David Fajgenbaum, MD, MBA, MSc: Possible Treatments

What are potential treatment options for this patient?

The first treatment option that should be considered for this patient is anti—IL-6 therapy with siltuximab. This is the only FDA-approved therapy that has ever been tried in a randomized controlled trial for idiopathic MCD. It’s proven to be safe and effective in a portion of patients. So that really should be the first line of therapy. In this patient, he had a very nice response to siltuximab. He had a nice response where he went from being on a ventilator, continuous dialysis in the intensive care unit to beginning to improve. He improved gradually to where he was able to be discharged from the hospital. Unfortunately, this patient relapsed 6 weeks after discharge from the hospital. This highlights to us just how complicated and complex this disease is. This patient had borderline elevated IL-6, yet IL-6 neutralization really stopped this disease in its tracks. Yet, even while on IL-6 neutralization therapy, the disease relapsed. This just kind of uncovers that this is a complex disorder. It’s not as simple as was previously thought, that this was an IL-6–driven disorder purely. This is a complex inflammatory disorder where IL-6 plays an important role and clearly was a linchpin during his first episode because neutralizing it resulted in remission.

But, with this patient relapsing 6 weeks later, we had to immediately start thinking about additional treatment options. Cytotoxic chemotherapy rose to the top of that list because of how quickly this patient deteriorated. In Castleman Disease, as with many disorders particularly including malignancies, the most sick patients often require the most intense and aggressive therapies. So, immediately, when you see a patient going downhill like this patient, we’ve seen him crash quickly before, we’ve seen him experience multiple organ failure, and he’s experiencing multiple organ failure again; so, in our case, we felt it was important to be very aggressive and to use cytotoxic chemotherapy.

Unfortunately, he didn’t have an immediate response to the chemotherapy but he did respond. And now we are looking at a whole host of what you would consider second-line therapies hopefully either in addition to siltuximab or in place of siltuximab to keep this patient in remission. Additional therapies could include Cytoxan, etoposide, rituximab. Those are some more classically used drugs, but also more recently there’s data suggesting that additional immunomodulator drugs, like anakinra which blocks IL-1, or like sirolimus or cyclosporine, which present T-cell activation, that these drugs have also been used effectively in Japan and the United States. So it’s important, as I said before, to think about idiopathic Multicentric Castleman Disease as a heterogeneous disorder where interleukin-6 blockade works in a large percentage of patients. In the patients where it doesn’t work, you really want to think about what subtype does this patient have. Does this patient have TAFRO syndrome? If so, let’s look at the literature of what drugs are working for TAFRO patients. In the literature, tocilizumab as well as cyclosporine have been tried. Etoposide and Cytoxan have certainly also been used, and, as I said, sirolimus as well.

Unfortunately, there are no recommended expert guidelines on treating idiopathic Multicentric Castleman Disease, but there’s only one FDA-approved therapy. I think it’s very important to use the one proven tried and true FDA-approved therapy to start, and if there are any recurrences or relapses we saw in this patient, you look into the data and see what has been working for TAFRO patients and immediately start thinking about second-line options.

Multicentric Castleman Disease: Case 2

Garrett is a 47-year old male carpenter who was formerly a Marine, with a 4-week history of fatigue, night sweats, and weight loss. He reported difficulty breathing for 2 weeks, and 1 week of fevers. He also reported that he’s noted fluid in his legs. He presented to the emergency department for a work-up. His past medical history was only notable for Raynaud’s phenomenon. His family history included a mother that died from a myocardial infarction at 71 and a father who died from lung cancer at 61. His physical exam was notable for bilateral cervical and inguinal lymphadenopathy (1-2 cm), moderate edema (10 lb weight gain in past 7 days), and pleural effusions.

Laboratory findings showed anemia (Hgb: 11 gm/dl), low platelets (109k), and elevated alkaline phosphatase levels. The patient was admitted with a presumed viral illness and then moved to MICU when the patient began experiencing severe difficulty breathing, transaminitis, and increased fluid gain (30 lbs). Further testing showed his CRP >300 mg/L, albumin 1.2 g/dL, renal dysfunction, and Hgb trending downward (now 9 gm/dl), and PLTs trending downward (now 35k). His infectious workup was pan-negative, except for possible EBV infection (8/29/10: EBV PCR positive). He was diagnosed with acute EBV mononucleosis early in admission, but the diagnosis was rescinded when he was found to be EBV IgG+. A rheumatology workup was negative except for a positive ANA (1:120).

The patient was started on 125mg BID of solumedrol without improvement. His hematology/oncology workup was notable for: .

• Elevated B-2-microglobulin
• CT scan: diffuse LAD, splenomegaly
• PET: patchy FDG uptake in SI only (while on high dose steroids)
• Normal Igs (IgG: 930, range: 650-2000; IgM 63, range: 40-270; IgA: 202, range: 50-500)
• Normal/moderately elevated IL-6 (6, nml <5)
• No light chain restriction
• Negative SPEP and UPEP

A bone marrow biopsy reported:

• Hypercellular marrow (90%) with myeloid and megakaryocytic hyperplasia, and emperipoesis.
• Small perivascular lymphohistiocytic aggregate
• Reticulin fibrosis was also noted with &ldquo;cytological atypia of the megakaryocyte lineage (FVIII+, CD61+)&hellip;&rdquo;
• &ldquo;increased CD68+ macrophages (10%)&hellip;&rdquo;
• &ldquo;myeloid: erythroid ratio of 6:1&rdquo;
• &ldquo;Large CD34- cKit+ blasts.&rdquo;
• &ldquo;Rare macrophages and megakaryocytes that contain red and white blood cells.&rdquo;

A lymph node biopsy was scheduled to be performed.