Initial management of HHV-8-negative/idiopathic multicentric Castleman disease

HHV-8: human herpesvirus 8; MCD: multicentric Castleman disease; POEMS: syndrome of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes; HCT: hematopoietic cell transplantation; ECOG: Eastern Cooperative Oncology Group; IL: interleukin; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-CVP: rituximab, cyclophosphamide, vincristine, prednisone; VDT-ACE-R: bortezomib, dexamethasone, thalidomide, adriamycin, cyclophosphamide, etoposide, and rituximab; CER: cyclophosphamide, etoposide, rituximab; CT: computed tomography; PET/CT: combined positron emission tomography with computed tomography; CBC: complete blood count; LDH: lactate dehydrogenase; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate.
* 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 one of the following: organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy); extravascular volume overload (edema, pleural effusion, or ascites); endocrinopathy (adrenal, pituitary, gonadal, parathyroid, thyroid, pancreatic); skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, 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 two of the following five 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 Patients with severe disease are followed daily with CBC, blood chemistries, LDH, CRP (ESR, if CRP not available), fibrinogen, and liver function tests with albumin to adjust treatment as necessary. For those with non-severe disease, a clinical assessment and laboratory studies (CBC, creatinine, albumin, CRP) are initially performed every two weeks until lab 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.
◊ Chemotherapy options include cyclophosphamide, etoposide, doxorubicin, rituximab, bortezomib, or combinations such as R-CHOP, R-CVP, VDT-ACE-R, or CER.
§ Siltuximab (a monoclonal antibody targeted against IL-6) is approved in the US 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 non-severe disease, these agents can be given with or without glucocorticoids. While glucocorticoids can decrease the time to symptom control, they also increase toxicity.
¥ CT or PET/CT of the chest, abdomen, and pelvis with contrast is performed six weeks after the initiation of therapy and then every three months until maximum response.
‡ 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 one of these agents proceed to maintenance with that agent. Patients that do not experience a sufficient response should try alternative immunomodulators/immunosuppressants.