Recombinant Interferon Alfa-2b Combined with a Regimen Containing Doxorubicin in Patients with Advanced Follicular Lymphoma
Philippe Solal-Celigny, Eric Lepage, Nicole Brousse, Felix Reyes, Corinne Haioun, Michel Leporrier, Michel Peuchmaur, Andre Bosly, Yolaine Parlier, Pauline Brice, Bertrand Coiffier, Christian Gisselbrecht, for The Groupe d'Etude des Lymphomes de l'Adulte
Background Interferon alfa and cytotoxic drugs have synergisticeffects in patients with non-Hodgkin's lymphoma. In 1986, wedesigned a clinical trial to evaluate the benefit of concomitantadministration of recombinant interferon alfa with a regimencontaining doxorubicin in patients with follicular non-Hodgkin'slymphoma.
Methods The trial involved 242 patients with advanced low-gradefollicular non-Hodgkin's lymphoma selected on the basis of clinical,radiographic, and biologic criteria. All patients were treatedwith a regimen consisting of cyclophosphamide, doxorubicin,teniposide, and prednisone (CHVP), given monthly for six cyclesand then every two months for one year. After randomization,123 patients also received interferon alfa-2b at a dosage of5 million units three times weekly for 18 months. The remaining119 patients received chemotherapy alone.
Results As compared with the patients treated with CHVP only,the patients treated with CHVP plus interferon alfa had a higheroverall 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 percentvs. 69 percent, P = 0.02). Granulocyte toxicity was greaterin the patients treated with CHVP plus interferon alfa thanin those treated with CHVP alone. There were no treatment-relateddeaths. 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 containingdoxorubicin increased the rate of response, event-free survival,and overall survival in patients with advanced follicular non-Hodgkin'slymphoma, without serious toxicity, although some patients wereunable to tolerate the side effects.
Follicular lymphomas are the commonest subgroup of non-Hodgkin'slymphomas, accounting for 25 to 40 percent of cases1,2. Low-gradefollicular non-Hodgkin's lymphoma has an indolent course, andpatients survive for a median of 7 to 10 years, but most ultimatelydie of the disease3. Nevertheless, the natural history of thedisease varies. Some patients have a small tumor burden andslow progression of disease4,5. In contrast, other patientshave a more aggressive course and die within three to five yearsafter diagnosis. Features suggestive of an adverse prognosisat diagnosis include older age,6,7,8,9 male sex,6,8 systemicsymptoms,9,10 bone marrow involvement,8,9,11,12 advanced AnnArbor stage,6,10,11,12 more than one extranodal site of involvement,8,12poor performance-status score,6 a high serum lactate dehydrogenaseconcentration,12 and a large tumor mass8,12. The optimal careof patients with these features remains controversial.
Interferon alfa is active in patients with low-grade non-Hodgkin'slymphoma, with a response rate of 50 percent in patients pretreatedwith combination chemotherapy13,14. Moreover, interferon alfaand some cytotoxic drugs (e.g., cyclophosphamide, doxorubicin,and vinca alkaloids) have synergistic or additive effects invitro15. These results prompted a multicenter cooperative groupin France and Belgium, the Groupe d'Etude des Lymphomes de l'Adulte,to conduct a trial in patients with follicular non-Hodgkin'slymphoma who had a large tumor burden in order to compare achemotherapy regimen containing doxorubicin with one containingdoxorubicin and interferon alfa-2b.
Methods
Eligibility Criteria
This study was an open phase 3 trial with 31 participating medicalcenters, initiated in October 1986. All previously untreatedpatients 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'slymphoma confirmed by nodal biopsy, were less than 70 yearsof age, had measurable disease, and were classified as beingin Ann Arbor stage II, III, or IV with a large tumor burden.Patients were considered to have a large tumor burden if theyhad at least one of the following, as determined by an analysisof the literature and a previous study9: any nodal or extranodaltumor mass with a diameter of more than 7 cm; involvement ofat least three nodal sites, each of which had a diameter ofmore than 3 cm; systemic symptoms; substantial splenic enlargement;serous effusion, orbital or epidural involvement, or ureteralcompression (alone or in combination); and leukemia. Patientswere not included if they had antibodies to the human immunodeficiencyvirus, a previous cancer, cardiac disease, uncontrolled diabetesmellitus, or liver or kidney failure. When the initial examiningpathologist suggested a diagnosis of low-grade follicular non-Hodgkin'slymphoma, all the slides were reexamined by two hematopathologists.In the event of discordant results, other pathologists studiedthe slides to reach a consensus. This study protocol was approvedby an ethics committee, and all patients gave informed consent.
Staging and Initial Treatment
The extent of disease was determined by a standardized stagingevaluation including computed tomography of the chest and abdomenand bone marrow biopsy. Performance status was graded with theZubrod scale16.
All patients received the same chemotherapy regimen, consistingof cyclophosphamide at a dose of 600 mg per square meter ofbody-surface area, doxorubicin at a dose of 25 mg per squaremeter, and teniposide (VM-26) at a dose of 60 mg per squaremeter, all given intravenously on day 1, and prednisone at adaily dose of 40 mg per square meter, given orally on days 1to 5 (CHVP). Treatment consisted of an induction phase of sixcycles administered monthly followed by a maintenance phasefor patients who responded and those with stable disease, consistingof one cycle every two months for one year. Before chemotherapybegan, the patients were randomly assigned to receive eitherchemotherapy alone or chemotherapy plus concomitant subcutaneousinterferon alfa-2b (Intron-A, Schering-Plough) at a dose of5 million units three times weekly for 18 months (Figure 1).
Figure 1. Treatment Protocols for CHVP and CHVP plus Interferon Alfa.
CHVP therapy consisted of cyclophosphamide at a dose of 600 mg per square meter, doxorubicin at a dose of 25 mg per square meter, and teniposide 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 through 5. The open arrows indicate the times of cancer staging, and the solid arrows the times of chemotherapy cycles.
In the group given CHVP, treatment was delayed if the polymorphonuclear-leukocytecount was below 1500 per cubic millimeter or if the plateletcount was below 75,000 per cubic millimeter. In the group givenCHVP plus interferon alfa, the same rules were applied, andtreatment with interferon alfa was briefly suspended if thepolymorphonuclear-leukocyte count fell below 1000 per cubicmillimeter or reduced by half if the count was between 1000and 1500 per cubic millimeter. Interferon alfa was stopped ifthe serum aspartate aminotransferase concentration exceededfive times the upper limit of normal or if the serum creatinineconcentration exceeded 20 mg per liter (1768 µmol perliter).
Determination of Response to Treatment
All initial sites of disease were reassessed after six cyclesof chemotherapy and every six months thereafter. A completeremission was defined as the disappearance of all clinical evidenceof disease and the normalization of all laboratory values, radiographicfindings, and bone marrow-biopsy findings. A partial remissionwas defined as a reduction of more than 50 percent in the largestdiameter of each measurable site of disease. The disease wasconsidered stable if tumor regression was less than 50 percent.Progression was defined as an increase in tumor size of morethan 25 percent or evidence of a new site of involvement. Therapiesfor patients with relapsing or progressive disease were chosenat the discretion of the investigator.
Statistical Analysis
The study was a prospective, randomized, unblinded trial. Theprimary study objective was to compare event-free survival inthe two treatment groups. For ethical reasons a first interimanalysis was planned after the enrollment of 200 patients. Theperiod of event-free survival was calculated from the time ofrandomization to death (regardless of cause), progression orrecurrence, or the last day of follow-up.
The first interim analysis of the results in the patients whohad completed induction chemotherapy was performed in January1992. There was a significant difference in event-free and overallsurvival between the two groups. Recruitment to the trial wastherefore stopped. The data reported here refer to patientswho 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 theirresponse rates were compared with the chi-square test. Logistic-regressionanalysis was used to determine which variables predicted a responseto treatment.
Survival was calculated with the product-limit method, and differencesbetween the two survival curves were tested for significancewith the log-rank test17. Proportional-hazards analysis wasused to determine which variables were associated with survivaland to assess the effect of treatment after adjustment for otherfactors18. Test statistics for the comparison of major treatmentend points were regarded as significant if the two-sided P valuewas 0.02 or less. Two-sided P values of 0.05 or less were consideredto 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 plusinterferon alfa). On review of the pathological results, thediagnosis of low-grade follicular non-Hodgkin's lymphoma wasnot confirmed in 26 patients (13 patients in each group). Fiveother patients were not included in the analysis: three didnot meet the eligibility criteria, and two had incomplete studydata. The analysis, therefore, included 242 patients (119 inthe group given CHVP and 123 in the group given CHVP plus interferonalfa). The clinical characteristics of the patients in the twotreatment groups were similar (Table 1).
Table 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 the119 patients (58 percent) treated with CHVP and 93 of the 123patients (76 percent) treated with CHVP plus interferon alfahad responded to therapy (P = 0.004) (Table 2). The differencein the rates of complete remission between groups (13 percentin the group given CHVP vs. 20 percent in the group given CHVPplus 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 withCHVP plus interferon alfa had responses during maintenance treatment.Overall, therefore, 82 patients given CHVP (69 percent) and104 patients given CHVP plus interferon alfa (85 percent) respondedto therapy (P = 0.006). Sixteen of the 69 patients who had aresponse to CHVP after the first six cycles and 4 of the 93who had a response to CHVP plus interferon alfa relapsed duringthe maintenance phase.
Table 2. Response to Induction Treatment of Patients with Low-Grade Follicular Non-Hodgkin's Lymphoma and Large Tumor Burdens, According to Treatment Group.
Several factors determined at the time of diagnosis were evaluatedas possible prognostic indicators of the maximal response totherapy. The response rates associated with each of these factorsare shown in Table 3. Statistically significant factors negativelyassociated 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 largetumor burden (P = 0.05).
Table 3. Overall Response to Treatment, Event-free Survival, and Overall Survival, According to the Patients' Characteristics.
The median follow-up was 35 months (range, 18 to 70). The medianevent-free survival for all patients was 28 months. There wasa significant difference in the median event-free survival betweenthe two treatment groups: 19 months in the patients treatedwith CHVP (95 percent confidence interval, 17 to 23 months)and 34 months in the patients treated with CHVP plus interferonalfa (95 percent confidence interval, 31 to 39 months; P<0.001)(Figure 2). The following factors adversely affected event-freesurvival 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 measuringmore than 3 cm in diameter (P = 0.003), and an erythrocyte sedimentationrate exceeding 30 mm per hour (P = 0.009).
Figure 2. Estimated Event-free Survival According to Treatment Group.
CI denotes confidence interval.
At the time the study was stopped on December 31, 1992, 65 patientshad 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'slymphoma, 12 [55 percent] with a premortem diagnosis of histologictransformation). The actuarial median survival was not reachedfor either of these groups. As shown in Figure 3, the overallsurvival at three years was significantly higher in the patientstreated with CHVP plus interferon alfa (86 percent; 95 percentconfidence interval, 83 to 89 percent) than in those treatedwith CHVP (69 percent; 95 percent confidence interval, 64 to74 percent; P = 0.02). The difference in survival rates at threeyears was also statistically significant when deaths unrelatedto non-Hodgkin's lymphoma were not taken into account (P = 0.02)or when all the 273 patients who entered the study were includedin the analysis (P = 0.02) (data not shown).
Figure 3. Estimated Overall Survival According to Treatment Group.
CI denotes confidence interval.
Univariate analysis showed that the presence of systemic symptoms(P = 0.001) and treatment with CHVP alone (P = 0.02) adverselyaffected survival (Table 3). These factors and those with aP value of less than 0.1 -- the presence of a bulky tumor (P= 0.06), bone marrow involvement (P = 0.06), and an erythrocytesedimentation rate exceeding 30 mm per hour (P = 0.06) -- wereincluded in a multivariate regression analysis. The followingfactors retained their negative influence on survival: treatmentwith 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 the119 patients treated with CHVP and 727 cycles in the 123 patientstreated with CHVP plus interferon alfa. During the maintenancephase, 465 cycles were evaluated in 101 patients treated withCHVP (i.e., patients with a response or stable disease afterthe induction) and 579 cycles in 111 patients treated with CHVPplus interferon alfa.
During the induction phase, neutropenia of World Health Organization(WHO) grade 3 or higher occurred in 2 percent of cycles in theCHVP group as compared with 12 percent of the cycles in thegroup treated with CHVP plus interferon alfa (P<0.001). Neutropeniaoccurred at some time in 6 patients in the group given CHVP(5 percent) and in 37 patients in the group given CHVP plusinterferon alfa (30 percent, P<0.001). There were 2 infectionsinvolving neutropenia of WHO grade 3 in the former group and11 in the latter group (P<0.001). During the maintenancephase, neutropenia of WHO grade 3 occurred in 1 percent ofCHVP cycles (5 percent of patients) and 6 percent of cycleswith 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 interferonalfa (6 percent) as opposed to one patient in the group givenCHVP (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 treatmentwith teniposide. Doxorubicin was stopped because of cardiactoxicity in one patient in each treatment group.
Tolerance of Interferon Alfa
Treatment with interferon alfa was stopped in 13 patients (11percent) because of adverse reactions: severe fatigue in 7 patients,liver injury in 3 patients, and pulmonary embolism, pulmonaryedema, and psychiatric disorder in 1 patient each. A furtherfour patients declined to continue treatment with interferonalfa. The dose of interferon alfa had to be decreased in 19other 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 toa regimen containing doxorubicin in a homogeneous group of patientswith follicular non-Hodgkin's lymphoma and a large tumor burden.The chemotherapy regimen chosen was characterized by a low doseof doxorubicin and long-term treatment (total, 18 months). Thismethod was selected for two reasons. First, it was similar indesign to the CHOP (cyclophosphamide, doxorubicin, vincristine,and prednisone) regimen that appeared promising in patientswith advanced chronic lymphocytic leukemia19. Second, low dosesof doxorubicin and cyclophosphamide could be given concomitantlywith interferon alfa without prohibitive hematologic toxicity.We selected low doses of interferon alfa (5 million units threetimes weekly) to avoid intolerable toxicity and to obtain anacceptable rate of compliance.
The overall rate of response in the patients treated with CHVPplus interferon alfa was significantly higher than that in thepatients treated with CHVP alone. The rates of complete remission(13 percent at the end of induction treatment in the group givenCHVP and 20 percent in the group given CHVP plus interferonalfa) were lower than those reported for other patients treatedwith CHOP regimens5,8,20. There are several possible explanationsfor the discrepancy. Our patients were selected on the basisof their large tumor burdens, the criteria chosen to definecomplete remission were more strict than in other studies,5and patients with even minimal residual radiographic abnormalitiesor bone marrow infiltration were rated as having a partial response.Some patients who had no response after induction treatmenthad a response during the maintenance phase. Finally, in somestudies, therapy included irradiation of bulky tumors8. In patientswith low-grade non-Hodgkin's lymphomas, the response rate isprobably less relevant in evaluating the efficacy of a treatmentthan is the length of time to treatment failure or the overallsurvival rate.
The first interim analysis demonstrated that patients treatedwith CHVP plus interferon alfa had a significantly longer event-freesurvival than those treated with CHVP alone; therefore, furtheraccrual of patients was stopped. Furthermore, overall survivalanalysis showed a significant difference between the two treatmentgroups, with a three-year survival rate of 86 percent in thepatients treated with CHVP plus interferon alfa as comparedwith a rate of 69 percent in the patients treated with CHVP(P = 0.02).
There are few reports of concomitant treatment of low-gradenon-Hodgkin's lymphomas with chemotherapy plus interferon alfa.A preliminary analysis in one randomized study showed no differencein the overall rates of response between patients treated withchlorambucil alone and those treated with chlorambucil plusinterferon alfa, but there was a significant prolongation ofremission in the latter group (P<0.015)21. Smalley et al.22reported the results of an Eastern Cooperative Oncology Grouptrial involving 249 patients with prognostically unfavorablelow-grade or intermediate-grade non-Hodgkin's lymphoma. Therewas no difference in response rates but a significantly longermedian time to treatment failure in the patients treated witha CHOP-like regimen plus interferon alfa than in the patientstreated with the CHOP-like regimen alone. Although there wasno significant difference in overall survival, treatment withinterferon alfa was a significant favorable prognostic factorin the multivariate analysis. It must be emphasized that themedian event-free survival in our study and the median timeto treatment failure in the Eastern Cooperative Oncology Groupstudy22 were both 19 months in the chemotherapy groups and were34 and 30 months, respectively, in the groups receiving chemotherapyplus interferon alpha. Several studies have focused on the useof interferon alfa in maintenance therapy. In one, the drugled to a longer remission in patients who had responded to aregimen consisting of CHOP and bleomycin than in historicalcontrols23. The first interim analysis in another study showedthat maintenance treatment with interferon alfa-2a after initialtreatment with cyclophosphamide, vincristine, and prednisonesignificantly increased progression-free survival (P = 0.02)but had no influence on overall survival24.
These results demonstrate the beneficial effects of adding interferonalfa to a CHOP-like regimen in patients with advanced low-gradefollicular non-Hodgkin's lymphoma. The increase in responserates together with the prolongation of event-free survivalimproved survival. This treatment needs to be compared withthat involving such new and promising drugs as fludarabine and2-chlorodeoxyadenosine.
Supported by grants from the Association Claude Bernard, Schering-PloughFrance, 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 theirtechnical assistance and assistance in the preparation of themanuscript.
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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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). 
3 in the former group and 11 in the latter group (P<0.001). During the maintenance phase, neutropenia of WHO grade 
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