Correspondence
Monoclonal Antibody Therapy and Non-Hodgkin's Lymphoma
N Engl J Med 2009; 360:192-193January 8, 2009
- Article
To the Editor:
In their review of monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma (Aug. 7 issue),1 Cheson and Leonard did not mention a potential cause of resistance to this treatment. Statins, by depleting cholesterol in the cell membrane, have been shown to diminish the antitumor effects of rituximab in vitro (as well as in a small exploratory study in vivo) by inducing conformational changes in CD20, resulting in reduced anti-CD20 binding.2 It is plausible that statins also induce changes in other surface antigens and likewise reduce the antitumor effects of other monoclonal antibodies. Physicians should be aware of this form of resistance, and suspend statin therapy during monoclonal antibody treatment of non-Hodgkin's lymphoma.
2 ReferencesMark R. Goldstein, M.D.
Fountain Medical Court, Bonita Springs, FL 34135
markrgoldstein@comcast.net Luca Mascitelli, M.D.
Comando Brigata Alpina “Julia”, 33100 Udine, ItalyFrancesca Pezzetta, M.D.
Ospedale di Tolmezzo, 33028 Tolmezzo, Italy1
Cheson BD ,Leonard JP . Monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma. N Engl J Med 2008;359:613-626
Full Text | Web of Science | Medline2
Winiarska M ,Bil J ,Wilczek E , et al. Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med 2008;5:e64-e64
CrossRef | Web of Science | Medline
To the Editor:
We are concerned about a safety issue in the use of rituximab-based immunochemotherapy in patients with B-cell non-Hodgkin's lymphoma and infection with either chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) (or serologic signs of previous contact with HBV virus). These infections are reportedly more prevalent in this group of patients than in the general population.1,2 Both severe HBV flares and progression to hepatic failure have been reported after the use of rituximab-based immunochemotherapy in patients with B-cell non-Hodgkin's lymphomas3 and HBV infection. Hepatitis flares have also been reported in patients with HCV infection and non-Hodgkin's lymphoma.4
Preemptive treatment of carriers of active or inactive HBV with nucleotide–nucleoside analogues (e.g., lamivudine, adefovir) reduces the incidence of hepatitis flares after treatment with rituximab.3,5 Such treatment should be strongly considered for patients who test positive for hepatitis B core antibody, negative for hepatitis B surface antibody, or positive for anti-hepatitis B surface antibody. There are no indications that HCV-related flares are associated with rituximab-based immunochemotherapy in patients with B-cell non-Hodgkin's lymphoma as these patients seem to follow a benign course, but biochemical surveillance is suggested.
5 ReferencesMassimo Marignani, M.D.
Stefano Angeletti, M.D.
Gianfranco delle Fave, M.D.
S. Andrea Hospital, 00189 Rome, Italy
mmarignani@hotmail.com 1
Gisbert JP ,Garcia-Buey L ,Pajares JM ,Moreno-Otero R . Prevalence of hepatitis C virus infection in B-cell non-Hodgkin's lymphoma: systematic review and meta-analysis. Gastroenterology 2003;125:1723-1732
CrossRef | Web of Science | Medline2
Marcucci F ,Mele A ,Spada E , et al. High prevalence of hepatitis B virus infection in B-cell non-Hodgkin's lymphoma. Haematologica 2006;91:554-557
Web of Science | Medline3
He YF ,Li YH ,Wang FH , et al. The effectiveness of lamivudine in preventing hepatitis B viral reactivation in rituximab-containing regimen for lymphoma. Ann Hematol 2008;87:481-485
CrossRef | Web of Science | Medline4
Ennishi D ,Terui Y ,Yokoyama M , et al. Monitoring serum hepatitis C virus (HCV) RNA in patients with HCV-infected CD20-positive B-cell lymphoma undergoing rituximab combination chemotherapy. Am J Hematol 2008;83:59-62
CrossRef | Web of Science | Medline5
Marzano A ,Angelucci E ,Andreone P , et al. Prophylaxis and treatment of hepatitis B in immunocompromised patients. Dig Liver Dis 2007;39:397-408
CrossRef | Medline
Author/Editor Response
Although we appreciate the information on statins provided by Goldstein et al., we believe that their recommendation to suspend the use of statins during therapy with rituximab is premature and could be dangerous. They base their suggestion on a single in vitro study in which B-cell lymphoma cells were incubated with statins, resulting in a decrease in antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity due to conformational changes in the CD20 target.1 Statins also interfered with the detection of CD20 on the B cells in that in vitro study, an occurrence that to our knowledge has not been validated in vivo with patients receiving statin therapy and rituximab.
The median age of patients with chronic lymphocytic leukemia and non-Hodgkin's lymphoma is 60 to 70 years; therefore, many patients with these disorders are in all likelihood also being treated with statins. The benefit of rituximab-based therapy has been shown in numerous clinical trials among all age groups with B-cell malignancies — such studies, with positive outcomes, undoubtedly included subjects who were also receiving statins. In the absence of clinical evidence of a deleterious effect of these agents on the efficacy of rituximab, a recommendation to discontinue a potentially beneficial therapy for cardiovascular disease is not justified in our view. Moreover, since the mechanisms of action of rituximab are not fully defined and may vary, depending on the context in which it is used, the relevance of the laboratory observation is unclear for individual patients. It would be useful to query large databases of patients who have been treated with rituximab and assess the outcomes among subgroups of patients who received lipid-lowering medications, even though this approach might be confounded by age and other coexisting conditions.
Moreover, in a recent study at the Mayo Clinic, investigators evaluated 293 patients in whom follicular lymphoma was newly diagnosed and 228 in whom diffuse large B-cell lymphoma was newly diagnosed; 19% of the former group and 22% of the latter were on statins at the time of diagnosis. The investigators were unable to find that statin therapy had a negative influence on the outcome for patients given chemotherapy with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone. Indeed, the use of statins during chemotherapy was associated with an improved, event-free outcome in the group with follicular lymphoma.2 Thus, we do not believe that currently available data support the recommendations of Goldstein et al., and in practice we would not generally modify statin therapy regimens in patients receiving rituximab.
The comments from Marignani et al. highlight the issue of potential flares of viral hepatitis after anti-CD20 therapy. Given the association of hepatitis B and hepatitis C with several B-cell malignancies, we agree that screening should be performed in this population and that preemptive therapy with appropriate antiviral agents and close monitoring be considered in carriers receiving anti-CD20 treatment.
2 ReferencesBruce D. Cheson, M.D.
Georgetown University Hospital, Washington, DC 20007John P. Leonard, M.D.
Weill Cornell Medical College, New York, NY 100211
Winiarska M ,Bil J ,Wilczek E , et al. Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med 2008;5:e64-e64
CrossRef | Web of Science | Medline2
Nowakowski GS ,Maurer MJ ,Habermann TM , et al. Statin use and prognosis with follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL). Blood 2008;112:219-219
CrossRef | Web of Science | Medline
- Citing Articles (5)
Citing Articles
1
Yu Xuan Koo, Daniel S. W. Tan, IAIN B. H. Tan, David W. M. Tai, Tam Ha, Whee Sze Ong, Richard Quek, Miriam Tao, Soon Thye Lim. (2011) Effect of concomitant statin, metformin, or aspirin on rituximab treatment for diffuse large B-cell lymphoma. Leukemia & Lymphoma 52:8, 1509-1516
CrossRef2
Panagiotis Samaras, Helen Heider, Sarah R. Haile, Ulf Petrausch, Niklaus G. Schaefer, Raffaele Daniele Siciliano, Alexander Meisel, Axel Mischo, Martin Zweifel, Alexander Knuth, Frank Stenner-Liewen, Christoph Renner. (2010) Concomitant statin use does not impair the clinical outcome of patients with diffuse large B cell lymphoma treated with rituximab-CHOP. Annals of Hematology 89:8, 783-787
CrossRef3
Tait D. Shanafelt, Kari G. Rabe, Neil E. Kay, Clive S. Zent, Timothy G. Call, Susan L. Slager, Deborah A. Bowen, Susan M. Schwager, Grzegorz S. Nowakowski. (2010) Statin and non-steroidal anti-inflammatory drug use in relation to clinical outcome among patients with Rai stage 0 chronic lymphocytic leukemia. Leukemia & Lymphoma 51:7, 1233-1240
CrossRef4
D. Ennishi, H. Asai, Y. Maeda, K. Shinagawa, K. Ikeda, M. Yokoyama, Y. Terui, K. Takeuchi, T. Yoshino, K. Matsuo, K. Hatake, M. Tanimoto. (2010) Statin-independent prognosis of patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP therapy. Annals of Oncology 21:6, 1217-1221
CrossRef5
B. Li, L. Zhao, H. Guo, C. Wang, X. Zhang, L. Wu, L. Chen, Q. Tong, W. Qian, H. Wang, Y. Guo. (2009) Characterization of a rituximab variant with potent antitumor activity against rituximab-resistant B-cell lymphoma. Blood 114:24, 5007-5015
CrossRef
