Long-Term Follow-Up of Patients With Follicular Lymphoma Receiving Single-Agent Rituximab at Two Different Schedules in Trial SAKK 35/98
We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma.
Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure).
At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, at 8 years 45% were still without event. The only favorable prognostic factor for EFS in a multivariate Cox regression was the prolonged rituximab schedule (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P = .009), whereas being chemotherapy naive, presenting with stage lower than IV, and showing a VV phenotype at position 158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-term toxicity potentially due to rituximab was observed.
Follicular lymphoma (FL) is usually considered an incurable disease.1,2 Even though aggressive interventions, such as autologous or allogeneic transplantation, may eventually cure some patients,3,4 in the majority of patients, treatment was traditionally aimed at relieving or preventing symptoms.5 It has been reported recently that chemotherapy with the addition of drugs acting on the immune system (as interferon alfa or rituximab) improved survival compared with chemotherapy alone.6,7 Based on its more favorable toxicity profile, rituximab has largely replaced interferon, and the combination of rituximab with chemotherapy is now considered standard therapy for most patients with FL. Nevertheless, single-agent rituximab remains a valuable alternative option, having shown to cause little toxicity and, when given at a prolonged schedule to specific patient subsets, to obtain remission durations comparable to those obtained with multiagent regimens.8–10
We aimed at defining the characteristics of patients having durably benefited from single-agent rituximab based on our large prospective trial now with a follow-up of almost 10 years. Here, we describe what we believe is the largest long-term cohort of patients with FL treated with single-agent rituximab administered with a prolonged schedule.
Patients were enrolled from January 1998 to January 2002 in 29 larger and smaller hospitals in Switzerland, Italy, and South Africa. The trial was approved by the local ethics committee of each participating institution and conducted in accordance with the Declaration of Helsinki and applicable amendments. All patients gave written informed consent.
Patients were initially treated with rituximab 375 mg/m2 per week for 4 weeks (ie, induction phase). Patients with stable disease or in partial or complete response (CR) at week 12 (from treatment start) were randomly assigned in a 1:1 ratio to no further treatment (arm A, standard treatment) or to treatment with a single infusion of rituximab 375 mg/m2 at week 12, and again at months 5, 7 and 9 (arm B, prolonged treatment). The randomization was stratified according to disease status at trial entry (first presentation v refractory or relapsed), response to induction treatment (stable disease v response) and participating center. Patients were centrally randomly assigned by the minimization method via fax at the Swiss Group for Clinical Cancer Research (SAKK) Coordinating Center in Bern. On disease progression or relapse, further treatment was at the treating physician's discretion.
Event-free survival (EFS) time was the primary end point and calculated as the time from first induction infusion to progression, relapse, second tumor, or death from any cause. For the randomized phase, a group sequential design with two interim analyses and one final analysis was adopted. The trial had reached the final stage in 2003 and the final analysis was performed as planned and published in 2004 with a median follow-up of 3 years.9
Inclusion criteria were a biopsy-proven follicular lymphoma of any grade and measurable disease defined as the presence of at least one previously unirradiated lesion with two measurable perpendicular diameters of which at least one should be of 2 cm. The interval between the last systemic lymphoma treatment and trial entry should be longer than 28 days. Other inclusion criteria were standard and have been reported previously.9 A central histology review was performed for all cases before random assignment.
The detailed examinations required by the trial were described before.9 Briefly, patients underwent a complete staging at trial entry, at week 12 and at 7, 12, 18, and 24 months, then annually or when clinically required until 5 years from study entry. For the purpose of this analysis, data on the follow-up of all patients who were still alive at the time of the last protocol-required data collection were requested by the investigators; a specially designed follow-up form was created for this purpose asking for remission status, date of relapse or progression, if applicable, survival status, date and cause of death if applicable, adverse effects possibly related to previous rituximab treatment and occurrence of second cancers. Of 106 requested follow-ups, data were obtained for 97 cases for EFS and for 97 cases for overall survival.
Median EFS and overall survival were estimated using the Kaplan-Meier method. Univariate comparisons between groups were carried out using log-rank test. The effects of multiple factors on EFS were analyzed using Cox regression. Hazard ratios and the corresponding 95% CIs were calculated as appropriate. All tests were two sided. No adjustment for multiple comparisons was performed. All analyses were performed using SAS version 9.1 for Windows (SAS Institute Inc, Cary, NC).
Table 1 summarizes the most relevant patient characteristics for the three main groups of interest: patients who entered the trial, those who were randomly assigned and, finally, the randomly assigned patients who were previously untreated. Registered and randomly assigned patients had very similar characteristics, while previously untreated patients had slightly more favorable characteristics, but still balanced between the two arms. As the Follicular Lymphoma International Prognostic Index11 was not available at the time of study design, we failed to collect the number of involved lymph node sites, and are therefore not able to retrospectively provide the Follicular Lymphoma International Prognostic Index. Patient's disposition is described in Figure 1, according to the CONSORT recommendations.
|Characteristic||Included||Randomly Assigned ||Chemotherapy-Naïve Randomly Assigned|
|PS ≤ 1, %||94||99||95||100||100|
|Stage III-IV, %||85||87||82||88||76|
|BM involved, %||52||51||48||50||36|
|Bulky disease, ≥ 5 cm, %||53||47||49||42||44|
|Elevated LDH, %||37||31||30||23||24|
|Previous chemotherapy, %||68||67||66||—||—|
|Median No. of chemotherapy regimens||1||1||1||—||—|
Abbreviations: PS, performance status; BM, bone marrow; LDH, lactate dehydrogenase.
The response data were previously published9 and remain unchanged: of 185 evaluable patients evaluated at week 12, 52% responded to the induction treatment. Of the randomly assigned patients, a total of 77% (31% CR) in the standard arm and 75% (38% CR) in the maintenance arm responded to the induction therapy.
At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median EFS was 13 months for the standard and 24 months for the prolonged exposure arm (P < .001). Updated results of baseline characteristics predicting longer EFS in the univariate analysis in the previous report are: disease diameter smaller than 5 cm (P = .011), being chemotherapy naive (P = .02), Ann Arbor stage lower than IV (P = .09), and a VV phenotype at position 158 of the Fc gamma receptor RIIIA (P = .079). By multivariate analysis, only treatment according to the prolonged schedule remains statistically significant (Table 2).
|Median (months)||P||Hazard Ratio||95% CI||P||Hazard Ratio||95% CI|
|Prolonged treatment, yes v no||24 v13||< .001||0.55||0.39 to 0.78||.009||0.59||0.39 to 0.88|
|Bulky disease, ≤ 5 v ≥ 5 cm||26 v 12||.011||0.64||0.46 to 0.91||.090||0.71||0.47 to 1.05|
|Chemotherapy, no v yes||33 v 12||.020||0.65||0.45 to 0.93||.129||0.71||0.45 to 1.11|
|Phenotype, VV v FV/FF||37 v 15||.079||0.63||0.38 to 1.06||.319||0.76||0.44 to 1.31|
|Disease stage, I-III v IV||23 v 12||.090||0.75||0.53 to 1.05||.324||0.81||0.54 to 1.23|
NOTE. Data were based on 114 patients for multivariate and for univariate analysis of phenotype, while it was based on 151 cases for the rest of the univariate analyses.
Abbreviations: V, valine at position 158 of the Fcγ RIII receptor; F, phenylalanine.
In the observation arm, patients without events were 13% at 5 years and 5% at 8 years, while in the prolonged exposure arm they were 27% at 5 and remained 27% at 8 years. After 8 years, 45% of previously untreated patients receiving prolonged treatment after responding to rituximab induction were still without events.
Prolonged treatment appeared to be of benefit only to patients having demonstrated a prior objective response (median EFS 3.1 v 1.4 years for standard) while for the subgroup of patients randomly assigned in stable disease the median EFS was similar in the two arms (0.9 v 0.5 years, respectively; Fig 2). The best outcome is observed in previously untreated patients responding to rituximab induction (n = 38): their EFS at 5 and 8 years is 45% for the prolonged treatment compared to 22% for the standard arm (Fig 3).
In the observation arm, 46% of patients have died compared to 32% in the prolonged treatment arm (Fig 4). The hazard ratio for death is 0.63 (95% CI, 0.37 to 1.06). The difference does not reach statistical significance (P = .0813).
Acute and subacute toxicities were observed and consisted mainly of infusion-related reactions, cytopenias, infections, and other rare conditions, which were previously described.9,12 As other immunosuppressive treatments can increase the incidence of second tumors, we carefully analyzed these events in both arms. We found 23 second tumors in 151 patients (15%), an incidence similar to the one reported in most studies of chemotherapy pretreated patients. Of these neoplasias, six were skin tumors, five were myelodysplastic syndromes, and eight were solid cancers, all equally distributed among the two study arms. One case in arm A and 2 cases in arm B were from chemotherapy-naive patients (two skin cancers and one colon carcinoma).
To our knowledge, this is the largest cohort of patients with FL treated with single-agent rituximab with a median follow-up of almost 10 years. The data confirm that to exert an optimal effect, rituximab should be given at a prolonged schedule. This was accomplished in our trial by administering one infusion of rituximab every 2 months for 4 times starting 2 months after the end of induction treatment, but similar observations were made when rituximab was given once every 3 to 4 months for 1 year,13 once a week for 4 weeks every 6 months for 2 years,8,10 or once a week for 4 weeks at 3-month intervals twice.14 We did not observe any unexpected long-term toxicity associated with the prolonged administration schedule used in this study.
The most interesting and somehow unexpected result of this analysis is the high proportion of patients still not progressing after many years, particularly when responders to rituximab induction are considered (35% not progressing after 8 years). Even more striking, in the small cohort of chemotherapy naive and responding patients receiving prolonged treatment (20 cases), 45% are still alive without disease progression at 8 years. This suggests that single-agent rituximab may be considered as a valid first-line treatment for selected patients, as those for whom a rapid response is not clinically needed. Maintenance therapy should be offered only to responding patients. This approach may delay chemotherapy for many years in this subset of patients. Whether delaying chemotherapy in favor of single-agent rituximab in symptomatic patients could compromise overall survival should be the subject of a randomized trial; in asymptomatic patients, delaying chemotherapy was shown to have no consequences on survival.15 Indeed, we know that adding rituximab to chemotherapy improves survival compared with chemotherapy alone,7 but, as rituximab is the drug making the difference, we still do not know if adding chemotherapy to rituximab is really necessary to impact on survival.
Our data must be compared with other treatments in similar patient populations to fully appreciate its clinical value. The EFS observed at 5 and 7 years in other trials of single-agent rituximab, radioimmunotherapy, single-agent chemotherapy, polychemotherapy or combination rituximab plus chemotherapy given as first-line to patients with FL and for whom such a long-term follow-up is available15–21 show that in the long-term, EFS for these treatments ranges from 15% to 50%, and is not substantially different from what is achieved with single-agent riuximab administered at a prolonged schedule.
A limitation of the present data is that this long-term analysis was unplanned. The trial protocol asked for regular tumor evaluation by computed tomography scan only until 5 years, so the later follow-up investigations were left to the discretion of the treating physician. The plateau seen after 5 years in the EFS curve of the experimental arm could, therefore, be due to a bias (delayed diagnosis of relapse). We expect this bias to be minimal as in the observation arm disease progression continued to be observed regularly even after 5 years. Also, according to several reports,22–24 77% to 86% of relapses in FL and other lymphomas are detected by history, physical examination, and blood tests, and only a minority of relapses are detected by regular radiologic follow-up. It is therefore unlikely that the lack of planned and regularly performed computed tomography scans could by itself explain a plateau of the curve lasting longer than 3 years.
A more sophisticated explanation for the long-term effect of four additional doses of rituximab during the first treatment year is that this maneuver could produce a T-cell–mediated vaccinal effect. Preliminary observations supporting this theory were recently reported25 and more investigations on the development of an antilymphoma immunity in patients with long-term response to rituximab are warranted. An argument supporting this hypothesis is the (persistent although not statistically significant) difference in survival seen between arms: such a long-term effect is difficult to explain only with a higher initial tumor debulking in the experimental arm.
In a scenario of many new monoclonal antibodies becoming available for lymphoma treatment, this study provides support to the concept that first-line treatment with monoclonal antibodies alone can be an effective strategy and should be further tested in controlled clinical trials.
Written on behalf of the Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland.
Supported in part by the State Secretariat for Education and Research of Switzerland; and by Roche Pharma Schweiz AG, which provided some research funding and rituximab.
Presented at the 45th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 31-June 2, 2009; and European Cancer Organisation-European Society for Medical Oncology in Berlin, Germany, September 20-24, 2009.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Thomas Cerny, Roche (C); Daniel Vorobiof, Roche (C); Michele Ghielmini, Roche (C) Stock Ownership: None Honoraria: Thomas Cerny, Roche; Daniel Vorobiof, Roche; Emanuele Zucca, Roche; Michele Ghielmini, Roche Research Funding: Daniel Vorobiof, Roche; Emanuele Zucca, Roche; Michele Ghielmini, Roche Expert Testimony: None Other Remuneration: None
Conception and design: Giovanni Martinelli, Shu-Fang Hsu Schmitz, Thomas Cerny, Roger Stupp, Rolf Stahel, Daniel Vorobiof, Andreas Lohri, Emanuele Zucca, Michele Ghielmini
Administrative support: Urs Utiger, Emmie Okkinga
Provision of study materials or patients: Giovanni Martinelli, Thomas Cerny, Urs Hess, Simona Bassi, Roger Stupp, Rolf Stahel, Marc Heizmann, Daniel Vorobiof, Andreas Lohri, Pierre-Yves Dietrich, Emanuele Zucca, Michele Ghielmini
Collection and assembly of data: Shu-Fang Hsu Schmitz, Urs Utiger, Emmie Okkinga, Michele Ghielmini
Data analysis and interpretation: Shu-Fang Hsu Schmitz,Michele Ghielmini
Manuscript writing: Giovanni Martinelli, Shu-Fang Hsu Schmitz, Daniel Vorobiof, Andreas Lohri, Pierre-Yves Dietrich, Emanuele Zucca, Michele Ghielmini
Final approval of manuscript: Giovanni Martinelli, Shu-Fang Hsu Schmitz, Urs Utiger, Thomas Cerny, Urs Hess, Simona Bassi, Emmie Okkinga, Roger Stupp, Rolf Stahel, Marc Heizmann, Daniel Vorobiof, Andreas Lohri, Pierre-Yves Dietrich, Emanuele Zucca,Michele Ghielmini
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