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Journal of Clinical Oncology, Vol 25, No 22 (August 1), 2007: pp. 3350-3356 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.6732 Prospective Study of Rituximab in Chemotherapy-Dependent Human Immunodeficiency Virus–Associated Multicentric Castleman's Disease: ANRS 117 CastlemaB Trial
From the Departments of Clinical Immunology, Pathology, and Infectious Diseases, Pharmacy, Laboratory of Virology, Paris VII University; Department of Biostatistics, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris; Department of Infectious Diseases, Hôpital Purpan, Toulouse; Department of Infectious Diseases, Hôpital Hôtel-Dieu, Clermont-Ferrand; and Department of Internal Medicine, Hôpital Côte de Nacre, Caen, France Address reprint requests to Laurence Gérard, MD, Département d'Immunologie Clinique, Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, 75010 Paris, France; e-mail: laurence.gerard{at}sls.aphp.fr
Purpose: Single-agent chemotherapy is usually effective in HIV-associated multicentric Castleman's disease (MCD). However, in most patients, chemotherapy cannot be discontinued. Patients and Methods: To evaluate the efficacy of four weekly rituximab infusions (375 mg/m2) after discontinuation of chemotherapy in HIV-associated MCD, 24 patients were enrolled onto a prospective open-label trial. Results: At study entry, the median time from MCD diagnosis was 21 months. All patients had stable disease on chemotherapy and were dependent on chemotherapy for a median time of 13 months. The median CD4 cell count was 270 x 106/L, and the plasma HIV RNA was less than 50 copies/mL in 18 patients. One patient died with progressive disease at day 15, and 23 patients completed the four cycles of rituximab. Sustained remission (SR) off treatment at day 60 (primary end point) was achieved in 22 patients (92%). From day 60 to day 365, one patient died with acute respiratory failure of undetermined origin, and four patients experienced relapse. Seventeen patients (71%) were alive in SR at day 365 without specific treatment, and the overall survival rate was 92% (95% CI, 71% to 98%). Rituximab was well tolerated, and the majority of adverse events were mild to moderate infections. Mild exacerbation of Kaposi's sarcoma (KS) lesions was observed in eight of 12 patients with previous KS. Conclusion: Rituximab was both effective and safe in HIV-infected patients with chemotherapy-dependent MCD.
In the context of HIV infection, multicentric Castleman's disease (MCD) is an uncommon but often fatal lymphoproliferative disorder associated with human herpesvirus 8 (HHV-8) infection.1-3 Clinical course is characterized by recurrent attacks with systemic symptoms associated with high serum C-reactive protein level and high HHV-8 viral load in peripheral-blood mononuclear cells (PBMCs).1 Diagnosis is based on pathologic examination of lymphadenopathy or spleen showing hyalinized atrophic germinal centers associated with vascular hyperplasia and plasma cell infiltration in the interfollicular area. Kaposi's sarcoma (KS) is often associated with MCD.2 The clinical course can be self-limited at the onset of the disease, but most patients die with active MCD or evolution towards HHV-8–associated non-Hodgkin's lymphoma (NHL).3 No standard of care has been established for the treatment of MCD. Resolution of systemic symptoms can be achieved with single-agent low-dose chemotherapy (etoposide or vinblastine).2 However, interruption of chemotherapy is usually associated with clinical recurrence, and most patients remain chemotherapy dependent for life.2,4 Several strategies have been used to avoid long-term toxicity of chemotherapy. Although combination antiretroviral therapy (cART) has dramatically decreased the incidence of KS, MCD may still develop in patients with controlled HIV replication.5-7 Splenectomy,2,8 corticosteroids,2,9 antiherpesvirus drugs,10,11 and monoclonal anti–interleukin-6 receptor antibody only have transient efficacy.12 Interesting results have been published concerning rituximab therapy, a specific monoclonal antibody directed against the CD20 B-cell antigen.13 In HIV-associated MCD, HHV-8 infects mu/lambda-restricted plasmablasts located in the mantle zone. These cells variably express the CD20 surface antigen.14,15 On the basis of case reports and short series, rituximab was effective in eight of 12 HIV-infected patients with MCD.13-18 In the largest series, three of five patients achieved complete remission with a follow-up time of 4 to 14 months, and two patients died with progressive disease.14 In two other patients, rituximab was used as a single-agent therapy in patients with active symptomatic disease and failed to induce long-term response.19 Overall, the efficacy of rituximab remains uncertain when used in active MCD. We report on a prospective multicenter clinical trial assessing the efficacy of rituximab to induce sustained remission (SR) after discontinuation of chemotherapy in patients with chemotherapy-dependent HIV-associated MCD.
Patients Eligible patients were 18 years of age or older, infected with HIV (regardless of their immunovirologic status), and treated by cART without modification during the last 3 months; patients could have had no prior treatment with rituximab. All patients were required to have biopsy-proven MCD. All diagnostic biopsy specimens were reviewed by a single pathologist (V.M.). Patients were required to have chemotherapy-dependent MCD; they should have been treated with chemotherapy for at least 3 months with clinical response and should have experienced at least one recurrence of MCD attack after attempt to discontinue chemotherapy. Patients were not eligible if they had active MCD (Table 1), lymphoma, active KS, or opportunistic infection requiring specific treatment at the time of inclusion.
Study Design This study was an open-label, phase II study designed to assess the efficacy and safety of rituximab therapy for chemotherapy-dependent patients with HIV-associated MCD after discontinuation of chemotherapy. The study was carried out in accordance with the Declaration of Helsinki and was approved by the local ethical board. All patients provided written informed consent. Study oversight was provided by an independent data and safety monitoring board. All patients were enrolled for a period of 365 days. The study was divided into two periods, an initial period from inclusion to day 60 and an extended period until day 365.
Patient Monitoring
Treatment
Virologic Analysis
End Points and Response Criteria Secondary outcomes included persistence of SR at day 365, disease- and event-free survival, overall survival, occurrence of lymphoma, occurrence or exacerbation of KS, safety of rituximab, and evolution of HHV-8 viral load and of B-lymphocyte count.
Statistical Analysis
Patient Characteristics A total of 24 patients (21 men and three women) were enrolled between March 2003 and December 2004 in 10 centers. The study investigators are listed in the Appendix (online only). Median age at enrollment was 43.5 years (range, 21 to 65 years). At study entry, the median duration of HIV infection was 3 years (range, 0.4 to 20.1 years), with a median CD4 cell count of 270 x 106/L (range, 24 to 1,325 x 106/L), and 18 patients had plasma HIV RNA of less than 50 copies/mL. Sixteen patients had experienced an AIDS-defining condition, including NHL in one patient and KS in 12 patients. KS was in complete remission or stable at study entry. All patients received cART for a median duration of 2 years (range, 0.3 to 5.3 years). The median time from MCD diagnosis to enrollment was 21 months (range, 4.1 to 142 months). The median duration on chemotherapy was 13.2 months (range, 3.6 to 107 months), with a median of three prior different chemotherapy regimens. The patients were all chemotherapy dependent, with one to 14 MCD attacks after attempt to discontinue chemotherapy. Therapy received by the patients at inclusion was etoposide in 18 patients, vinblastine in four patients, and liposomal doxorubicin in two patients. In addition, 11 patients had been splenectomized without sustained response. The baseline characteristics of the 24 patients are listed in Table 2.
At study entry, none of the patients had active MCD, and in all but one of the patients, the serum C-reactive protein level was less than 20 mg/L. Eastern Cooperative Oncology Group performance status was  2 in all patients. Direct Coombs test was positive in 10 of 21 patients, and 21 patients (87.5%) had a positive HHV-8 serology.
Histopathologic Findings
Response to Therapy and Survival Data During the treatment period, transient MCD flares were observed in eight (36%) of 22 patients who achieved SR at day 60. None of these patients required resumption of chemotherapy, and all of the patients recovered within the week after the fourth infusion of rituximab. Within the same period, serum C-reactive protein level increased from a median of 6.4 mg/L (range, 1 to 42 mg/L) at day 0 to a median of 26.5 mg/L (range, 2 to 470 mg/L) at day 15 (Fig 1A).
During the extended period, one patient (patient 12) died at day 112 with acute respiratory failure considered as infection related by the investigator. However, no causative organism could be demonstrated, and an MCD-related death could not be excluded. At day 365, four patients had experienced relapsed. In three of these patients, chemotherapy was resumed with favorable response. One patient (patient 8) received four further infusions of rituximab after six cycles of etoposide and was persistently off therapy at day 365. In the last patient (patient 19), MCD-related symptoms resolved spontaneously. Splenomegaly returned to normal size in eight of 10 patients. Overall, 17 of 22 patients who were in SR at day 60 were still alive in SR off chemotherapy at day 365. The estimated 1-year overall survival, event-free survival, and disease-free survival rates were 92% (95% CI, 71% to 98%; Fig 2A), 71% (95% CI, 48% to 85%; Fig 2B), and 77% (95% CI, 54% to 90%; Fig 2C), respectively. No patient developed lymphoma during the 1-year study period.
Adverse Events Adverse events related to the infusion of rituximab were observed in nine patients and generally occurred within 24 hours after the first infusion. The most common adverse events reported during therapy were chills, fever, headache, pruritus, rash, dizziness, and hypotension. In all cases, the symptoms were characterized as mild to moderate and resolved after the infusion was slowed down or stopped. One patient developed serum sickness after the second rituximab infusion. Grade 3 to 4 neutropenia (< 750 x 106/L) was observed in three patients, who experienced a total of four episodes, and resolved spontaneously within 1 week. During the extended study period, the most frequent reported adverse events were infections (28 events in 17 patients; Table 3). All infections were mild to moderate. The most frequent infectious events were herpesvirus-related infections, including two episodes of varicella.
HIV Infection No AIDS-defining opportunistic infection was observed. Exacerbation of KS lesions was observed in eight patients. None of these patients required specific treatment. These KS flares were observed before day 29 in three patients and after day 60 in five patients. No patient without KS at baseline developed KS lesions during the study period. T-cell counts were not modified by rituximab (data not shown). None of the 18 patients with undetectable HIV RNA at baseline had a detectable HIV viral load after therapy, whereas one patient with detectable HIV viral load before treatment had undetectable viral load at the end of the study. cART was modified in four patients during the study period.
Evolution of B-Cell Count
Evolution of HHV-8 DNA in PBMCs
Treatment of HIV-associated MCD has been largely unsatisfactory. Single-agent chemotherapy is usually effective to control MCD attacks and remains the standard first-line therapy; however, most patients experience relapse after discontinuation of chemotherapy. The prolonged use of chemotherapy is associated with toxicity and decreased quality of life. Alternative treatments have been proposed, but to date, no therapy has been associated with sustained response off therapy. In addition, prognosis remains poor, with a median survival time of 14 months in the only published study conducted before the wide use of cART.2 To our knowledge, this report is the first prospective therapeutic trial in HIV-associated MCD. In these patients with long-standing and highly chemotherapy-dependent MCD, rituximab, once weekly for 4 weeks, provided a high SR rate (92%) at day 60. At 1 year, 17 (71%) of the 24 patients remained in remission, indicating that rituximab could provide durable response and permit the discontinuation of chemotherapy in most patients. Two patients died, providing a 1-year overall survival rate of 92%. Of note, in the previous reported treatment failures of rituximab in MCD, therapy was initiated in patients with active and symptomatic disease,14,19 and to date, rituximab as a single agent cannot be recommended as first-line therapy. During the 4-week treatment period, one patient died with active MCD, and another patient experienced relapse and returned to chemotherapy. Furthermore, eight patients experienced mild MCD flares and recovered spontaneously without treatment. These flares were associated with a substantial increase in serum C-reactive protein level and with a transient increase of circulating HHV-8 DNA copy numbers, which are both covariates known to correlate with exacerbation of MCD.1 Among the eight patients who presented with transient MCD flares during the treatment period, four patients experienced relapse or died during follow-up, whereas, among the 14 patients who did not, only one patient experienced relapse. Recurrence of MCD symptoms during the treatment period could be explained by the discontinuation of chemotherapy 1 week before rituximab initiation, demonstrating the high chemotherapy dependence of these patients, and by a delayed effect of rituximab. To avoid early recurrence of MCD symptoms, it could be recommended to overlap chemotherapy and rituximab and to discontinue chemotherapy only after the fourth rituximab infusion. MCD-associated multiple organ failure and development of aggressive HHV-8–associated NHL are the major causes of death in this population.2,3 The expected frequency of lymphoma in HIV-associated MCD patients is as high as 15 times the frequency observed in HIV-infected patients without MCD. In the present study, no patient developed lymphoma during the 1-year study period. This could be explained by the SE hazard or by a protective effect of rituximab, which has a proven efficacy when administered as a single agent in the treatment of B-cell lymphoma.22-25 A longer follow-up period is required to confirm this result. Besides demonstrating the efficacy of rituximab in HIV-associated MCD, this trial provided further information about its safety in HIV-infected patients. Rituximab infusions were well tolerated in most of the patients. Few studies have been conducted with rituximab in HIV-infected patients, and all of the studies have been of patients treated for lymphoma with rituximab associated with combined chemotherapy, making the assessment of specific toxicity difficult in such a population.26,27 In one study, a significantly increased risk of infectious death was observed in patients receiving rituximab.26 In the present study, fatal acute respiratory failure was observed in one patient with a previous history of pneumococcal pneumonia. However, the exact cause of death could not be determined. Seventeen patients developed mild infectious complications, mostly herpesvirus associated. Moreover, rituximab had no adverse effect on clinical, virologic, and immunologic markers of HIV infection. Overall, five of seven patients with KS reported in the literature experienced an exacerbation of KS lesions after rituximab infusions.14,18 KS was closely monitored in the present study. Exacerbation of the lesions was noted in eight of 12 patients who had a previous history of KS. However, none of these patients required specific therapy. KS flares could have been associated with the B-cell depletion because it has been shown that the nadir B-cell count is correlated with the risk of KS.28 Rapid and complete circulating B-cell depletion was observed in most patients, and B-cell depletion was sustained for 9 to 12 months, as described in HIV-uninfected patients. In summary, the present study demonstrates that rituximab can induce prolonged SR, allowing discontinuation of chemotherapy in HIV-infected patients with chemotherapy-dependent MCD. Despite a good safety profile, the risk of exacerbation of KS lesions warrants cautious use of such therapy in patients with active KS lesions.
The author(s) indicated no potential conflicts of interest.
Conception and design: Laurence Gérard, Emmanuelle Boulanger, Sylvie Chevret, Felix Agbalika, Eric Oksenhendler Administrative support: Laurence Gérard, Isabelle Madelaine-Chambrin Provision of study materials or patients: Alice Bérezné, Lionel Galicier, Martine Obadia, Nathalie De Castro, Christine Jacomet, Renaud Verdon, Eric Oksenhendler Collection and assembly of data: Laurence Gérard, Alice Bérezné, Véronique Meignin Data analysis and interpretation: Laurence Gérard, Eric Oksenhendler Manuscript writing: Laurence Gérard, Eric Oksenhendler Final approval of manuscript: Laurence Gérard, Alice Bérezné, Lionel Galicier, Véronique Meignin, Martine Obadia, Nathalie De Castro, Christine Jacomet, Renaud Verdon, Isabelle Madelaine-Chambrin, Emmanuelle Boulanger, Sylvie Chevret, Felix Agbalika, Eric Oksenhendler
In addition to the authors, the following members participated to the ANRS 117 CastlemaB Study Group: O. Fain, M. Grimaud, A. Sackho (Assistance Publique-Hôpitaux de Paris, Hôpital Jean Verdier, Bondy); Y. Levy, C. Jung, M. Bouvier-Alias, C. Antoine (Assistance Publique-Hôpitaux de Paris, Hôpital Henri Mondor, Créteil); D. Neau, I. Raymond, I. Garrigue, J.P. Dupin (Hôpital Pellegrin, Bordeaux); F. Balsarin, A. Jaafar, J. Izopet, M. Canonge (Hôpital Purpan, Toulouse); C. Henquell, C. Coudert, M. Baer (Hôpital Hotel Dieu, Clermont-Ferrand); Y. Poinsignon, A. Maillard, C. Ghnassia (Hôpital Bretagne-Atlantique, Vannes; Hôpital Pontchaillou, Rennes); S. Dargère, P. Goubin, A. Vabret, C. Ollivier (Hôpital Côte de Nacre, Caen); C. Goujard, R. Kotb, M. Mole, N. Idri, C. Le Tiec (Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Kremlin-Bicêtre); J.M. Molina, P. Palmer (Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris).
Roche France contributed to the trial in supplying the experimental drug. The data were monitored by Nicolas Leturque. The Data Safety Monitoring Board was composed of A. Laplanche, MD; O. Lortholary, MD, PhD; C. Piketty, MD, PhD; N. Dupin, MD, PhD; and C. Michon, MD. Thanks to the ANRS 117 CastlemaB Study Group for its participation in the study (Appendix, online only).
Supported by the French National Agency for Research on AIDS and Viral Hepatitis, a public organization supporting research on AIDS and viral hepatitis. Presented in abstract form at the 13th Conference on Retroviruses and Opportunistic Infections, February 5-8, 2006, Denver, CO. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Oksenhendler E, Carcelain G, Aoki Y, et al: High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients. Blood 96:2069-2073, 2000 2. Oksenhendler E, Duarte M, Soulier J, et al: Multicentric Castleman's disease in HIV infection: A clinical and pathological study of 20 patients. AIDS 10:61-67, 1996[Medline] 3. Oksenhendler E, Boulanger E, Galicier L, et al: High incidence of Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood 99:2331-2336, 2002 4. Scott D, Cabral L, Harrington WJ Jr: Treatment of HIV-associated multicentric Castleman's disease with oral etoposide. Am J Hematol 66:148-150, 2001[CrossRef][Medline] 5. Aaron L, Lidove O, Yousry C, et al: Human herpesvirus 8-positive Castleman disease in human immunodeficiency virus-infected patients: The impact of highly active antiretroviral therapy. Clin Infect Dis 35:880-882, 2002[CrossRef][Medline] 6. Dupin N, Krivine A, Calvez V, et al: No effect of protease inhibitor on clinical and virological evolution of Castleman's disease in an HIV-1-infected patient. AIDS 11:1400-1401, 1997[Medline] 7. Zietz C, Bogner JR, Goebel FD, et al: An unusual cluster of cases of Castleman's disease during highly active antiretroviral therapy for AIDS. N Engl J Med 340:1923-1924, 1999 8. Coty P, Astrow A, Gallinson D, et al: Splenectomy is an effective treatment for HIV-associated multicentric Castleman's disease. Blood 102:49b, 2003 (abstr) 9. Dispenzieri A, Gertz MA: Treatment of Castleman's disease. Curr Treat Options Oncol 6:255-266, 2005[Medline] 10. Casper C, Nichols WG, Huang ML, et al: Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. Blood 103:1632-1634, 2004 11. Berezne A, Agbalika F, Oksenhendler E: Failure of cidofovir in HIV-associated multicentric Castleman disease. Blood 103:4368-4369, 2004 12. Nishimoto N, Sasai M, Shima Y, et al: Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 95:56-61, 2000 13. Corbellino M, Bestetti G, Scalamogna C, et al: Long-term remission of Kaposi sarcoma-associated herpesvirus-related multicentric Castleman disease with anti-CD20 monoclonal antibody therapy. Blood 98:3473-3475, 2001 14. Marcelin AG, Aaron L, Mateus C, et al: Rituximab therapy for HIV-associated Castleman disease. Blood 102:2786-2788, 2003 15. Marrache F, Larroche C, Memain N, et al: Prolonged remission of HIV-associated multicentric Castleman's disease with an anti-CD20 monoclonal antibody as primary therapy. AIDS 17:1409-1410, 2003[CrossRef][Medline] 16. Kofteridis DP, Tzagarakis N, Mixaki I, et al: Multicentric Castleman's disease: Prolonged remission with anti CD-20 monoclonal antibody in an HIV-infected patient. AIDS 18:585-586, 2004[CrossRef][Medline] 17. Newsom-Davis T, Bower M, Wildfire A, et al: Resolution of AIDS-related Castleman's disease with anti-CD20 monoclonal antibodies is associated with declining IL-6 and TNF-alpha levels. Leuk Lymphoma 45:1939-1941, 2004[CrossRef][Medline] 18. Casquero A, Barroso A, Fernandez Guerrero ML, et al: Use of rituximab as a salvage therapy for HIV-associated multicentric Castleman disease. Ann Hematol 85:185-187, 2006[CrossRef][Medline] 19. Neuville S, Agbalika F, Rabian C, et al: Failure of rituximab in human immunodeficiency virus-associated multicentric Castleman disease. Am J Hematol 79:337-339, 2005[CrossRef][Medline] 20. Rabkin CS, Schulz TF, Whitby D, et al: Interassay correlation of human herpesvirus 8 serologic tests: HHV-8 Interlaboratory Collaborative Group. J Infect Dis 178:304-309, 1998[Medline] 21. Kennedy MM, Lucas SB, Jones RR, et al: HHV8 and Kaposi's sarcoma: A time cohort study. Mol Pathol 50:96-100, 1997 22. 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] 23. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al: IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 15:3266-3274, 1997[Abstract] 24. 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 92:1927-1932, 1998 25. Foran JM, Rohatiner AZ, Cunningham D, et al: European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 18:317-324, 2000 26. Kaplan LD, Lee JY, Ambinder RF, et al: Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood 106:1538-1543, 2005 27. Boue F, Gabarre J, Gisselbrecht C, et al: Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. J Clin Oncol 24:4123-4128, 2006 28. Stebbing J, Gazzard B, Newsom-Davis T, et al: Nadir B cell counts are significantly correlated with the risk of Kaposi's sarcoma. Int J Cancer 108:473-474, 2004[CrossRef][Medline] Submitted January 12, 2007; accepted May 1, 2007. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
