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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by van der Kolk, L. E. Articles by van Oers, M. H. J. Search for Related Content PubMed PubMed Citation Articles by van der Kolk, L. E. Articles by van Oers, M. H. J. Related Collections Immunobiology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 September 2002, Vol. 100, No. 6, pp. 2257-2259 BRIEF REPORT Rituximab treatment results in impaired secondary humoral immune responsiveness Lizet E. van der Kolk, Joke W. Baars, Martin H. Prins, and Marinus H. J. van Oers From the Department of Hematology and the Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, and the Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands.     Abstract Top Abstract Introduction Study design Results and discussion References In lymphoma patients, treatment with chimeric CD20 monoclonal antibodies (rituximab) results in a depletion of normal and malignant B cells, persisting for 6 to 9 months. This B-cell depletion leads neither to a decrease in immunoglobulin levels nor an increase in the number of infectious complications. However, the effect of rituximab treatment on the immune responsiveness is unknown. In 11 patients with relapsed, low-grade lymphoma, we investigated the effect of rituximab treatment on the humoral immune response to 2 primary antigens and 2 recall antigens. After rituximab treatment, the humoral immune response to the recall antigens was significantly decreased when compared with the response before treatment. Already before rituximab treatment, none of these patients was able to mount a response to the primary antigens. These findings are relevant regarding the feasibility of rituximab in maintenance treatment and may also offer a rationale for the treatment of antibody-mediated autoimmune diseases with rituximab. (Blood. 2002;100:2257-2259) © 2002 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Rituximab, the chimeric CD20 monoclonal antibody (mAb), has become an important treatment modality in B-cell malignancies.1,2 It targets the CD20 antigen, expressed on more than 95% of normal and malignant B cells. In patients with relapsed, low-grade non-Hodgkin lymphoma (NHL), peripheral blood B-cell depletion occurred within 24 to 48 hours after the first infusion of rituximab. Recovery of B-cell counts started 6 to 9 months after the completion of therapy, and normal levels were obtained after 9 to 12 months.1 The prolonged period of rituximab-induced B-cell depletion might compromise the immune system. However, no studies directly addressing the immune responsiveness of patients treated with rituximab have been published. We investigated the humoral immune responses of patients with low-grade lymphoma to 2 primary antigens (keyhole limpet hemocyanin [KLH] and hepatitis A vaccine [HAV]) and 2 recall antigens (tetanus toxoid [TT] and poliomyelitis vaccine [PV]), both before and after treatment with rituximab.     Study design Top Abstract Introduction Study design Results and discussion References Patients The present immunization study was part of a phase I/II study evaluating the safety and efficacy of the combination of rituximab (375 mg/m2 weekly for 4 weeks) and granulocyte-colony-stimulating factor (G-CSF; 5 µg/kg per day, administered on 3 consecutive days starting 2 days before each infusion).3 Inclusion criteria for the immunization study were those of the phase II study. Both studies were approved by the ethics committee, and all patients gave written informed consent according to the rules of the institute. Antigen One thousand micrograms KLH (Calbiochem, San Diego, CA; dissolved in NaCl as described previously4) was administered subcutaneously. HAV (1440 IE of inactivated hepatitis A virus strain HM-175; Havrix) was obtained from SmithKline Beecham (Rijswijk, The Netherlands) and administered intramuscularly. TT (0.5 mL tetanus vaccine containing 80 IE/mL tetanus toxoid) and inactivated PV (type 1, at least 30 DE [PV1]; type 2, at least 6 DE [PV2]; type 3, at least 24 DE [PV3]) were obtained from the RIVM (Utrecht, The Netherlands) and were administered intramuscularly and subcutaneously, respectively. Measurement of antibody titers Anti-KLH-specific immunoglobulin levels (IgG) and anti-TT antibodies were measured with an enzyme-linked immunosorbent assay (ELISA).4 Anti-hepatitis A virus-specific IgG levels were measured by ELISA (HAVAB 2.0 Quantitative; Abbott Laboratories, Diagnostics, Abbott Park, IL). Titers of neutralizing antibodies against PV1, PV2, and PV3 were measured by the poliovirus-neutralizing antibody test.5 For KLH, a positive response was defined as a ratio of IgG antibodies (after immunization versus before immunization) greater than 1.25.4 Seroconversion to HAV was defined as an increase in HAV titers to more than 20 mIU/mL.6 Immunization schedule Because it was expected that this group of patients with pretreated low-grade lymphoma would have impaired immune responsiveness when compared with healthy volunteers,7,8 it was considered more appropriate to use the patients as their own controls. To avoid boosting effects (ie, turning a primary antigen into a recall antigen and inappropriately amplifying recall responses), in each patient different vaccines were needed for the immunizations performed before and after rituximab treatment. Therefore, 2 primary antigens (KLH and HAV) and 2 recall antigens (TT and PV) were used. Each patient simultaneously received one primary and one recall antigen 2 weeks before treatment and crossed over to the other 2 vaccines 4 weeks after treatment. To correct for a possible influence of one of the vaccines on the response to the other vaccines, 4 different immunization schedules had to be used (Table 1). Patients were sequentially assigned to 1 of the 4 groups. Before immunization and 2 weeks after immunization, serum samples were collected and stored at 20°C until use. Pretreatment immunizations were performed during the necessary pretreatment work-up. Therefore, the start of rituximab treatment was not delayed in any of the patients.                                View this table: [in this window] [in a new window]   Table 1. Immunizations received by each patient Statistics Antibody responses are expressed as the ratio between the antibody titers 14 days after immunization and those before immunization. To compare the responses to the 2 different primary antigens and recall antigens within one patient, for each vaccine the ratios of antibody responses were ranked. Each of the patients received a rank obtained for his or her response to, for example, TT (independent of the moment of immunization, before or after rituximab treatment), and a rank was obtained for his or her response to PV. The rank a patient obtained before rituximab (eg, for TT) and the rank that this same patient obtained after rituximab (for PV1, PV2, and PV3, or vice versa) formed pairs. The pairs of ranks achieved by all patients were analyzed using the Wilcoxon signed rank test. P <.05 was considered significant.     Results and discussion Top Abstract Introduction Study design Results and discussion References Patients All patients had progressive disease at the time of first immunization. Median age was 53 years (range, 27-70 years), and the median number of prior chemotherapy regimens was 1 (range, 1-3). Not every patient received all 4 immunizations because of various reasons (Table 1). Effect of rituximab treatment on peripheral blood B-cell counts and immunoglobulin levels In all patients, complete depletion of B cells from the peripheral blood was observed 72 hours after the first infusion. One month after the last rituximab treatment (ie, at time of second immunization), B cells were still absent in all but one patient (patient H). Immunoglobulin levels (IgG, IgA, and IgM) remained stable during treatment and follow-up (data not shown). Response to recall antigens Nine patients were immunized with TT and PV. Antibody responses, expressed as the ratio of titers before and after immunization, are shown in Table 2. To allow for comparison of the responses to TT and PV within one patient, ratios to TT and ratios to PV were ranked (Table 2). Responses to the poliovirus subtypes PV1, PV2, and PV3 are separately documented and analyzed in combination with TT. For example, the 3 pairs of ranks obtained by patient A were 9-2, 9-2, and 7-2 for PV1-TT, PV2-TT, and PV3-TT, respectively.                                View this table: [in this window] [in a new window]   Table 2. Immune responses to recall antigens Pairs of ranks obtained by each patient were analyzed using the Wilcoxon signed rank test (n = 9 paired samples). The response to recall antigens after rituximab treatment was significantly lower than the response before treatment (P = .078, P = .013, and P = .012 for TT in combination with PV1, PV2, and PV3, respectively). Primary immune responses In 11 patients the primary immune response could be evaluatedin 5 patients before and in 6 patients after rituximab treatment (Table 1). None of these patients developed a humoral immune response to either primary antigen before or after rituximab treatment (data not shown). Five patients were found to have high anti-HAV antibody titers, indicating that these patients either had experienced hepatitis A infection or had been immunized against hepatitis A. In the present study, we have demonstrated that the humoral immune response to recall antigens decreases significantly with rituximab treatment. Surprisingly, although all patients responded to recall antigens, none of the patients responded to the primary antigens before or after rituximab treatment. At time of vaccination, all patients had progressive disease requiring treatment. Disease status at the time of vaccination might explain this strongly impaired immune response to primary antigens observed in our patients.9 The observed significantly decreased response to recall antigens after rituximab treatment might be attributed to a decrease in the amount of memory B cells after rituximab treatment. Previous studies showed that although rituximab treatment induces B-cell depletion for 6 to 9 months, this does not lead to a decrease in immunoglobulin levels, possibly because of the presence of long-lived plasma cells.10 However, our observation predicts that prolonged treatment with rituximab may eventually lead to a decrease in circulating plasma cells because of a decreased replenishment from the pool of memory B cells. This might have consequences for the immunoglobulin levels and, consequently, the incidence of infectious complications during rituximab maintenance therapy. Recently, rituximab treatment was found to be effective in several antibody-mediated autoimmune diseases,11,12 with some responses ongoing for more than 9 to 14 months.12 We suggest that rituximab, by depleting (memory) B cells, interrupts the ongoing humoral autoimmune response in autoimmune diseases. Although plasma cells surviving rituximab treatment may continue to produce (auto-)antibodies for a certain period of time, deletion of the autoreactive B-cell clone eventually leads to a decrease in antibody production. Our data might have implications for studies investigating the feasibility of rituximab as maintenance therapy. Furthermore, these findings provide a rationale for the treatment of antibody-mediated autoimmune diseases with rituximab.     Acknowledgments We thank Dr T. Out and Prof Dr R.A.W. van Lier for critical reading of the manuscript and for helpful discussions and F. de Wilde for measurements of KLH- and tetanus-specific antibodies by ELISA.     Footnotes Submitted June 18, 2001; accepted May 8, 2002. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: M. H. J. van Oers, Academic Medical Center, Department of Internal Medicine, F4-222, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; e-mail: m.h.vanoers{at}amc.uva.nl.     References Top Abstract Introduction Study design Results and discussion References 1. McLaughlin P, Grillo-López A, 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;16:2825-2833[Abstract]. 2. McLaughlin P. Rituximab: perspective on single agent experience, and future directions in combination trials. Crit Rev Oncol Hematol. 2001;40:3-16[Medline] [Order article via Infotrieve]. 3. van der Kolk LE, Grillo-López A, Gerritsen W, Baars JW, van Oers MHJ. Chimeric anti-CD20 monoclonal antibody (rituximab) plus G-CSF in relapsed B-cell lymphoma: a phase I/II clinical trial [abstract]. Blood. 1998;92:4037. 4. Korver K, Zeijlemaker WP, Schellekens PT, Vossen JM. Measurement of primary in vivo IgM- and IgG-antibody response to KLH in humans: implications of pre-immune IgM binding in antigen-specific ELISA. J Immunol Methods. 1984;74:241-251[CrossRef][Medline] [Order article via Infotrieve]. 5. Albrecht P, van Steenis G, van Wezel A, Salk J. Standardization of poliovirus neutralizing antibody tests. Rev Infect Dis. 1984;6(suppl 2):S540-S544[Medline] [Order article via Infotrieve]. 6. Victor J, Knudsen JD, Nielsen LP, et al. Hepatitis A vaccine: a new convenient single-dose schedule with booster when long-term immunization is warranted. Vaccine. 1994;12:1327-1329[CrossRef][Medline] [Order article via Infotrieve]. 7. King GW, Yanes B, Hurtubise PE, Balcerzak SP, LoBuglio AF. Immune function of successfully treated lymphoma patients. J Clin Invest. 1976;57:1451-1460[Medline] [Order article via Infotrieve]. 8. Gast GC, Halie MR, Nieweg HO. Immunological responsiveness against two primary antigens in untreated patients with Hodgkin's disease. Eur J Cancer. 1975;11:217-224[Medline] [Order article via Infotrieve]. 9. Hsu FJ, Caspar CB, Czerwinski D, et al. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma: long-term results of a clinical trial. Blood. 1997;89:3129-3135[Abstract/Free Full Text]. 10. Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity. 1998;8:363-372[CrossRef][Medline] [Order article via Infotrieve]. 11. Ratanatharathorn V, Carson E, Reynolds C, et al. Anti-CD20 chimeric monoclonal antibody treatment of refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease. Ann Intern Med. 2000;133:275-279[Abstract/Free Full Text]. 12. Perrotta A, Sunneberg T, Scott J, et al. Rituxan in the treatment of chronic idiopathic thrombocytopenic purpura (ITP) [abstract]. 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[Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by van der Kolk, L. E. Articles by van Oers, M. H. J. Search for Related Content PubMed PubMed Citation Articles by van der Kolk, L. E. Articles by van Oers, M. H. J. Related Collections Immunobiology Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?

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