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Originally published as JCO Early Release 10.1200/JCO.2008.19.8457 on March 2 2009 © 2009 American Society of Clinical Oncology.
Maintenance or Eradication of Residual Disease in Indolent Lymphoma: Where Do We Stand?Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Although advanced-stage indolent non-Hodgkin's lymphoma (NHL), with follicular NHL as the most frequent histological subtype, is not curable in the vast majority of patients, recent reports suggest that this disease entity has turned step-by-step to a more and more chronic illness.1 Median survival times for follicular NHL were for the past 30 years thought to be in the order of 10 to 12 years, but are now reported to be in excess of 18 years.2 Though only in a small, select subpopulation of younger patients, longer disease-free survival times and even cures are achieved using allogeneic stem cell transplantation acting through its graft-versus-lymphoma effect.3 Focusing on follicular NHL, it was clear in the conventional chemotherapy era that remissions could be achieved in a significant portion of patients, but after each relapse the remissions were shorter. However, since the introduction of new treatment modalities, such as high-dose chemotherapy followed by autologous stem cell transplantation, monoclonal antibody treatment, and radio-immunotherapy, this picture has now changed. Salvage treatments have become more and more effective. In concert with improved supportive care, the outlook for patients in terms of survival has become better. In particular, since the introduction more than 10 years ago of the human mouse-chimeric anti-CD20 monoclonal antibody rituximab, a number of prospective randomized phase III clinical trials have shown for the first time an increase in patient overall survival after combining conventional chemotherapy with rituximab as first-line treatment.4–7 Although the optimal induction chemotherapy regimen is not yet known, rituximab in combination with chemotherapy is now accepted worldwide as standard first-line treatment. Recently, the old concept of maintenance treatment, developed for acute lymphoblastic leukemia, was reintroduced in the treatment of indolent NHL. In the original concept, cytostatic agents (chlorambucil, cyclophosphamide8,9) or interferon10 were administered for a prolonged time during remission. However, although effective, these approaches were abandoned because of toxic adverse effects and patient noncompliance. In this issue of Journal of Clinical Oncology, Hochster et al11 present the first data on the role of rituximab maintenance after first-line cyclophosphamide, vincristine, and prednisone (CVP) treatment in 311 patients with advanced-stage indolent NHL, of which 228 were follicular NHL patients (Eastern Cooperative Oncology Group [ECOG] 1496 study). Patients who achieved complete response (CR), partial response (PR), or stable disease after induction chemotherapy were randomly assigned to rituximab maintenance (375 mg/m2 once per week for 4 consecutive weeks every 6 months for a maximum of 2 years) versus observation. With up to 16 infusions of rituximab, progression-free survival (PFS) as calculated from the time of random assignment was prolonged by 36 months (4.3 v 1.3 years; HR, 0.4; P = 4.4 x 10–10). PFS results were similar for the follicular lymphoma subset of patients. The 3-year overall survival (OS) for all evaluable patients was 92% versus 86% (maintenance v observation) at borderline significance (HR, 0.6; P = .05). For follicular NHL patients, these data were 91% versus 86% (HR, 0.6; P = .08). How do these encouraging data compare with other published studies on rituximab maintenance in indolent NHL? Two previously published studies explored rituximab maintenance after induction treatment with rituximab only, mainly in patients with relapsed/refractory indolent NHL. In a phase III trial from Switzerland, a two-fold increase in event-free survival was reported (12 v 23 months).12 In a randomized phase II trial from the United States, a more than four-fold increase in PFS was observed (7.4 v 31.1 months).13 Different rituximab maintenance regimens were used, but the results were positive. As a better comparator to the ECOG 1496 study, the European Organisation for Research and Treatment of Cancer (EORTC) Intergroup Study should be mentioned in which the role of rituximab maintenance was investigated in 465 relapsed/refractory follicular NHL patients induced either with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab plus CHOP (R-CHOP).14 In this study, responding patients (CR, PR) were randomly assigned between rituximab maintenance (375 mg/m2 every 3 months until relapse or for a maximum of 2 years) or observation. From the time of random assignment, PFS was increased, with 36.6 months in the maintenance group (51.5 v 14.9 months; HR, 0.4; P < .001). Although the EORTC study was performed in relapsed/refractory patients, the increase in PFS was strikingly similar to the one reported in the Hochster study, that is, 36.6 versus 36 months. In the EORTC study, this was achieved with only eight infusions of rituximab maintenance, versus 16 in the Hochster/ECOG study. How to explain this comparable outcome of rituximab maintenance in first versus second or third remission? Both studies had a similar composition of patients in Follicular Lymphoma International Prognostic Index subgroups: a comparison of ECOG versus EORTC showed intermediate risk 33% versus 33%, and high risk 43% versus 37%. A major difference seems to be the more aggressive induction treatment in the EORTC study (CHOP v CVP in the ECOG study). One might hypothesize that in the EORTC study, only eight infusions of rituximab in patients with a lower tumor load after (R-) CHOP induction were able to produce the same increase in PFS of 3 years, as compared with 16 infusions of rituximab after less efficient lymphoma cell kill with CVP. From this, it might be deduced that the more effective the reduction in tumor load is before rituximab maintenance is initiated, the more effective rituximab maintenance will be. This strategy would be in concert with the idea that immunotherapy is most effective in patients with a small tumor load. Indeed, in the ECOG study it was observed that achievement of minimal disease after CVP significantly predicted longer PFS in patients receiving rituximab maintenance. Another reason to explain why 50% fewer infusions of rituximab in the maintenance setting were equally effective in terms of prolonging PFS might be the difference between the EORTC (every 3 months) and the ECOG maintenance regimens (every 6 months). Intervals in excess of 3 months between rituximab infusions might leave a significant proportion of patients for a couple of months without therapeutic serum (and possibly tissue) rituximab levels.15 This might allow regrowth of lymphoma between rituximab infusions. However, the optimal rituximab maintenance regimen still remains to be established. So far in the various studies, the maximum duration of rituximab maintenance has been limited to 2 years. The Swiss Group for Clinical and Epidemiological Cancer Research (SAKK) is currently investigating the efficacy and toxicity of rituximab maintenance for 5 years. This study will reveal whether prolonged rituximab maintenance will lead to prolongation of PFS, whether there will be a fraction of patients developing rituximab resistance, and whether long-term rituximab maintenance will lead to an exhaustion of plasma cells with decreasing immunoglobulin serum levels and subsequent immunodeficiency. Obviously, at the time the ECOG study was designed (in 1996), rituximab was not a standard component of induction treatment. Thus, the question whether rituximab maintenance in first remission is as effective after rituximab-chemotherapy induction as after chemotherapy-only induction as was shown in the EORTC study14 in relapsed patients remains to be answered. The international European Primary Rituximab and Maintenance (PRIMA) study, which was recently closed, addresses this crucial issue. The first interim analysis, which will take place in the course of 2009, is eagerly awaited. One might expect that a certain fraction of patients may develop resistance to rituximab after heavy rituximab pretreatment. Indeed, analyzing the fraction of patients with follicular NHL who become refractory to rituximab after first- and second-line rituximab-containing treatment regimens, including rituximab maintenance, yields a number of approximately 50%. Therefore, it is envisaged that there is a role for rituximab non–cross-resistant anti-CD20 or other antibodies in improving PFS and possibly OS after introducing these in the long-term treatment of this chronic disease. As far as OS is concerned, the ECOG study led to a borderline significant increase; in the EORTC study a first analysis showed a significant increase, which disappeared at a recent second analysis after a prolonged median follow-up of 6 years from start of maintenance.17 This might be explained by the introduction of more effective rituximab-containing salvage regimens. So, where do we stand as far as rituximab maintenance treatment in indolent NHL is concerned? Remissions are certainly being maintained, but so are viable lymphoma cells in residual disease. It is unlikely that rituximab maintenance will eradicate minimal residual lymphoma, even if applied for prolonged periods of time. Arising rituximab-refractory lymphoma cells might be the major cause of this predicted failure. Thus, apart from the introduction of non–cross-resistant monoclonal antibodies, other treatment modalities which have proven their efficacy in follicular NHL should in some way be combined with rituximab maintenance. Again, analogous to the treatment of acute lymphoblastic leukemia, intense rituximab-containing remission-induction chemotherapy, leading to a maximal decrease in tumor load, should be followed by consolidation treatment and thereafter a serious attempt should be made to eradicate minimal residual lymphoma through maintenance- (or better, eradication-) treatment. For consolidation, to date, two major modalities are recognized, that is, marrow-ablative chemotherapy followed by autologous peripheral blood stem cell transplantation and radioimmunotherapy. As was recently shown in a large international randomized phase III clinical trial in follicular NHL, just one infusion of 90Yttrium ibritumomab tiuxetan (Zevalin, Bayer Schering Pharma, Berlin, Germany) administered during first chemotherapy-only induced CR/PR prolonged median PFS by 2 years, calculated from the time of radioimmunotherapy (36.5 months v 13.3 months in the observation arm; HR, 0.5; P < .0001).16 The radioimmunotherapy compound can therefore be labeled as the most effective single drug with a favorable toxicity profile in the treatment of follicular NHL. Combining these most active ingredients may finally lead to a true plateau in the OS curve of patients with advanced-stage indolent NHL. However, one should realize that it might take quite some years before this can ultimately be proven. Therefore, we all need to maintain, or as the Dutch say in a typical Dutch national saying, "Je maintiendrai." AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Fisher RI, LeBlanc M, Press OW, et al: New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 23:8447–8452, 2005. 2. Tan D, Rosenberg SA, Levy R, et al: Survival in follicular lymphoma: The Stanford experience, 1960-2003. Blood 110: 2007 abstr 3428. 3. Khouri IF, McLaughlin P, Saliba RM, et al: Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 111:5530–5536, 2008. 4. Herold M, Haas A, Srock S, et al: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: An East German Study Group Hematology and Oncology Study. J Clin Oncol 25:1986–1992, 2007. 5. Salles G, Mounier N, de Guibert S, et al: Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: Results of the GELA-GOELAMS FL2000 study. Blood 112:4824–4831, 2008. 6. Hiddemann W, Kneba M, Dreyling M, et al: Front-line therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725–3732, 2005. 7. Marcus R, Imrie K, Solal-Celigny P, et al: Phase III study of R-CVP compared with cyclophosphamide, vincristine and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 26:4579–4586, 2008. 8. Ezdinli EZ, Harrington DP, Kucuk O, et al: The effect of intensive intermittent maintenance therapy in advanced low-grade non-Hodgkin's lymphoma. Cancer 60:156–160, 1987.[CrossRef][Medline] 9. Steward WP, Crowther D, McWilliam LJ, et al: Maintenance chlorambucil after CVP in the management of advanced stage, low-grade histologic type non-Hodgkin's lymphoma. A randomized prospective study with an assessment of prognostic factors. Cancer 61:441–447, 1988.[CrossRef][Medline] 10. Rohatiner AZ, Gregory WM, Peterson B, et al: Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 23:2215–2223, 2005. 11. Hochster H, Weller E, Gascoyne RD, et al: Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: Results of the randomized phase III ECOG 1496 study. J Clin Oncol 27:1607–1614, 2009. 12. Ghielmini M, Schmitz SF, Cogliatti SB, et al: Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event free survival and response duration compared with the standard weekly x 4 schedule. Blood 103:4416–4423, 2004. 13. Hainsworth JD, Litchy S, Shaffer DW, et al: Maximizing therapeutic benefit of rituximab: Maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma—A randomized phase II trial of the Minnie Pearl Cancer Res Network. J Clin Oncol 23:1088–1095, 2005. 14. van Oers MHJ, Klasa R, Marcus RE, et al: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin's lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 108:3295–3301, 2006. 15. Gordan LN, Grow WB, Pusateri A, et al: Phase II trial of individualized rituximab dosing for patients with CD20-positive lymphoproliferative disorders. J Clin Oncol 23:1096–1102, 2005. 16. Morschhauser F, Radford J, Van Hoof A, et al: Phase III trial of consolidation therapy with 90Y-ibritumomab tiuxetan after first remission in advanced follicular lymphoma. J Clin Oncol 26:5156–5164, 2008. 17. Oers MHJ, van Glabbeke M, Baila L, et al: Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: Long-term outcome of the EORTC 20981 phase III randomized Intergroup study. Blood, 112; 2008 abstr 836.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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