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Originally published as JCO Early Release 10.1200/JCO.2005.09.924 on January 18 2005 © 2005 American Society of Clinical Oncology.
Optimizing Rituximab in B-Cell LymphomaStanford Cancer Center, Stanford University, Stanford, CA
Along came an anti-CD20 In this issue of the Journal of Clinical Oncology, three groups1-3 report their results with rituximab monotherapy in B-cell lymphoma. Following the approximately 50% response rate in recurrent or refractory indolent lymphoma reported in the pivotal trial, investigators have studied alternate dosing schedules in untreated and previously treated patients and have proposed both host and tumor characteristics that may predict the quality of response.4-10 How are the reports in the current issue of the Journal informative for current practice and clinical investigations? Witzig et al1 administered four weekly rituximab infusions to 36 previously untreated, follicular grade 1 lymphoma patients who, in their judgment, required no immediate therapy. Although the primary objective was to estimate the response rate, an important secondary end point was the time to initiating chemotherapy after rituximab treatment. The alternative of rituximab to the conservative approach of observation alone as initial management for selected patients may be considered advantageous if quality of life is improved or if the time to requiring chemotherapy is prolonged. The overall response rate in the North Central Cancer Treatment Group study was 72%, with a median time to progression of 2.2 years from registration—longer than previously reported in treatment-naive patients. The time to subsequent chemotherapy was, however, unexpectedly brief, at just 2.3 years after rituximab or approximately 2.4 years after registration. In two prior randomized phase III studies comparing observation to immediate therapy, time to initiating treatment was 2 and 2.4 years, respectively, after initial observation.11,12 In the study by Brice et al, the time to treatment failure was 3.6 years following 3 months of initial interferon alfa. Clearly, it can be hazardous to draw conclusions from a small patient sample, as reported by Witzig et al, in a disease as heterogeneous as follicular lymphoma. Perhaps these patients had more biologically aggressive disease than predicted at diagnosis, or perhaps the treating physicians had a lower threshold for administering chemotherapy, as the North Central Cancer Treatment Group did not establish standard criteria for initiating chemotherapy. It is also important to recall that the time to progression or time to initiating chemotherapy may be as much a function of the underlying biology of indolent lymphoma as the effect of prior treatment. Finally, the potential therapeutic benefit of rituximab was not maximized by the study design used by Witzig et al, which did not include re-treatment of responding patients. Previously, a 40% response rate was reported in follicular lymphoma patients with disease progression after initial response to rituximab and were subsequently re-treated weekly for 4 weeks.13 The goal, therefore, of rituximab monotherapy might then be best expressed as prolonging the time to requiring alternate therapy, allowing for rituximab re-treatment. Hainsworth et al2 studied this end point in a prospective trial in previously treated, but rituximab-naive, indolent B-cell lymphoma patients. The trial was a randomized phase II study, in which patients received four weekly rituximab infusions, with assessment of response at 6 weeks and random assignment of stable or responsive patients to maintenance rituximab delivered as four weekly treatments every 6 months, for a maximum of four courses or re-treatment (standard 4-week course) on disease progression. The purpose of this type of study is to evaluate various approaches so that the most promising can be selected for further study. Randomized phase II studies do not have adequate statistical power for definitive treatment comparisons, but seek to estimate treatment effect and toxicity in each arm, without patient selection bias. The primary study end point, duration of rituximab benefit as defined by the administration of alternative treatment, was not different between the two approaches in this trial. However, these results are only estimates, and imbalances in histology and the number of patients progressing before either maintenance or re-treatment may have influenced the results. In addition, rituximab benefit was based on a subjective end point—the requirement for alternate therapy—rather than an objective definition of response or duration of response. As in the Witzig et al study, the criteria for requiring alternate therapy were left to physician discretion, which likely varied among the physicians in the 25 practice groups treating these 90 patients. The longer time to progression with extended rituximab observed in the Minnie Pearl study is consistent with the authors' prior study in untreated indolent lymphoma patients and in the randomized trial results of standard course compared with extended rituximab, published by Ghielmini et al.4,11 However, because rituximab "re-treatment" was not allowed for patients progressing after the completion of extended or maintenance therapy in any of these trials, the optimal duration of rituximab was not definitively assessed. A 6-month interval between rituximab treatments may have been too long, or the period of maintenance, too brief. Gordan et al3 utilized rituximab pharmacokinetics to define the dosing interval between rituximab treatments for a series of B-cell lymphoma patients with disease that had recurred after chemotherapy. This study resulted in the important observation that rituximab resistance was not regularly associated with lower serum antibody levels. Although the choice of a 25-µg/mL serum level may be considered arbitrary, the investigators were able to define a dosing interval of 3 months to achieve this steady-state level in the majority of patients. With the pharmacokinetic-based dosing interval utilized in this study throughout a 12-month period, 95% of patients required three or fewer infusions to be maintained in the target range. The efficacy of the approach in this study, however, is difficult to judge based on the small sample size and the inclusion of multiple histologic subtypes, both indolent and aggressive. How do these three trials affect current practice? Rituximab monotherapy is effective and safe in patients with indolent follicular lymphoma, both at diagnosis and at progression after prior therapy. Studies in untreated patients have selected either asymptomatic patients with low tumor burden or those not in need of a treatment response. The relatively poor performance of rituximab in follicular grade 1 patients with an elevated lactate dehydrogenase in the North Central Cancer Treatment Group study suggests that rituximab monotherapy should be limited to a favorable subset of follicular lymphoma patients. Until more data are available, the Hainsworth et al study suggests that re-treatment at progression results in a prolonged duration of rituximab benefit, free from requiring alternate therapy that is not different from maintenance therapy and with less cost to the health care system. Is it still appropriate to observe asymptomatic patients with low-grade lymphoma in light of these data? Although patient preferences and physician judgment may determine the answer to this question, rituximab does present a far less toxic alternative to chemotherapy for patients who are not comfortable with being observed without treatment. It is disappointing that Witzig et al found that the median time to subsequent chemotherapy after initial rituximab was not longer than that reported in prior studies with initial deferral of therapy. However, the unexpectedly close approximation of the time to progression after rituximab, to the initiation of subsequent chemotherapy, may have been unique to physician practice or patient preferences in this study. Delaying the onset of chemotherapy remains an important goal for selected follicular lymphoma patients. This end point, with defined criteria for initiating chemotherapy, is being assessed in an ongoing phase III European trial that compares rituximab monotherapy to observation in low-risk patients. The three studies in this issue of the Journal strengthen the rationale for physicians to participate in ongoing trials seeking to optimize rituximab therapy through careful clinical investigations, paired with important biologic correlates. Investigators in the Eastern Cooperative Oncology Group are comparing a rituximab-extended schedule with a re-treatment strategy (the RESORT trial, E4402) for low-tumor burden follicular lymphoma. The clinical end point is time to rituximab resistance, defined as no response or progression within 6 months. After a standard rituximab induction, patients are randomly assigned to a single infusion at 12-week intervals, based on the data of Gordan et al, continued in an open-ended administration schedule until disease progression or re-treatment. Other investigators are seeking to determine if rituximab maintenance, with treatment intervals similar to those suggested by the data from Gordan et al, adds value after chemotherapy plus rituximab induction, or if the addition of rituximab to chemotherapy as second-line treatment adds value after failure of initial rituximab monotherapy.
Although the three studies in this issue of the Journal provide valuable information regarding the use of rituximab, many questions remain. Preliminary data from cDNA microarrays suggest that gene expression may differ in lymphomas responsive to rituximab monotherapy.4 Informative data have emerged from Fc- The practical issue today is how to integrate rituximab in follicular lymphoma treatment: before chemotherapy, in combination with chemotherapy, as a maintenance treatment after chemotherapy, or reserved for management of recurrent disease (the approved indication)? As practitioners, we recognize the heterogeneity of follicular lymphoma and use clinical clues, based on experience or on more formally proposed prognostic schemes such as the follicular lymphoma international prognostic index, to make management recommendations.17 For low-tumor burden patients, observation remains the conservative standard, but rituximab can provide a less toxic therapeutic intervention for those who do not wish to wait, preferably in the context of a clinical trial such as E4402. Neither observation nor rituximab is a good option for symptomatic patients or for those with higher-risk presentations. Interpretation of the results reported in the three studies in this issue of the Journal is limited due to small sample sizes and patient heterogeneity. Exciting data were reported in December 2003 from the Leukemia Lymphoma Myeloma Profiling Project, in which the gene signatures at diagnosis in follicular lymphoma correlated with overall survival, challenging the paradigm of stochastic, ongoing genetic damage in this disorder.18 If we can utilize molecular diagnostics to predict long-term survival for follicular lymphoma, the efficacy of numerous therapeutic options, such as rituximab, combination chemotherapy, radioimmunotherapy, or autologous or allogeneic transplantation can be defined in biologic subsets in future clinical investigations, to ultimately lead to new therapeutic algorithms for clinical practice. Patients who consent to both tissue acquisition and clinical trials, and oncologists who commit to continuous therapeutic progress will be required to fully translate these important new data to optimize therapy for follicular lymphoma. Author's Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Sandra J. Horning, Biogen IDEC, Genentech, Roche. Honoraria: Sandra J. Horning, Biogen IDEC, Genentech, Roche. Research Funding: Sandra J. Horning, Genentech. Other Remuneration: Sandra J. Horning, Genentech, Roche. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue. REFERENCES
1. Witzig TE, Vukov AM, Habermann TM, et al: Rituximab therapy for patients with newly diagnosed, advanced-stage follicular grade I non-Hodgkin's lymphoma: A phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 23:1103-1108, 2005
2. 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 Research Network. J Clin Oncol 23:1088-1095, 2005
3. 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
4. Bohen SP, Troyanska OG, Alter O, et al: Variation in gene expression patterns in follicular lymphoma and the response to rituximab. Proc Natl Acad Sci U S A 100:1926-1930, 2003
5. Cartron G, Dacheux L, Salles G, et al: Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99:754-758, 2002
6. 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
7. Hainsworth JD, Litchy S, Burris HA 3rd, et al: Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma. J Clin Oncol 20:4261-4267, 2002 8. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract]
9. Piro LD, White CA, Grillo-Lopez AJ, et al: Extended rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Ann Oncol 10:655-661, 1999
10. Weng WK, Levy R: Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21:3940-3947, 2003
11. Brice P, Bastion Y, Lepage E, et al: Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: A randomized study from the Groupe d'Etude des Lymphomes Folliculaires—Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 15:1110-1117, 1997 12. Ardeshna KM, Smith P, Norton A, et al: Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: A randomised controlled trial. Lancet 362:516-522, 2003[CrossRef][Medline] 13. Davis T, Grillo-Lopez AJ, White CA, et al: Retreatments with Rituxan (rituximab, IDEC-C2B8) have significant efficacy, do not cause HAMA, and are a viable minimally toxic alternative in relapsed or refractory non-Hodgkin's lymphoma. Blood 90:509a, 1997 14. Marcus R, Imrie K, Belch A, et al: An international multi-centre, randomized, open-label, phase III trial comparing rituximab added to CVP chemotherapy to CVP chemotherapy alone in untreated stage III/IV follicular non-Hodgkins lymphoma. Blood 102:28a, 2003 (abstr 87) 15. Hiddemann W, Dreyling M, Forstpointner R, et al: combined immuno-chemotherapy (R-Chop) significantly improves time to treatment failure in first line therapy of follicular lymphoma results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). Blood 102:104a, 2003 (abstr 352) 16. Hochster HS, Weller E, Ryan T, et al: Results of E1496: A phase III trial of CVP with or without maintenance rituximab in advanced indolent lymphoma. Proc Am Soc Clin Oncol 22:6502, 2003 (abstr)
17. Solal-Celigny P, Roy P, Colombat P, et al: Follicular lymphoma prognostic index. Blood 104:1258-1265, 2004 18. Dave SS, Wright G, Tan B, et al: A molecular predictor of survival following diagnosis of follicular lymphoma. Blood 2003 102:617 (abstr)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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receptor polymorphisms that correlate with the quality and duration of response to rituximab monotherapy.
