny at Centre Hayem, Hopital Saint-Louis, 1 Ave. Cl. Vellefaux, 75010 Paris, France.
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