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Originally published as JCO Early Release 10.1200/JCO.2007.14.4204 on May 19 2008 © 2008 American Society of Clinical Oncology. Rituximab Improves the Efficacy of High-Dose Chemotherapy With Autograft for High-Risk Follicular and Diffuse Large B-Cell Lymphoma: A Multicenter Gruppo Italiano Terapie Innnovative nei Linfomi Survey
From the Dipartimento Medicina-Oncologia Sperimentale, Divisione Universitaria di Ematologia, and Divisione Universitaria di Medicina Nucleare, Azienda Ospedaliera S. Giovanni B., Torino; Divisione Universitaria di Oncologia, Istituto Nazionale Tumori; Hematology Division and Bone Marrow Transplantation Unit, Istituto Scientifico H.S. Raffaele; and Divisione di Ematologia, Istituto Nazionale Tumori, Università di Milano, Milano; Dipartimento di Medicina Clinica e Sperimentale, Sezione e Divisione di Ematologia, Università e Azienda Ospedaliera di Verona, Verona; Divisione Ospedaliera Ematologia, Ospedali Riuniti di Bergamo, Bergamo; Divisione Ospedaliera di Ematologia, Azienda Ospedaliera V. Cervello, Palermo; Divisione di Ematologia, Azienda Ospedaliera S. Croce, Cuneo; Divisione di Ematologia, Azienda Ospedaliera S. Maurizio, Bolzano; and Divisione di Ematologia, Azienda Ospedaliera S. Camillo/Forlanini, Roma, Italy Corresponding author: Corrado Tarella, MD, Divisione Universitaria di Ematologia, Az. Osp. S. Giovanni Battista, Via Genova 3, 10126 Torino, Italy; e-mail: corrado.tarella{at}unito.it
Purpose To investigate the impact of adding rituximab to intensive chemotherapy with peripheral-blood progenitor cell (PBPC) autograft for high-risk diffuse large B-cell lymphoma (DLB-CL) and follicular lymphoma (FL). Patients and Methods Data were collected from 10 centers associated with Gruppo Italiano Terapie Innnovative nei Linfomi for 522 patients with DLB-CL and 223 patients with FL (median age, 47 years) who received the original or a modified high-dose sequential (HDS) chemotherapy regimen. HDS was delivered to 396 patients without (R–) and to 349 patients with (R+) rituximab; 154 (39%) and 178 patients (51%) in the R– and R+ subsets, respectively, underwent HDS for relapsed/refractory disease. Results A total of 355 R– (90%) and 309 R+ patients (88%) completed the final PBPC autograft. Early treatment-related mortality was 3.3% for R– and 2.8% for R+ (P = not significant). Two parameters significantly influenced the outcome: disease status at HDS, with 5-year overall survival (OS) projections of 69% versus 57% for diagnosis versus refractory/relapsed status, respectively, and rituximab addition, with 5-year OS of 69% versus 60% in the R+ versus R– groups, respectively. In the multivariate analysis, these two variables maintained an independent prognostic value. The marked benefit of rituximab was evident in patients receiving HDS as salvage treatment: the 5-year OS projections for R+ versus R– were, respectively, 64% versus 38%, for patients with refractory disease or early relapse and 71% versus 57%, for patients with late relapse, partial response, or second/third relapse. Conclusion The results of this large series indicate that rituximab should be included in the current practice of PBPC autograft for DLB-CL and FL.
The management of patients with B-cell non-Hodgkin's lymphoma has improved considerably after addition of the anti-CD20 monoclonal antibody rituximab to conventional chemotherapy.1,2 Several randomized trials in which rituximab was added to a variety of different chemotherapy regimens confirm the superiority of rituximab plus chemotherapy over chemotherapy alone in most B-cell lymphomas, particularly in the diffuse large B-cell lymphoma (DLB-CL) and follicular lymphoma (FL) subtypes.3-9 Thus rituximab chemotherapy is now the standard treatment approach for FL and DLB-CL. Intensive chemotherapy with autologous stem-cell transplantation (ASCT) is an additional option to conventional chemotherapy and is commonly used in patients with disease that is refractory or relapsing after conventional chemotherapy.10-13 Again, the effectiveness of ASCT and its superiority compared with conventional salvage programs has been documented in FL and DLB-CL.13-19 ASCT-based programs are also sometimes used as first-line therapy in patients with high-risk presentation; however, the role of ASCT in this setting is still controversial.12,20-22 Recent studies suggest the benefit of also adding rituximab to intensive programs with autograft, where it may offer the dual advantages of additional antitumor activity as well as an in vivo purging effect on peripheral-blood progenitor cell (PBPC) collections.23-29 The high-dose sequential (HDS) chemotherapy schedule is a typical ASCT-based program, including the delivery of high-dose drugs from the start of treatment, with a final autograft performed and PBPCs collected in the high-dose phase.30,31 The original HDS schedule was designed in 1986. In subsequent years, several centers in Italy have treated high-risk patients with lymphoma using this approach with either the original or variously modified schedules.32-34 Since it became available in 1998, rituximab has gradually been incorporated into HDS programs.23,26 Thus a retrospective multicenter analysis was conducted among Italian centers belonging to the Gruppo Italiano Terapie Innnovative nei Linfomi (GITIL) who have used the HDS program with or without rituximab over the past 20 years. The aim was to investigate the impact of adding rituximab on the outcome of a large series of patients with FL and DLB-CL who underwent an HDS program, either as salvage or as first-line therapy for high-risk presentation.
Patients Ten GITIL centers contributed to this survey, reporting all DLB-CL and FL cases treated at their institutions beginning in 1986 until April 2005. There was no selection criteria: all consecutive patients who received HDS with (R+) or without (R–) rituximab were included. The main patient characteristics are reported in Table 1. Stage, prognostic score, and disease status at HDS were defined by standard criteria.35-38
Treatment Plans HDS regimen. The HDS regimen is a comprehensive program that includes an initial debulking phase (one to two courses of doxorubicin, prednisone, and vincristine ± one to two courses of dexamethasone, cisplatin, and cytarabine) and a high-dose chemotherapy phase with PBPC collection followed by a final myeloablative treatment with autograft (ASCT).30,33 Over the past 10 years, the schedule has been slightly modified and adapted to the different histologic subtypes. The main modification includes the introduction of a course of high-dose cytarabine (Ara-C).39 Thus two main schedules are apparent: (1) Original HDS. After the debulking phase, the high-dose phase includes the sequential administration, at 10- to 15-day intervals, of high-dose cyclophosphamide (7 g/m2) with granulocyte colony-stimulating factor, high-dose methotrexate (8 g/m2), and high-dose etoposide (VP16; 2 g/m2), with granulocyte colony-stimulating factor. PBPC collection is performed after cyclophosphamide administration. Patients with FL received an inverted cyclophosphamide/etoposide sequence with PBPC collection occurring after cyclophosphamide.33 Among 745 patients included in this survey, 353 patients (132 patients with FL and 221 patients with DLB-CL) received the original HDS schedule (Table 1). (2) High-dose cytarabine HDS. To further intensify the program, the schedule was supplemented with a 6-day course of high-dose cytarabine 2 g/m2 every 12 hours. In addition, the etoposide dose was increased to 2.4 g/m2 and delivered with low-dose cisplatin (100 mg/m2).39 Overall, 392 patients (91 patients with FL and 301 patients with DLB-CL) received high-dose cytarabine–supplemented HDS (Table 1). Rituximab addition. Rituximab was delivered in four doses during the high-dose phase immediately before PBPC collection to exploit the drug's in vivo purging effect.23,26 Two additional doses were usually delivered after ASCT. Overall, 349 patients (47%) received HDS with rituximab: 149 patients received four doses, 164 patients received six doses (three of these received two additional rituximab doses), and 36 patients received no more than two doses because of treatment discontinuation for different reasons. Autograft. Among 664 patients (89%) completing the program with ASCT, 379 patients (57%) were conditioned with the mitoxantrone/melphalan combination, and 181 patients (27%) received the carmustine, etoposide, cytarabine, and melphalan regimen.40,41 The remaining 104 patients received other regimens, including total-body irradiation–containing regimens (54 patients; 8%), high-dose melphalan (15 patients; 2.2%), or thiotepa-containing regimens (11 patients; 1.6%).
Radiotherapy
Response Assessment and Statistical Analysis
All 745 patients were evaluated. Patients’ characteristics were compared between the two main R–/R+ arms using the Pearson The long-term outcome was assessed in terms of overall survival (OS) and event-free survival (EFS). OS was defined as the time from the start of treatment to death for any cause. EFS was defined as the time from the start of treatment to progression/relapse/death for any cause, whichever came first. Follow-up was updated in February 2007, and all living patients had been observed at least once in the previous 3 months. OS and EFS were analyzed by the Kaplan-Meier method.43 Five-year projections were calculated by life tables. The two HDS arms were compared using the log-rank test; univariate analysis was performed for several covariates: differences in survival were identified by generalized log-rank analysis.44 Multivariate analysis was then applied to OS and EFS using the Cox proportional hazards model.45 The cumulative incidence of developing secondary malignancies along with risk factors were determined using the Fine and Gray models.46,47 Data as of June 2007 were analyzed with SPSS 13.0.1 (SPSS Inc, Chicago, IL).
Feasibility, Fatal Toxicity, Response, and Long-Term Outcome The HDS schedule was feasible, and addition of rituximab did not influence either treatment feasibility or early TRM. Of 745 patients who entered the program, 355 patients (90%) in the R– and 309 patients (87%) in the R+ groups completed the whole schedule with ASCT (P = .910). Overall, 13 patients (3.3%) in the R– group and 10 patients (2.8%) in the R+ group died of causes related to early TRM (P = .905). There were no significant differences in terms of response between the two subgroups, with 73% and 81% CR rate for patients receiving HDS without or with rituximab, respectively. At the closing date of this analysis, 492 patients (66%) were alive, 417 patients (58%) were without signs of disease, and at a median follow-up of 5 years, the actuarial survival curves for the entire group display 5-, 10-, and 15-year projections of 64%, 58%, and 54% and 55%, 49%, and 45%, respectively, for OS and EFS, respectively.
Factors Influencing Long-Term Outcome
The main prognostic factors were evaluated in the multivariate analysis. A highly significant independent adverse prognostic value on both OS and EFS was observed for status of refractory or relapsed disease, no rituximab added to HDS, and presentation with an age-adjusted International Prognostic Index score  2. An unfavorable prognosis on EFS was also associated with age older than 47 years, although with borderline significance, whereas FL histology (v DLB-CL) had a favorable impact on OS only (Appendix Table A1, online only). The analysis of time-dependent effects of rituximab on OS and EFS was performed using a time-dependent Cox analysis: incorporating rituximab into the model as a time-dependent covariate did not modify its influence on OS (P = .372) and EFS (P = .520) over time.
Impact of Rituximab on Long-Term Outcome
The long-term outcome was separately assessed for FL and DLB-CL. As shown in Figures 3A and 3B, patients with FL had an overall significantly better outcome compared with patients with DLB-CL in terms of OS, whereas the EFS was almost identical for the two groups. When the addition of rituximab was assessed, a significant improvement was observed both in DLB-CL and FL (Fig 3C through 3F). Again, rituximab proved to be most effective in refractory or relapsed disease, as detailed in Table 3.
The long-term outcome of a large series of high-risk patients with FL and DLB-CL treated with an HDS program at 10 Italian GITIL centers was retrospectively evaluated. Two main groups were considered according to whether or not rituximab was added to HDS. As in all retrospective studies, the two groups displayed some degree of heterogeneity in terms of clinical presentation and the type of HDS schedule received. Nevertheless, with the large number of patients included in the study, a significant benefit of rituximab was clearly demonstrated, with an improved outcome demonstrable in most patient subgroups with either FL or DLB-CL histology. Data were collected from 745 patients with FL and DLB-CL treated with an HDS schedule over an approximately 19-year period (1986 to 2005). Rituximab was progressively incorporated into the HDS programs beginning in 1998, and recently, almost all CD20+ B-cell lymphoma patients who were candidates for HDS received the R+ schedule. Some patients still received rituximab-free programs, usually because of the lack of approval of rituximab use in autograft programs outside of clinical trials. Hence the timeframes when the two patient groups were treated differ but largely overlap. One might speculate that differences in the outcome between the two groups could simply be ascribed to changes in supportive care measures over such a long time period. However, no major differences were observed for treatment feasibility or the overall TRM, between the R– and R+ groups. This seems to exclude the possibility that improvements in supportive care might explain the prolonged survival of patients receiving rituximab-supplemented HDS. Furthermore, the observation suggests that the marked immunosuppression caused by rituximab does not impose a significant increase in the overall TRM. It seems quite likely that the availability of improved diagnostic tools along with effective prophylaxis and treatment measures may offset the increased risk of severe complications associated with rituximab when added to chemotherapy and autografts.48-51 Several reports suggest that ASCT is most effective when performed after maximal cytoreduction.52-55 Thus an adequate debulking is probably the best prerequisite for the optimal use of ASCT. The HDS schedule is based on this concept, with the delivery of high-dose drugs since the early beginning and a final autograft with PBPCs collected in the high-dose phase.30,31 After initial experiences, the HDS schedule has been adjusted over the years. The most relevant amendment was the introduction of a high-dose cytarabine course.23,39 Moreover, since its availability, rituximab was progressively incorporated into the schedule, with four doses delivered near the time of PBPC collection plus two additional doses after the autograft. Indeed, adding rituximab significantly improved the outcome of patients undergoing HDS, and its benefit is clearly documented in both univariate and multivariate analysis, whereas high-dose cytarabine addition has had a marginal, statistically insignificant effect. Moreover, the advantage associated with rituximab was proven in HDS schedules with or without high-dose cytarabine. Besides the addition of rituximab, other factors significantly influenced the outcome in terms of both OS and EFS, including status at HDS (ie, disease at onset or refractory/relapsed disease, and prognostic presentation according to age-adjusted International Prognostic Index score) and the ability to proceed with the final autograft. The improved outcome of patients receiving HDS at diagnosis compared with those receiving salvage HDS for relapsed or refractory disease seems quite reasonable. Also, the prognostic value of the age-adjusted International Prognostic Index score is well established. On the other hand, the impact of HDS completion might overstress the role of the autograft. Patients dying from toxicity under treatment and patients with refractory disease and who are thus unable to proceed with the treatment schedule account for most of the poor outcomes in the group of patients who did not complete the program. In previous studies, we stressed the issue of patients whose disease was unresponsive, even to the high-dose courses of the HDS regimens.39,56 These patients with unresponsive disease, approximately 10% to 20% of all patients receiving HDS, usually have a rapidly fatal outcome. This justifies the markedly better outcome of patients who complete the whole schedule with autograft. Rituximab was associated with better outcome under nearly all conditions; however, the most remarkable improvement was seen when HDS was used as salvage therapy. The 65% 5-year OS projection observed in patients receiving salvage HDS with rituximab is noteworthy and provides a good reason for the preferential use of autograft-based approaches to treat refractory/relapsed lymphoma rather than in patients at disease onset. In fact, the first-line use of intensive treatment with autograft is still controversial.20-22,57 In particular, cyclophosphamide, doxorubicin, vincristine, and prednisone and an HDS schema similar to our original version yielded identical and poor results in the Multicenter International Studies on the Treatment of Aggressive Lymphomas randomized study for aggressive lymphoma at diagnosis. The study included B cell as well as non–B-cell histotypes, showed disappointingly low response to cyclophosphamide, doxorubicin, vincristine, and prednisone, had a slow accrual rate, and did not include either the most recent HDS schedule or rituximab. Nevertheless, results of the Multicenter International Studies on the Treatment of Aggressive Lymphomas and a recent meta-analysis argue against high-dose therapy as first-line treatment.20,57 Additionally, the increased efficacy of conventional chemotherapy after the addition of rituximab further questions the use of autograft-based programs in the first-line setting. Indeed, randomized controlled trials may still be required to verify the right place for high-dose therapy and autograft now in the rituximab era. Rituximab proved beneficial in all settings where salvage HDS was used, including patients with refractory or early relapsed disease. It should be pointed out that most patients with relapsed/refractory disease were rituximab-naïve; those few patients who underwent salvage therapy after a rituximab-containing induction treatment had a poorer survival compared with those who were rituximab-naïve, suggesting that the efficacy of salvage HDS with rituximab may somehow be reduced in rituximab-pretreated patients. Nevertheless, the encouraging results in terms of OS and EFS observed with HDS with rituximab in the whole series of patients with refractory/relapsed disease indicate that rituximab should always be considered whenever autograft is used as salvage treatment after failure of induction therapy. Improved results after adding rituximab were recently reported by the Cologne group using an analogous HDS schedule in a limited group of patients with refractory and relapsed disease.58 Thus the HDS with rituximab approach is a feasible, tolerable, and highly effective salvage treatment and should be viewed as a well-established approach to be compared with other intensive chemoimmunotherapy schemes recently developed for relapsed/refractory lymphoma.59,60 Although retrospective, the results reported in the present study clearly show that rituximab can be incorporated into ASCT programs with undeniable improvements, not only in terms of EFS but also in terms of prolonged survival. Some concerns might be raised regarding the long-term risk of secondary malignancy.61,62 Significant differences in the risk of secondary myelodysplastic syndrome/acute leukemia between R+ and R– schemes were not documented in our analysis. Nevertheless, a prolonged follow-up is still required to define the possible influence of rituximab on the development of secondary malignancies after intensive chemotherapy and ASCT. At present, the results of the survey indicate that rituximab should be always considered when designing intensive programs with ASCT for high-risk FL and DLB-CL. The approach reported here is peculiar in that rituximab is given immediately before PBPC collection to maximally exploit the in vivo purging effect. Indeed, it is quite likely that the main activity of rituximab stems from its in vivo purging effect on PBPC collections, as previously reported by other groups and ourselves.23-29 Thus it seems reasonable that an effective ASCT-based strategy for high-risk patients with B-cell lymphoma should include adequate tumor debulking, collection of PBPCs along with rituximab for the in vivo purging effect, and a final autograft phase performed with in vivo purged PBPCs.
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: Tiziano Barbui, Roche (C); Alessandro Rambaldi, Roche (C) Stock Ownership: None Honoraria: Corrado Tarella, Roche; Tiziano Barbui, Roche; Sergio Cortelazzo, Roche; Ignazio Majolino, ADIS International Ltd; Salvo Mirto, Roche; Paolo Corradini, Roche; Giovanni Pizzolo, Roche; Alessandro Rambaldi, Roche Research Funding: Corrado Tarella, Roche, Sanofi-aventis; Caterina Patti, Roche; Sergio Cortelazzo, Roche; Alessandro Rambaldi, Roche Expert Testimony: None Other Remuneration: Corrado Tarella, Roche, GlaxoSmithKline, Amgen; Tiziano Barbui, Roche; Alessandro Rambaldi, Roche
Conception and design: Corrado Tarella, Alessandro M. Gianni, Alessandro Rambaldi Financial support: Corrado Tarella, Alessandro Pileri, Mario Boccadoro Provision of study materials or patients: Corrado Tarella, Michele Magni, Fabio Benedetti, Caterina Patti, Tiziano Barbui, Alessandro Pileri, Mario Boccadoro, Fabio Ciceri, Andrea Gallamini, Sergio Cortelazzo, Ignazio Majolino, Salvo Mirto, Paolo Corradini, Giovanni Pizzolo, Alessandro M. Gianni, Alessandro Rambaldi Collection and assembly of data: Manuela Zanni, Roberto Passera Data analysis and interpretation: Corrado Tarella, Manuela Zanni, Tiziano Barbui, Sergio Cortelazzo, Paolo Corradini, Roberto Passera, Giovanni Pizzolo, Alessandro M. Gianni, Alessandro Rambaldi Manuscript writing: Corrado Tarella Final approval of manuscript: Corrado Tarella, Manuela Zanni, Michele Magni, Fabio Benedetti, Caterina Patti, Tiziano Barbui, Alessandro Pileri, Mario Boccadoro, Fabio Ciceri, Andrea Gallamini, Sergio Cortelazzo, Ignazio Majolino, Salvo Mirto, Paolo Corradini, Roberto Passera, Giovanni Pizzolo, Alessandro M. Gianni, Alessandro Rambaldi
published online ahead of print at www.jco.org on May 19, 2008. Supported in part by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca; the Michelangelo Foundation for Advances in Cancer Research and Treatment; and the Piedmont Regional Government (Regione Piemonte). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or the Fisher's exact test for discrete variables and the t test for continuous variables.
