Treatment History in Castleman Disease. A Real-world Case Series from Italian Tertiary Referral Centres

Introduction:
Castleman disease (CD) is a group of rare, heterogeneous lymphoproliferative disorders that share histological features and have varying grades of severity. CD is classified into unicentric (UCD) and multicentric (MCD); MCD can be idiopathic (iMCD) or caused by uncontrolled human herpes virus-8 infection (HHV-8-associated MDC) or by polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome. The difficulty of the diagnosis stems from the variability of clinical presentation of the disease, which may mimic neoplastic, haematological, infectious, or rheumatologic conditions. Since the publication of international, evidence-based consensus on the treatment of iMCD in 2018, as a first-line treatment, patients are treated with siltuximab, a monoclonal antibody anti-interleukin-6 with/without corticosteroids. Here we reviewed the treatment history of 6 cases with iMCD and 1 with POEMS-associated MCD diagnosed in the decade between 2011 and 2021.
Methods:
Cases of iMCD referred to haematologists were identified in electronic patient records of seven Italian tertiary referral centres (University of Eastern Piedmont and AOU Maggiore della Carità, Novara; AOU Policlinico “G. Rodolico - S. Marco”, Catania; Policlinico San Martino IRCCS, Genoa; Spedali Civili Hospital, Brescia; Parma University Hospital, Parma; General Hospital, AULSS2 Veneto Marca Trevigiana, Treviso and Policlinico Tor Vergata, Rome). Data on clinical and laboratory signs and symptoms at presentation, and treatment history were considered.
Results:
We identified seven cases (5 males and 2 females, aged 54.8 ± 7.1 years) in whom the differential diagnosis was in favour of MCD and in whom there was no diagnostic delay. Four patients were diagnosed before 2018. Patients presented most frequently with lymphadenopathy (6 cases), fever (5 cases), oedema (2 cases), night sweats (2 cases), painful joints (2 cases), weight loss (2 cases). Laboratory examinations showed elevated C-reactive protein and erythrocyte sedimentation rate in most cases, a variable degree of anaemia and of platelet count alteration. IL-6 was increased in the only case in whom it was measured. In one of the patients, iMCD occurred after the diagnosis of POEMS in 2011. The patient with POEMS-associated iMCD had the most complicated treatment history (combination chemotherapy, steroids, rituximab, siltuximab with corticosteroids, bortezomib, lenalidomide). In this case, siltuximab treatment led to a near-complete resolution of symptoms for 9 months. The other three cases diagnosed prior to 2018 received rituximab, chemotherapy and steroids and were eventually switched to siltuximab. The switch to siltuximab determined the onset of complete and durable response in all three cases. Patients diagnosed after 2018, instead, were offered siltuximab upfront when the diagnosis of iMCD was confirmed. One of them achieved complete remission, whereas in the other two cases the response was partial, although, in one of them siltuximab was stopped due to COVID-19.
Discussion:
Here, we show that the publication of the international guidelines determined a change in the management of patients with iMCD. Indeed, patients diagnosed before the publication of the international guidelines received heterogenous first-line treatment that included steroids, rituximab and/or chemotherapy, whereas patients who presented with iMCD after, received upfront siltuximab. All seven cases had at least partial response to siltuximab.