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Prospective Study of Rituximab in Chemotherapy-Dependent Human Immunodeficiency Virus–Associated Multicentric Castleman's Disease: ANRS 117 CastlemaB Trial

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

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

	ABSTRACT

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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.

	INTRODUCTION

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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 AND METHODS

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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.

Patient Monitoring
Patients were monitored for efficacy and safety using medical history, physical examination, Eastern Cooperative Oncology Group performance status, and laboratory assessments including CBC counts and serum biochemical analyses. MCD attack was assessed through a predefined list of clinical and biologic items (Table 1). A computed tomography of the thorax and abdomen was performed at baseline, day 60, and day 365. At each visit, differential (CD19⁺, CD20⁺, CD3⁺, CD4⁺, and CD8⁺) lymphocyte count was measured by flow cytometry. HHV-8 serology was performed at entry, and HHV-8 DNA was quantified in PBMCs at each visit. Adverse events were recorded at each visit and graded according to the Agence Nationale de Recherche sur le Sida et les Hépatites Virales toxicity grading system (http://www.anrs.fr/).

Treatment
Study treatment consisted of four intravenous infusions of rituximab, at the standard dose of 375 mg/m², once weekly for 4 weeks. Ongoing chemotherapy was discontinued within 6 to 10 days before the first rituximab infusion. Antiretroviral therapy was to remain stable throughout the study. Concurrent therapeutic use of corticosteroids, chemotherapy, interferon, interleukin-2, or anti-inflammatory drugs was not allowed during the study period.

Virologic Analysis
Samples were stored at –80°C, centralized, and subsequently assayed for HHV-8 serology and HHV-8 DNA at the end of the study. HHV-8 serology was performed using the BCP-1 cell line for the detection of antibodies against latent nuclear antigens using an indirect immunofluorescence assay.²⁰ Quantitative evaluation of HHV-8 DNA was performed from 1 µg of DNA (150,000 cells) extracted from PBMCs using quantitative polymerase chain reaction detection of HHV-8 using a TaqMan technique (Applied Biosystems, Foster City, CA) derived from Kennedy et al.²¹

End Points and Response Criteria
Patients were assessable for efficacy if they had completed at least one infusion of rituximab. The primary end point was the SR rate at day 60, which was defined as the absence of MCD relapse off chemotherapy, according to the definition described in Table 1. Resumption of chemotherapy for any reason was considered as treatment failure. Presence of mild symptoms during the treatment period was accepted in the SR definition if the symptoms did not require resumption of chemotherapy and if all symptoms resolved before day 29. Recurrence of MCD symptoms was reported as treatment failure before day 60 and as relapse after day 60. In case of disease progression, patients received alternative treatment according to individual decision of the local investigator.

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
Calculation of sample size was based on the assumption that the proportion of patients with SR at day 60 would be at least 50% and not less than 20%. A sample of 23 patients was required to provide the study with 80% power and a type I error rate of 5%. The primary analysis was based on the intent-to-treat principle. Survivals were estimated by the Kaplan-Meier product-limit method using the STATA computer package (STATA Satistical Software; STATA Corp, College Sation, TX).

	RESULTS

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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.

Histopathologic Findings
Centralized pathologic review confirmed the diagnosis of MCD in the 24 patients. HHV-8–positive cells, detected using HHV-8 latency-associated nuclear antigen immunohistochemistry (clone 13B10; Novocastra, Newcastle, United Kingdom), were present in all patients. Foci of KS were detected in three patients.

Response to Therapy and Survival Data
All patients received at least one infusion of rituximab, and all but one patient received the four scheduled infusions. One patient (patient 4) died at day 15 from progressive MCD after the second rituximab infusion. One patient (patient 6) had progressive disease after four infusions of rituximab, and chemotherapy was resumed at day 23 with rapid improvement. At day 60, 22 patients were alive and free of MCD-related symptoms after discontinuation of chemotherapy, yielding an SR rate of 92% (95% CI, 80% to 103%).

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).

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Evolution of (A) serum C-reactive protein (CRP) levels, (B) B-cell count, and (C) log human herpesvirus-8 (HHV-8) DNA in peripheral-blood stem cells (PBMCs) during the 1-year study period in 24 HIV-infected patients treated with rituximab for chemotherapy-dependent multicentric Castleman's disease.

View larger version (6K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Overall survival and (B) event-free survival in 24 HIV-infected patients treated with rituximab for chemotherapy-dependent multicentric Castleman's disease. (C) Disease-free survival in 22 HIV-infected patients with sustained remission at day 60.

Evolution of B-Cell Count
The median B-cell count at baseline was 143 x 10⁶/L (range, 17 to 914 x 10⁶/L) and declined during the treatment period (Fig 1B). In all but two patients, B cells were no longer detectable in blood after the first course of rituximab. B-cell count increased from day 90 and returned to initial values at day 365, with a median count of 127 x 10⁶/L at day 365 (range, 18 to 565 x 10⁶/L). Serum gamma-globulin levels did not changed significantly after rituximab infusions (data not shown).

Evolution of HHV-8 DNA in PBMCs
At baseline, DNA copy numbers in PBMCs were less than the limit of detection (50 copies/1 µg DNA) in 18 patients and ranged from 99 to 1,046 copies/1 µg DNA in six patients. Longitudinal evaluation of HHV-8 DNA in PBMCs is presented in Figure 1C. HHV-8 viral load increased substantially during rituximab therapy and returned to baseline level after the fourth infusion. Seven of 23 patients had detectable HHV-8 DNA in PBMCs at day 60 (56 to 5,465 copies/1 µg DNA). Four of six patients who experienced relapse or died had detectable HHV-8 DNA in PBMCs at the time of or just before the event.

	DISCUSSION

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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.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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

	Appendix

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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).

	ACKNOWLEDGMENTS

 
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).

	NOTES

 
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.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted January 12, 2007; accepted May 1, 2007.

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