Version July 2025
CBC: complete blood count; CER: cyclophosphamide, etoposide, and rituximab; CRP: C-reactive protein; CT: computed tomography; ECOG: Eastern Cooperative Oncology Group; HHV-8: human herpesvirus 8; IL-6: interleukin-6; iMCD: idiopathic MCD; IVIg: intravenous immune globulin; MCD: multicentric Castleman disease; PET: positron emission tomography; POEMS: syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes; VDT-ACE-R: bortezomib, dexamethasone, thalidomide, adriamycin, cyclophosphamide, etoposide, and rituximab.
* The diagnosis of POEMS syndrome in a patient with iMCD requires both polyneuropathy and monoclonal plasma cell proliferative disorder (positive M protein, almost always lambda) along with at least 1 of the following: organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy); extravascular volume overload (edema, pleural effusion, or ascites); endocrinopathy (adrenal, pituitary, gonadal, parathyroid, thyroid, or pancreatic); skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemagiomata, plethora, acrocyanosis, flushing, and white nails); papilledema; thrombocytosis or polycythemia.
¶ A more aggressive treatment approach is used for patients who present with poor performance status thought to be due to the iMCD or life-threatening organ failure. We consider patients with any 2 of the following 5 markers to have severe disease: ECOG performance status ≥2; estimated glomerular filtration rate <30 or creatinine >3; hemoglobin ≤8 g/dL; anasarca, ascites, pleural effusion, and/or pericardial effusion; pulmonary involvement and/or interstitial pneumonitis with dyspnea.
Δ Siltuximab (a monoclonal antibody targeted against IL-6) is approved in the United States and Europe for the treatment of HHV-8-negative MCD and is preferred for this population. If siltuximab is not available, tocilizumab (a monoclonal antibody targeted against the IL-6 receptor) is an acceptable alternative. For patients with mild to moderate disease, these agents can be given with or without glucocorticoids. While glucocorticoids can decrease the time to symptom control, they also increase toxicity.
◊ Patients with severe disease are followed daily with CRP, hemoglobin and platelet counts, albumin, creatinine, and liver function tests to adjust treatment as necessary. For those with mild to moderate disease, we perform a clinical assessment and laboratory studies (CRP, CBC, creatinine, albumin) every 2 weeks until laboratory values normalize. The time between evaluations is then gradually extended. Of note, IL-6 assays cannot be used to guide therapy for at least 18 to 24 months after the administration of siltuximab or tocilizumab because these assays detect complexed IL-6+drug and are therefore uninterpretable.
§ CT or PET/CT of the chest, abdomen, and pelvis with contrast is performed 6 weeks after the initiation of therapy and then every 3 months until maximum response.
¥ Multiagent systemic chemotherapy is added for those on siltuximab (with or without glucocorticoids) who experience progressive organ dysfunction that meets the criteria for severe disease. The optimal systemic chemotherapy approach has not been determined, but cyclophosphamide-based regimens with or without etoposide, rituximab, and/or doxorubicin have been shown to be effective. Limited data guide therapy selection. CER is our preferred initial regimen. If CER does not appear to be working or if there are increased plasma cells on lymph node and/or bone marrow histology ("plasmacytic" histopathology), we use VDT-ACE-R.
‡ Immunomodulator/immunosuppressant options include sirolimus, cyclosporine, anakinra, thalidomide, bortezomib, and IVIg. Immunomodulators/immunosuppressants are used for patients with organ failure not responding to siltuximab plus chemotherapy and for patients without organ failure who do not respond to siltuximab. Patients who achieve a sufficient response following therapy that incorporates 1 of these agents proceed to maintenance with that agent. Patients who do not experience a sufficient response should try alternative immunomodulators/immunosuppressants.
† We select a maintenance regimen based on whether the iMCD is likely to be sensitive to siltuximab. If the patient received 3 or more doses of siltuximab before the chemotherapy was started, the iMCD is siltuximab refractory, and other immunomodulators should be used in maintenance. If fewer than 3 doses of siltuximab were given before the chemotherapy was started, it is reasonable to offer maintenance siltuximab.
