Editorials

Which Anti-CD20 Antibody Is Better in Follicular Lymphoma? James O. Armitage, M.D., and Dan L. Longo, M.D. Rituximab changed the treatment of patients with follicular lymphoma. When added to standard chemotherapy regimens, it increased the response rate and the complete remission rate.1,2 Rituximab has often been administered as maintenance therapy after a remission that was induced either by single-agent rituximab or by rituximab combined with standard chemotherapy drugs, and it has been shown to prolong the duration of remission.3,4 Since 2000, when rituximab became widely available, survival among patients with low-grade follicular lymphoma has increased from a median of approximately 10 years to a median of approximately 15 to 20 years.5,6 In this issue of the Journal, Marcus et al.7 report the use of a new anti-CD20 antibody, obinutuzumab, that was engineered to have a lower complement-dependent cytotoxicity but greater antibody-dependent cellular cytotoxicity and phagocytosis and greater direct B-cell killing. A randomized trial was undertaken of chemo­ immunotherapy induction followed by maintenance antibody therapy, comparing rituximab with obinutuzumab, to see whether the improved characteristics of obinutuzumab led to an improved antilymphoma effect without a higher risk of toxic effects. The authors found a similar overall response rate in the two groups and a marginally higher rate of complete response among patients who received rituximab (23.8%) than among those who received obinutuzumab (19.5%). However, the rate of progression-free survival at 3 years favored the patients receiving obinutuzumab (80.0%, vs. 73.3% in the rituximab group; P = 0.001). Adverse events of grade 3 or higher were more frequent among the patients receiving obinutuzumab than among those receiving rituximab (74.6% vs. 67.8%), but the risk of fatal toxic effects was similar in the two groups. Patients received obinutuzumab at a dose of 1000 mg, whereas those in the rituximab group received a dose of 375 mg per square meter of body-surface area. Thus, patients treated with obinutuzumab received a higher dose of the antibody. No evidence is presented that suggests that the antibodies differ in target affinity. This raises the question about whether there might have been a difference in outcome if rituximab

had been administered at the same dose as obinutuzumab. This is interesting, given that women benefited more from obinutuzumab than men did (hazard ratios for progression, relapse, or death with obinutuzumab vs. rituximab, 0.49 among women and 0.82 among men; P = 0.06 for interaction). The difference was less striking when patients’ weight and body-surface area were analyzed (Figs. S4 and S5 in the Supplementary Appendix of the article by Marcus et al., available at NEJM.org). Whether the better result in women was simply a dose effect or whether it could be related to more rapid clearance of obinutuzumab in men than in women, as has been reported for rituximab, 8 is unclear. Since there was no major difference in the response to the initial chemoimmunotherapy regimen regardless of the antibody used, the advantage of obinutuzumab in prolonging remission appears to be related to the maintenance treatment. This conclusion is undermined a bit by the allusion in the discussion by Marcus and colleagues to data not included in the article that patients who received obinutuzumab were more likely to have negative minimal residual disease status than were those who received rituximab.9 Minimal residual disease was assessed in a subgroup of patients, apparently a subgroup of convenience. Patients with detectable tumor cells in peripheral blood or bone marrow (or both) after induction chemotherapy were more likely to have a relapse than were those without such cells. Among patients in whom minimal residual disease status was assessed, patients who received obinutuzumab were somewhat more likely than those who received rituximab to have a negative minimal residual disease status at the end of induction therapy (94% vs. 89%).9 However, no data (as a function of treatment group) are provided about minimal residual disease levels after maintenance therapy or about relapse rates among patients who become negative for minimal residual disease at any point during treatment, as compared with those who do not. The authors do not make available the relative treatment outcomes according to the three induction chemotherapy regimens used — bendamustine plus antibody, CHOP (cyclophosphamide,

n engl j med 377;14 nejm.org  October 5, 2017

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Editorials

doxorubicin, vincristine, and prednisone) plus antibody, and CVP (cyclophosphamide, vincristine, and prednisone) plus antibody — except to note that the bendamustine regimen was more toxic. In previous studies, CHOP plus antibody has been shown to be superior to CVP plus antibody.10 The comparison of bendamustine plus rituximab with CHOP plus rituximab has led to conflicting results. One study showed that bendamustine plus rituximab was superior, but other studies have shown the regimens to be similar.11,12 Even so, bendamustine plus rituximab has become the more widely used treatment in the United States. In this regard, the increased death rate and the second cancers that were associated with the bendamustine-containing groups in this trial raise concern. It is also worrisome that the second hematologic cancers all occurred in the obinutuzumab-treated patients. The odds of randomly achieving a 6:0 ratio are 1 in 64 (0.015625), and the difference between the groups was significant (P = 0.03 by Fisher’s exact text). Both cases of the myelodysplastic syndrome also occurred in the obinutuzumab group. There were more toxic effects associated with the use of obinutuzumab than with the use of rituximab. This situation was related primarily to infusion reactions, an observation that confirms previous experience.13 However, the rate of fatal toxic effects was not significantly higher among patients receiving obinutuzumab than among those receiving rituximab. Should obinutuzumab replace rituximab as the standard antibody in the treatment of patients receiving chemoimmunotherapy regimens for follicular lymphoma? Results from this trial would suggest that there might be no advantage for an obinutuzumab-containing chemoimmunotherapy regimen if maintenance treatment was not planned. Even with maintenance therapy, there is no evidence from this trial of an overall survival benefit with obinutuzumab. These findings, combined with the higher rate of toxic effects and, presumably, the higher cost of obinutuzu­ mab, raise important questions regarding the advantage of its use. This issue is complicated further because it is possible that giving rituximab at a dose of 1000 mg might reduce or eliminate any difference in progression-free survival — that is, if the difference is primarily a dose effect. When the data on minimal residual disease are made available, the case in favor of obinutu1390

zumab may appear to be more compelling if indeed a higher proportion of patients who received obinutuzumab have minimal residual disease status at some point in treatment and remain in remission longer than those who received rituximab. At the moment, the competition between these agents looks too close to call. Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org. From the University of Nebraska, Omaha (J.O.A.). 1. 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 2008;​26:​4579-86. 2. Hiddemann W, Kneba M, Dreyling M, et al. Frontline ther­ apy 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 LowGrade Lymphoma Study Group. Blood 2005;​106:​3725-32. 3. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011;​377:​42-51. 4. Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label random­ ised phase 3 trial. Lancet Oncol 2014;​15:​424-35. 5. Swenson WT, Wooldridge JE, Lynch CF, Forman-Hoffman VL, Chrischilles E, Link BK. Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 2005;​23:​501926. 6. Armitage JO, Longo DL. Is watch and wait still acceptable for patients with low-grade follicular lymphoma? Blood 2016;​127:​ 2804-8. 7. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med 2017;​ 377:​1331-44. 8. Müller C, Murawski N, Wiesen MH, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood 2012;​119:​3276-84. 9. Pott C, Hoster E, Kehden B, et al. Minimal residual disease in patients with follicular lymphoma treated with obinutuzumab or rituximab as first-line induction immunochemotherapy and maintenance in the phase 3 GALLIUM study. Blood 2016;​128:​ Suppl:​613. abstract. 10. Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advancedstage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 2013;​31:​1506-13. 11. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013;​381:​1203-10. 12. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 2014;​ 123:​2944-52. 13. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;​370:​1101-10. DOI: 10.1056/NEJMe1706154 Copyright © 2017 Massachusetts Medical Society.

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The New England Journal of Medicine Downloaded from nejm.org on October 4, 2017. For personal use only. No other uses without permission. Copyright © 2017 Massachusetts Medical Society. All rights reserved.

Which Anti-CD20 Antibody Is Better in Follicular Lymphoma?

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