Herpes 101

Ask the Hematologists: Treatment of Castleman Disease

1Charité Universitätsmedizin Berlin, Pediatric Pneumology and Immunology, Berlin, Germany. In the U.S., HHV-8 infection is primarily a sexually transmitted disease among male homosexuals (JW Dermatology Feb 12 2002), and seropositivity is rare in children. Analysis of cytotoxic T lymphocyte (CTL) responses to viral proteins expressed during a primary infection revealed a distinct but relatively non-robust immune response (Wang, Jenkins, Jacobson, Kingsley, Day, Zhang, Meng, Pellet, Kousoulas, Baghian, & Rinaldo, Jr., 2001). Of 44 patients with HIV-MCD with an incidence of 4·3/10 000 patient years, four individuals (9%) were diagnosed with HPS. Although HHV-8 infection of tumor cells is predominately latent, accumulating data point to the importance of both lytic phase viral gene products and production of infectious virus. Several features of the RNA molecules encoding the K3 product, including multiple transcriptional start sites, multiple donor splicing sites, and potential alternative ATG usage, suggest that there exists a finely tuned modulation of ORF K3 expression. HIV loads were stable in all patients.

After sixth cycle of R-CEOP, the patient achieved unconfirmed complete remission. The diagnosis is made when excisional lymph node biopsy shows characteristic Castleman changes. Approximately 90 percent of UCD cases demonstrate the hyaline vascular (HV) subtype. An infection with Epstein-Barr virus (EBV) is also present in the majority of PEL cases. It is not known if SYLVANT® passes into your breast milk. Drug Interactions – Cytochrome P450 (CYP450) Substrates – Upon initiation or discontinuation of SYLVANT®, in patients being treated with CYP450 substrates with narrow therapeutic index, perform therapeutic monitoring of effect (eg, warfarin) or drug concentration (eg, cyclosporine or theophylline) as needed and adjust dose. You should not do both.

In the bone marrow, the spindle cells were located in the myxoid mesenchyma and were separated from each other (Figure 2, b). But anyone with a suppressed immune system who has HHV-8 is at high risk for Kaposi’s. Involution of lymphadenopathy after radiotherapy has also been reported. Difficult cases require a multimodal approach and are best managed at an experienced center. HHV-8–positive MCD presents with generalized lymphadenopathy and constitutional symptoms, and can progress to multi-organ failure leading to death. If you have a severe infusion or allergic reaction, your healthcare provider may stop your treatment completely. HHV-8–positive MCD was first described during the AIDS epidemic and is classically thought to be due to lytic replication of HHV-8 in the setting of HIV infection.4However, there are also patients with HHV-8–positive MCD who are HIV negative.

KS lesions in the gut and in the lungs can be fatal if not treated or controlled. A diagnosis of HHV-8–positive MCD can be rendered if the patient has 1) a pathologic diagnosis of CD made on an excisional lymph node biopsy and 2) actively replicating HHV-8 virus detected in the peripheral blood by molecular testing (quantitative polymerase chain reaction [PCR]) or a positive stain of the lymph node for the HHV-8 latency associated nuclear antigen (LANA-1). HIV-positive, HHV-8–positive MCD patients may have coexistent Kaposi sarcoma and are prone to develop HIV-associated lymphomas. Lymph node pathology shows plasmacytic or plasmablastic changes, and the plasma cells may exhibit light chain restriction. Intranodal microlymphomas have also been reported. HHV-8–positive MCD is effectively treated with rituximab, which depletes the reservoir of HHV-8–positive cells and significantly reduces the risk of lymphoma.6More severely afflicted patients may require additional etoposide. Some experts recommend maintenance therapy with valganciclovir.

The current WHO classification defines an entity “other iatrogenic immunodeficiency-associated lymphoproliferative disorders”14(pp350-351) that occur in patients with autoimmune diseases who are treated with immunomodulatory drugs. Siltuximab, which is a monoclonal antibody to IL-6, has not been studied in HHV-8–positive MCD because it did not bind to viral IL-6 in preclinical studies. HHV-8–negative MCD presents with generalized lymphadenopathy, constitutional symptoms, and can also develop multiorgan failure. Examination of an excised axillary lymph node was negative for lymphoma or KS but showed features consistent with the presence of an atypical immunoproliferative disorder. The questionnaires were administered at children (3–13 years old) in schools or health care centres. Chest CT 6 months after diagnosis showed bilateral new and enlarging pulmonary nodules. In both cases, the presentation of HHV-8 acute infection was very similar with respect to the clinical manifestations and their duration, with spontaneous remission within 8 weeks.

In the first series to describe such a variant, CD patients with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal proteins and skin changes), also known as Crow-Fukase, were found to have lymph nodes which resembled those in PCV, but also had large plasma cells in the mantle zone with copious cytoplasm and prominent single or multiple nucleoli (Menke et al, 1996, 2000). Early observations made during studies of ganciclovir therapy for cytomegalovirus (CMV) retinitis in HIV-positive patients found that ganciclovir reduced the rate of new KS development; the reduction was found to range from 40%, by Mocroft et al. Currently, a diagnosis of iMCD can be made when patients have 1) histopathology typical of CD on excisional lymph node biopsy, 2) multiple regions of enlarged lymph nodes, 3) negative quantitative PCR for HHV-8 in the peripheral blood or negative LANA-1 staining of the lymph node biopsy, and 4) systematic exclusion of diseases known to demonstrate Castleman-like histopathology (e.g., systemic lupus erythematosus, Epstein-Barr virus, lymphoma, IgG4-associated lymphadenopathy). Hence, both HHV-8–positive and –negative MCD are not purely pathologic diagnoses. Being a spouse of a patient with KS is a risk factor for HHV8 seropositivity. In addition, a significant portion of patients have pre-existing Kaposi’s sarcoma or MCD, reflecting the other known manifestations of HHV-8 infection. The results of three of the six secondary endpoints were statistically significant.

Corticosteroids may temporarily control symptoms, but patients relapse on tapering. Specific IFNγ-enzyme-linked immunosorbent spot assay (IFNγ-ELISPOT) monitoring, either for lytic (orfK8.1; ▴) or for latent (orf73/LANA; ○) HHV8-derived antigens, was applied to assess HHV8-specific T-cell frequencies in our series of 15 PT-KS patients, either at PT-KS diagnosis or after remission, and in 2 PT-LPD patients (PEL or MCD; gray symbols), as well as in 5 HHV8-seropostive posttransplantation asymptomatic carriers (PT-AC). This inability may suggest that HHV8-infected patients with a low CD4 cell count and/or uncontrolled HIV viral replication quickly become symptomatic for HHV8 infection. Fajgenbaum, van Rhee, and Nabel recently proposed that iMCD represents a common end point that can be reached through multiple processes, each involving immune dysregulation and a common pathway of elevated proinflammatory cytokine release. The combined durable symptomatic and tumor response was 34 percent, and 50 percent of patients remained on drug for the duration of the study. This study provided the first placebo-controlled evidence for an iMCD therapy, and siltuximab is the first drug approved for iMCD by the U.S. Food and Drug Administration and European Medicines Agency.

Both siltuximab and tocilizumab are safe and well-tolerated.13For patients that do not respond to anti–IL-6 therapy, immunosuppressants, immunomodulators, biologics, and cytotoxic chemotherapies, including cyclosporine, sirolimus, bortezomib, thalidomide, anakinra, interferon-α, cyclophosphamide, and etoposide, have been reported to have some success in case reports or small series. In the authors’ opinion, patients with iMCD should first be treated with anti–IL-6 therapy approved in that region (siltuximab in North America and the European Union; tocilizumab in Japan). Patients with few symptoms or laboratory abnormalities suggestive of little excess IL-6 may not respond well to anti–IL-6 blockade and should be considered for rituximab and steroids. Severe hypercytokinemia and organ failure may not respond sufficiently to anti–IL-6 targeting monoclonal antibodies, and they require combination chemotherapy or consideration of experimental treatment. S3). Progressive motor polyneuropathy suggesting coexistent POEMS does not respond well to rituximab or to IL-6–targeted therapy, and these patients require autologous stem cell transplantation as part of their treatment plan. The atypical cells were restricted to the intravascular compartment, and had a high Ki-67 proliferation index.

However, anti–IL-6 therapy is not effective for all patients, and they are not curative, as cessation of treatment results in relapse. In 2012, we co-founded the Castleman Disease Collaborative Network (CDCN; www.castlemannetwork.org) to accelerate research and elucidate the pathogenesis of MCD. In 2.5 years, we have assembled a 23-member Scientific Advisory Board representing seven countries; built and facilitated collaboration among our community of more than 200 researchers and physicians worldwide; leveraged the community to establish and execute an international research agenda; and engaged patients throughout the entire process. We are currently finalizing plans to establish a registry/natural history study, which we believe will be crucial for establishing a diagnostic criteria and improving patient care. The three bone marrow trephine biopsies were highly oedematous. The impact of antivirals on KS treatment might be augmented if combined with agents that induce the activation of HHV-8 latently infected cells to undergo lytic replication in vitro, such as valproic acid, hydroxyurea, or glycyrrhizinic acid [61,62], but such approaches have not been validated in clinical trials to date.