Guess the Diagnosis: Case 1 - Episode 5

David Fajgenbaum, MD, MBA, MSc: Potential Treatment Options

What are potential treatment options?

Dr. David Fajgenbaum, Perelman School of Medicine, University of Pennsylvania, says HHV-8—negative MCD has been treated with corticosteroids, rituximab (Rituxan), anti-IL-6 therapies, and/or chemotherapeutic agents derived from the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen. Corticosteroids may temporarily control symptoms, but patients usually relapse on tapering, and sustained high steroid doses are not feasible. Rituximab has not been systematically evaluated in iMCD, and the limited number of case reports available suggests that patients often relapse with single-agent rituximab. A course of rituximab is often perceived as single-shot curative therapy, but there are no systematic studies that provide supportive evidence. Most of the published cases and series are confined to HIV and HHV-8–positive patients. However, there are some case reports of response, rituximab is widely used for other disorders, and its side effect profile is well known.

Monoclonal antibodies targeting IL-6 have been recently developed and subjected to the most rigorous clinical evaluation. A single-arm study of 28 Japanese patients on tocilizumab (Actemra) demonstrated a high response rate in symptoms, laboratory parameters, and reduction in lymphadenopathy. Siltuximab (Sylvant) was evaluated in a double-blind, placebo-controlled, randomized study using a control arm of best supportive care, including up to 60 mg of prednisone. The combined durable symptomatic and tumor response was 34%, and 50% of patients re- mained on drug for the duration of the study. This study provided the first placebo-controlled evidence for an iMCD therapy, and siltuximab is the only drug approved for iMCD by the US Food and Drug Administration (FDA). Both siltuximab and tocilizumab are safe and well tolerated. Elevations of cholesterol, mild thrombocytopenia, and occasional infusion reactions have been reported. Opportunistic infections with single-agent tocilizumab and siltuximab have not been reported, but both drugs may blunt the acute-phase reaction. The downside of IL-6—targeting agents is that therapy is not curative, and in principle, lifelong relapses have been reported on cessation of therapy. In some patients, dosing intervals can be extended. Also, [some] patients do not respond, because IL-6 is not always the critical cytokine driving the disease. 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 in a small series of patients that do not respond to anti–IL-6 therapy.

This patient is symptomatic and requires therapy. Treatment of iMCD is also necessary to prevent transformation to lymphoma. The risk of developing lymphoma is estimated to be 10% to 15%, but there are no long-term longitudinal studies that have quantified the exact risk. Her symptoms are accompanied by abnormal laboratory parameters, which are in keeping with the presence of a proinflammatory syndrome likely driven by IL-6 because her IL-6 was substantially elevated. The patient was started on siltuximab 11 mg/kg every 3 weeks. Her symptoms and laboratory work rapidly normalized on therapy and were back to normal after 4 months. However, as anticipated, the resolution of her lymphadenopathy was slow, and complete resolution occurred after 18 months. Siltuximab neutralizes IL-6 and abrogates a major growth signal for lymphocytes and plasma cells in iMCD. However, it is not directly cytotoxic, which explains the slow involution of her lymphadenopathy.

Guess the Diagnosis: Case 1

Lisa B. is a 47-year-old female store owner from St. Louis, with a 10-month history of fatigue, night sweats, and weight loss.

  • She presents to her PCP with generalized lymphadenopathy, most prominent in the cervical region; there is no polyneuropathy, and patient does not report joint pain. She is referred to a hematologist to rule out lymphoma
  • Medical history is unremarkable; family history relevant for a mother with systemic lupus erythematous and father who died with prostate cancer at 65 years old
  • Her physical exam is notable for bilateral cervical lymphadenopathy (1-2 cm), mild splenomegaly, and mild edema
  • Laboratory findings: anemia (Hgb 11 gm/dL), elevated CRP (35 mg/L) and ESR (80mm/hr), elevated platelets (400,000/mK), Igs (IgG: 4500 mg/dL, IgM: 1500 mg/dL, IgA: 300mg/dL)
  • PET scan showed generalized lymphadenopathy with a maximum SUV of 4.5; FNA of the lymph node is uninformative; she was referred to a general surgeon for excisional lymph node biopsy

Lisa’s pathology report shows the following findings:

  • Regressed germinal centers, scattered hyperplastic follicles, preserved architecture with patent peripheral sinuses and florid interfollicular plasmacytosis with no light chain restriction
  • Prominent vascularization and hyalinization is present

In view of these findings, the hematologist orders further tests, which yield the following results:

  • Lymph node: negative EBER, LANA-1, and IgG4 stains; negative PCR for B-cell clonality
  • Additional laboratory work: negative ANA, negative dsDNA, anti-Smith and anti-phosholipid antibodies; monospot negative