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The Uncertainties of Rituximab and Related Therapies, 20 Years After Approval

The Uncertainties of Rituximab and Related Therapies, 20 Years After Approval

Oncology (Williston Park). 31(5):412, 414.

Rituximab was first approved by the US Food and Drug Administration (FDA) in 1997 for the treatment of follicular lymphoma, and it eventually became broadly indicated for B-cell non-Hodgkin lymphomas.[1] Ofatumumab and obinutuzumab are newer anti-CD20 monoclonal antibodies that are also now FDA-approved in particular settings, specifically indolent disease. At least six additional anti-CD20 monoclonal antibodies are under investigation in non-Hodgkin lymphomas.[2] In this issue of ONCOLOGY, Drs. Reagan and Friedberg present a comprehensive review of the current indications, dosing strategies, and toxicities of rituximab, ofatumumab, and obinutuzumab in B-cell non-Hodgkin lymphomas and chronic lymphocytic leukemia (CLL).[3]

While much has been learned about rituximab over the past 20 years, there are still notable deficiencies in our knowledge. For example, we have not precisely defined the optimal dosing and remain uncertain about the dominant mechanism(s) of action of rituximab. Of particular interest in our changing healthcare environment is the role of rituximab biosimilars in B-cell lymphomas. We will focus on these key issues in this commentary.

The standard dosing of rituximab—375 mg/m2—was established in early trials, which found no dose-limiting toxicity or clear dose-response correlation.[4-6] The pharmacokinetics of rituximab vary depending on a number of factors, including sex, age, and weight. In diffuse large B-cell lymphoma (DLBCL), outcomes of elderly women treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) are superior to those of men; this has been postulated to be due to slower metabolism of the drug in females, who therefore experience a higher effective dose.[7,8] Elderly males with DLBCL who are given the same treatment appear to receive inadequate doses. Similar findings were reported in indolent B-cell lymphoma patients treated with rituximab plus chemotherapy. However, trials with single-agent weekly rituximab did not show a difference between women and men, possibly because more frequent dosing enabled the therapeutic threshold to be achieved.[9,10] Interestingly, doses of up to 2,250 mg/m2 of rituximab were tolerated in a dose-escalation trial in CLL, a finding that was also potentially consistent with a dose-response effect.[11] The clinical concern is that rituximab may be underdosed in a variety of settings and that obinutuzumab’s higher dosing and extended schedule may well be responsible for its improved clinical efficacy in the approved settings.

In contrast to newer targeted drugs, a robust biomarker of rituximab’s effect in patients with B-cell malignancies is not known. Although a reduction in lymphocyte count is often noted following rituximab treatment, this does not necessarily correlate with response to the drug. CD20 expression is usually maintained. As a result, patients with B-cell lymphomas typically receive rituximab at multiple points in the course of their disease—in contrast to chemotherapy agents, which often are deemed inactive after a time and are not repeated in the relapsed/refractory setting. For example, DLBCL patients who relapse after treatment with R-CHOP are subsequently treated with rituximab plus a second chemotherapy combination.[12] Because comparative clinical trials have been limited, it is not clear whether a higher dose of rituximab (such as 500 mg/m2, sometimes given in an attempt to penetrate the central nervous system[13]), would overcome resistance, if present, or whether use of a novel agent in the relapsed/refractory setting would be more appropriate.

What may prove to have the greatest impact on the use of anti-CD20 antibodies is the introduction of biosimilar products without clinically significant differences in safety or efficacy from the biologic products they resemble. Despite their close resemblance, biosimilars do not have the exact same structure as the original compound. Approval strategies require only that in vivo activity not be meaningfully affected by the structural difference. The introduction of rituximab biosimilars in the United States will coincide with the expiration of the patent on rituximab. The first such biosimilar to become available in the world was Reditux, introduced in India, which has increased access for patients sixfold.[14] Its cost is half that of rituximab; its toxicity is similar; and it was shown to be associated with equivalent overall survival and progression-free survival in DLBCL in a retrospective review.[15,16] Rituximab biosimilars are now also available in Russia, Argentina, and Mexico.[15] In the United States, it appears that biosimilars generally will not be required to rigorously show equivalent efficacy to the original compound; structural and functional similarity and clinical efficacy and safety may be adequate.[2] Furthermore, comparable efficacy and safety in one indication may be sufficient for a biosimilar to become approved for all indications. At least six rituximab biosimilars are in clinical trials for lymphoma; primary endpoints include overall response rate, safety, and pharmacokinetics.[2] Rituximab biosimilars may become widely used if approved, as has occurred with filgrastim biosimilars—although their availability also may result in a push for additional research if there is a perception that the efficacy of biosimilars is inferior to that of rituximab.

Along with the pertinent clinical questions raised by Drs. Reagan and Friedberg—including the appropriate antibody for treatment at various points in the course of the disease in patients with B-cell non-Hodgkin lymphomas or CLL, and the scheduling of extended treatment and maintenance—we advocate ongoing research to clarify the remaining unanswered questions regarding rituximab and other anti-CD20 agents. Given the benefit of rituximab to patients, it will be important that the use of biosimilar compounds not compromise the efficacy of treatment. However, measures to improve access to anti-CD20 therapy in a cost-effective manner (through use of biosimilars or otherwise) will clearly provide benefit to patients with lymphoma.

Financial Disclosure: Dr. Leonard has consulted for Genentech. Dr. Rutherford has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References

1. Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood. 1997;90:2188-95.

2. Rioufol C, Salles G. Biosimilar monoclonal antibodies in lymphoma: a critical appraisal. Expert Rev Anticancer Ther. 2015;15:569-78.

3. Reagan PM, Friedberg JW. Reassessment of anti-CD20 therapy in lymphoid malignancies: impact, limitations, and new directions. Oncology (Williston Park). 2017;31:402-11.

4. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116:2040-5.

5. Maloney DG, Liles TM, Czerwinski DK, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood. 1994;84:2457-66.

6. 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. 1998;16:2825-33.

7. Pfreundschuh M, Muller C, Zeynalova S, et al. Suboptimal dosing of rituximab in male and female patients with DLBCL. Blood. 2014;123:640-6.

8. Muller 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. Sawalha Y, Rouphail B, Jia X, et al. Is rituximab sub-optimally dosed in indolent B cell lymphoma? Br J Haematol. 2016;174:721-9.

10. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998;92:1927-32.

11. O’Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:2165-70.

12. Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184-90.

13. Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007;25:4730-5.

14. Qureshi ZP, Magwood JS, Singh S, Bennett CL. Rituximab and biosimilars—equivalence and reciprocity. Biosimilars. 2013;2013:19-25.

15. Pavanello F, Zucca E, Ghielmini M. Rituximab: 13 open questions after 20 years of clinical use. Cancer Treat Rev. 2017;53:38-46.

16. Roy PS, John S, Karankal S, et al. Comparison of the efficacy and safety of rituximab (Mabthera) and its biosimilar (Reditux) in diffuse large B-cell lymphoma patients treated with chemo-immunotherapy: a retrospective analysis. Indian J Med Paediatr Oncol. 2013;34:292-8.

 
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