International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease

Abstract

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Figure 1.

CDCN severity classification for rapid assessment and allocation of therapy. Patients with severe iMCD must have at least 2 of the 5 criteria listed above. Patients should be classified as nonsevere iMCD if the above criteria are not met. ECOG, Eastern Cooperative Oncology Group; eGFR, estimated glomerular filtration rate.

Figure 2.

Treatment algorithm for iMCD. iMCD patients should be stratified for disease severity per Figure 1. For nonsevere iMCD, siltuximab is recommended as frontline therapy for patients with nonsevere iMCD. Tocilizumab can be used if siltuximab is not available or approved. Steroids are useful adjunctive therapy, and the dose can be tailored according to the severity of the disease. Patients responding to anti–IL-6 mAb therapy should be continued indefinitely. *For patients with mild symptomatology, a limited course of rituximab is an alternative option. Patients not responding to anti–IL-6 mAb therapy should be considered for rituximab-based therapy + steroids ± immunomodulatory/immunosuppressive agents. ♠Immunomodulatory/immunosuppressive agents for second- or third-line therapy include thalidomide, cyclosporine A, sirolimus, anakinra, or bortezomib, but we recommend consulting with an expert at this stage. For severe iMCD, severe disease must be closely monitored, as life-threatening events may occur in this population. Severely ill patients should be treated with siltuximab and high-dose steroids, but if no clear response occurs within 1 week (or if status worsens at any time), then combination chemotherapy should be considered. When possible, expert advice should be sought to identify the most appropriate therapy for a given patient. Further therapy is best individualized. †Examples of chemotherapy include R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-VDT-PACE (rituximab, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide), or etoposide/ cyclophosphamide/rituximab. Siltuximab is the preferred anti–IL-6 therapy. However, in countries where siltuximab is not available or approved, tocilizumab can be used instead. Supporting evidence category 1, green boxes; category 2A, yellow boxes; category 2B, blue boxes. CTC, common toxicity criteria.

Figure 3.

CDCN response criteria based on evaluation of biochemical, lymph node, and symptom response. Biochemical, lymph node, and response criteria have been detailed in the text. For lymph node response, Cheson criteria have been modified to include assessment of skin manifestations. An overall CR requires a complete biochemical, lymph node, and symptomatic response. An overall PR requires nothing less than a PR across all categories, but not meeting criteria for CR. Overall SD requires no PD in any of the categories and not meeting the criteria for CR or PR. An overall PD occurs when any category has a PD. Symptomatic and biochemical response evaluation should be done on a monthly basis until maximum response has been achieved. Radiological assessment of lymph node response by CT scanning is first recommended at 6 weeks and at 3-monthly intervals thereafter until maximum regression of lymph nodes has occurred. Lymph node response may take several months in patients treated with anti–IL-6 mAbs.