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Blood, 1 December 2001, Vol. 98, No. 12, pp. 3473-3475
BRIEF REPORT
Long-term remission of Kaposi sarcoma-associated
herpesvirus-related multicentric Castleman disease with anti-CD20
monoclonal antibody therapy
Mario Corbellino,
Giovanna Bestetti,
Chiara Scalamogna,
Sara Calattini,
Morena Galazzi,
Luca Meroni,
Daniele Manganaro,
Marco Fasan,
Mauro Moroni,
Massimo Galli, and
Carlo Parravicini
From the Institute of Infectious Diseases and Tropical
Medicine, University of Milan; and the First Division of Infectious
Diseases and the Department of Pathology, Luigi Sacco Hospital, Milan,
Italy.
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Abstract |
Kaposi sarcoma-associated herpesvirus (KSHV)-related multicentric
Castleman disease (MCD) is potentially lethal. Growing evidence indicates that, as in Epstein-Barr virus-driven lymphoproliferative disorders after transplantation, KSHV DNA burden in peripheral blood
mononuclear cells (PBMCs) may represent the most accurate marker of
disease activity. This report describes a patient with human
immunodeficiency virus who was followed up clinically and by
quantitative polymerase chain reaction for KSHV DNA sequences in PBMCs
for more than 3 years following the diagnosis of KSHV-related MCD.
Therapy with the antiherpesvirus agent cidofovir, antihuman interleukin-6 antibody BE-8, antiblastic chemotherapy, and
combination antiretroviral agents did not achieve durable clinical or
virologic remission of the disease. By contrast, administration of the
anti-CD20 monoclonal antibody rituximab was well tolerated and allowed
a 14-month remission of clinical symptoms and KSHV viremia. Rituximab should be added to the therapeutic armamentarium for KSHV-related MCD.
(Blood. 2001;98:3473-3475)
© 2001 by The American Society of Hematology.
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Introduction |
Kaposi sarcoma-associated herpesvirus (KSHV) is
implicated in the pathogenesis of 2 rare lymphoproliferative disorders,
primary effusion lymphoma, and a subset of multicentric Castleman
disease (MCD).1 The concomitant presence of human
immunodeficiency virus (HIV) infection does not alter the clinical
picture of KSHV-related MCD, which is characterized by a rapidly
progressive and often fatal course.2 Kaposi sarcoma (KS)
may precede, coexist with, or follow the diagnosis of MCD, and the
development of aggressive non-Hodgkin lymphoma is not a rare outcome in
patients with this disorder.3
KSHV is a lymphotropic  2-herpesvirus homologous to the
Epstein-Barr virus (EBV) that may be present in the CD19+
peripheral blood mononuclear cells (PBMCs) of patients with
KS.4 Lymph nodes of patients with KSHV-related MCD
specifically harbor the virus in B cells located in the mantle
zone,2,5 which stain positively for the CD20 surface
antigen.6 The humanized anti-CD20 antibody Mabthera
(rituximab) is increasingly used for the treatment of EBV-driven
lymphoproliferative disorders after transplantation. In this context,
single-dose administration of rituximab induces complete clinical
remission of the disease.7 We treated an HIV-positive
patient with KSHV-related MCD with a single dose of anti-CD20 antibody.
This resulted in a 14-month remission of the disorder.
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Study design |
PBMCs were isolated by Ficoll-Hypaque density gradient
centrifugation (Pharmacia, Uppsala, Sweden). DNA was extracted from PBMCs after digestion in a proteinase K-containing buffer by the phenol-chloroform method.8 One microgram PBMC DNA was
subjected to polymerase chain reaction (PCR) using KSHV and human
 -globin-specific primers.9 Quantitation of viral and
human genomes was carried out using the limiting-dilution
technique.10 Twenty replicates for each target were made
around the end-point dilution using single-copy, sensitivity-nested PCR
assays.11 Viral DNA load in PBMCs was expressed as the
absolute number of viral genomes in 150 000 human diploid cells. PBMC
samples that tested negative by PCR were considered to have less than 1 viral genome per 150 000 cells. Immunohistochemical demonstration of
the KSHV protein viral interleukin-6 (v-IL-6) was performed using
specific antisera, as previously described. 2,5
Case report
On November 26, 1997, a 52-year-old woman with HIV-1 infection
came to the emergency department because of a 2-week history of
progressive fatigue, high-grade fever (39°C), profuse sweating, and
dyspnea. She had acquired HIV infection 4 years earlier through sexual
contact. The absolute number of CD4+ T cells was 383 cells/µL, and HIV-1 viral load in plasma was less than 500 copies/mL.
She was receiving antiretroviral therapy with d4T and 3TC. Generalized
lymphadenopathy and splenomegaly were evident on physical examination.
Chest radiography findings were normal. Her hemoglobin concentration
was 7 g/dL. C-reactive protein (CRP) concentration was 4.8 mg/dL, and
lactic dehydrogenase (LDH) level was 893 IU/L. She had hemolytic
anemia, positive Coombs test findings, and evidence of cryoagglutinins.
A latero-cervical lymph node was excised. Microscopic examination and
immunohistochemistry for KSHV v-IL-6 revealed KSHV-related MCD (Figure
1).
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| Figure 1.
KSHV v-IL-6 expression in a lymph node of the patient
with multicentric Castleman disease.
MCD lymph node section showing KSHV v-IL-6 expression (black)
restricted to lymphocytes in the mantle zone of lymphoid
follicles.
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Treatment
With the approval of the Institutional Review Board and the
informed consent of the patient, cidofovir was administered
intravenously for 18 weeks beginning on December 17, 1997. Murine
antihuman IL-6 monoclonal antibody BE-8 was administered to the patient as described by Beck et al12 for 12 weeks beginning the
next day, December 18. Fever and CRP levels dramatically abated within 48 hours of BE-8 administration. However, in the next 12 days hemolytic
anemia, lymphadenopathy, and splenomegaly were not affected by combined
antiherpesvirus and antihuman IL-6 therapy.
On December 30, the patient's hemoglobin concentration was 3.9 g/dL.
That day she underwent chemotherapy with doxorubicin (20 mg/m2), vincristine (2 mg), and bleomycin (15 mg).
Her condition improved rapidly with this cytotoxic therapy. On January
28, 1998 she was referred to our outpatient clinic after 2 cycles
of the therapy; she had a hemoglobin concentration of 9.8 g/dL and no
signs of ongoing hemolysis. Combination antiretroviral therapy with
d4T, nevirapine, and indinavir was introduced on February 16, when tests showed 104 CD4+ T cells/µL and 14 690 copies of
HIV-1 RNA/mL plasma. After 4 months, HIV-1 RNA reached plasma
values lower than 80 copies/mL, and it has since remained below this threshold.
Chemotherapy was continued for 8 cycles at intervals of 3 weeks. On
June 16, 1998, treatment with intravenous liposomal daunorubicin (40 mg/m2) administered every 2 to 4 weeks was started and was
continued until February 24, 2000. On October 19, 1998, total body
computed tomography documented complete remission of lymphadenopathy
and splenomegaly. However, constitutional symptoms (ie, profuse night sweating and asthenia) monotonously re-emerged after each successive cycle with the antineoplastic agents and were regularly paralleled by
increasing KSHV levels in the circulation (Figure
2A). Furthermore, the intervals with
undetectable virus in the blood were never longer than few days,
despite 60 weeks of antiblastic therapy (Figure 2A).
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| Figure 2.
Kinetics of circulating KSHV DNA burden and lymphocyte
subsets during a 3-year follow-up period in the patient with
multicentric Castleman disease.
Changes in KSHV DNA load in PBMCs (A), peripheral blood
CD19/CD20+ B cell counts (B), CD4+ T-cell
counts (C), and CD4+/CD8+ T-cell ratio (D) in
an HIV-1- infected patient with multicentric Castleman disease during
treatment with cidofovir, antihuman IL-6 monoclonal antibody (BE-8),
and cytotoxic therapy (horizontal arrows) and after a single dose of
anti-CD20 monoclonal antibody (shaded area). Throughout most of the
study period, the patient was under effective, highly active
antiretroviral therapy.
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On March 8, 2000, with the approval of the Institutional Review Board
and the informed consent of the patient, the anti-CD20 chimeric
monoclonal antibody Mabthera (Roche, Basel, Switzerland) was
administered intravenously at the standard dose of 375 mg/m2 according to the instructions of the manufacturer. No
adverse effects were encountered during infusion of the drug.
Circulating CD19+ B cells were undetectable 48 hours from
Mabthera administration and remained so for 14 weeks (Figure 2B).
During this time, KSHV DNA in PBMCs was always negative by the PCR
(Figure 2A). This finding indirectly argues for a restricted tropism of
KSHV for the CD20+ circulating B cells in MCD. B cells
returned to preimmunotherapy absolute counts 6 months after Mabthera
administration (Figure 2B). During the 11-week phase of B-cell
reconstitution and in the next 8 months with restored B-lymphocyte
counts, the patient remained asymptomatic; KSHV viremia was present
only episodically and always at low titers (Figure 2A). This was in
striking contrast with the crescendo of constitutional symptoms and
circulating KSHV burden shown within days of each successive cycle of
chemotherapy. Finally, therapy with rituximab did not have detrimental
effects on the immunologic and virologic markers of HIV-1 infection.
Under antiretroviral therapy, CD4+ T cell levels kept
rising, whereas the CD4+/CD8+ T-cell ratio did
not significantly change when compared with the pre-Mabthera period of
observation (Figure 2C-D).
| |
Results and discussion |
KSHV-related MCD is a life-threatening disorder. Detection of the
virus in secondary lymphoid organs is essential for diagnosis because
histologic findings do not allow distinction between KSHV-negative and
KSHV-positive MCD.2,5,6,13,14 Elevated viral burden in PBMC
may be a characteristic feature of this disorder,15 and
blood viral monitoring may be the most accurate marker of disease
activity and response to therapy15,16 similar to
circulating EBV DNA levels in lymphoproliferative disorders after
transplantation.17
Antiherpesvirus therapy has been advocated in KSHV-related
MCD.16 Cidofovir is the most potent inhibitor of KSHV
productive infection.18 Clinical and viral evidence
presented here demonstrates that 4 months of therapy with cidofovir had
no effect on KSHV-related MCD. Other mechanisms beyond productive viral
replication are thus operational in perpetuating the high viremic
levels typical of the disease.
Alleviation of the systemic manifestations of MCD may be achieved by
use of an anti-IL-6 antibody.14,19 Our patient did not
improve despite 3 months of daily anti-huIL-6 immunotherapy. Nevertheless, the normalization of serum CRP levels observed within hours of BE-8 administration suggests efficient neutralization of
systemic huIL-6.20 However, BE-8 may not affect viral
IL-6, the functional homologue of huIL-6 encoded by KSHV.
KSHV-MCD responds to the administration of cytotoxic
agents.21 Clinical remission may be achieved by
chemotherapy, but the periods free of systemic symptoms and KSHV
viremia are typically short-lived. In addition, patients with KSHV-MCD
are at risk for the development of non-Hodgkin lymphoma and Kaposi
sarcoma.1 In a recent report, Dupin et al22
demonstrate that KSHV-infected B cells in secondary lymphoid
organs of patients with MCD are positive for the CD20 surface antigen
and display monotypic rearrangements of the immunoglobulin  -chain.
These cells may represent microscopic foci of in situ neoplastic clones
that may progress to overt plasmablastic, KSHV-related, non-Hodgkin
lymphoma.22 Furthermore, expression of the CD20 antigen
has been recently demonstrated in 1 patient with acquired
immunodeficiency syndrome (AIDS)-associated primary effusion lymphoma
in vivo and in vitro.23 Long-term ablation of KSHV viremia
should thus be viewed a therapeutic goal to prevent the periodic
exacerbations of MCD and the subsequent development of lymphoma.
In contrast to highly active antiretroviral therapy (HAART)-induced
remission of early-stage AIDS-KS,24 the resolution of immune suppression as a result of antiretroviral therapy may not per se
affect HIV-1-related MCD. In our patient, 21 months of HAART had no
effect on disease activity, as judged clinically and by the kinetics of
KSHV viremia. We cannot, however, exclude that after Mabthera-induced
purging of KSHV-infected neoplastic B cells and the concomitant
interruption of cytotoxic chemotherapy, control of KSHV viremia was
achieved through a HAART-mediated, reconstituted antiviral response.
In conclusion, Mabthera is an effective agent for KSHV-related MCD. Of
note, rituximab was introduced in this patient after chemotherapy-induced remission of her generalized lymphadenopathy, splenomegaly, and hemolytic anemia. Open issues thus remain concerning the role of Mabthera, alone or in combination with cytotoxic drugs, as
a first-line agent in this disorder.
| |
Acknowledgments |
We are profoundly indebted to our patient for the admirable
compliance shown throughout the course of her disease. We thank Dr John
Wijdenes (Diaclone, Besançon, France) for the kind gift of the
antihuman IL-6 antibody BE-8. Finally, we thank Fabio Franzetti, Andrea
Gori, Laura Galimberti, Annalisa Ridolfo, and Laura Milazzo for their
skillful care of our patient.
| |
Footnotes |
Submitted April 10, 2001; accepted July 11, 2001.
Supported by grants from Istituto Superiore di Sanità AIDS
Research Program, Rome, and ANLAIDS, Sezione Lombarda, Milan, Italy.
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: Mario Corbellino, Institute of Infectious Diseases
and Tropical Medicine, University of Milan, Luigi Sacco Hospital, Via
G.B. Grassi, 74 20157, Milan, Italy; e-mail:
mcorbell{at}mailserver.unimi.it.
| |
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Abstract
Introduction
