Treatment consistent with idiopathic multicentric Castleman disease guidelines is associated with improved outcomes

Abstract

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with an unknown etiology. Clinical presentation is heterogeneous, ranging from mild constitutional symptoms with lymphadenopathy to life-threatening multiorgan dysfunction. International, consensus treatment guidelines developed in 2018 relied upon a limited number of clinical trials and small case series; however, to our knowledge, real-world performance of these recommendations has not been subsequently studied. Siltuximab, a monoclonal antibody against interleukin 6 (IL6), is approved for the treatment of iMCD and recommended first-line, and tocilizumab, a monoclonal antibody directed against the IL6 receptor, is recommended when siltuximab is unavailable. Chemotherapy, rituximab, and immunomodulators are recommended as second- and third-line treatments based on limited evidence. Corticosteroid monotherapy is used by clinicians, although not recommended. Here, we draw upon the ACCELERATE Natural History Registry to inventory regimens and evaluate regimen response for 102 expert-confirmed iMCD cases. Siltuximab with/without (w/wo) corticosteroids was associated with a 52% response, whereas corticosteroid monotherapy was associated with a 3% response. Anti-IL6-directed therapy with siltuximab or tocilizumab demonstrated better response and more durability than was observed with rituximab w/wo corticosteroids. Cytotoxic chemotherapy was associated with a 52% response and was predominantly administered in patients characterized by thrombocytopenia, anasarca, fever, renal failure/reticulin fibrosis, and organomegaly. Our results provide evidence in support of current recommendations to administer anti-IL6 as first-line treatment, to administer cytotoxic chemotherapy in patients with severe refractory disease, and to limit corticosteroid monotherapy. Evidence remains limited for effective agents for patients who are refractory to anti-IL6-directed therapy. This trial was registered at www.clinicaltrials.gov as #NCT02817997.

Graphical abstract

Figure 1.

Many treatments across several treatment categories are used in the treatment of iMCD. (A) Patients with iMCD receive a variety of treatments, including corticosteroids (91%), immunomodulators (68%), antineoplastic agents (30%), and anti-IL6–directed therapy (85%). (B) Forty-one unique drugs have been administered across a cohort of 102 patients with iMCD, and siltuximab, the first-line recommended therapy, has been administered to 65% of this cohort as part of various regimens.

Figure 2.

Treatment regimen administration in iMCD is highly variable and more generalized regimens are often administered before confirmed diagnosis. (A) Thirteen different regimen categories were identified and administered among this cohort. A total of 304 regimens were administered among the 102 patients with iMCD. Fifty-one (50%) patients received siltuximab w/wo corticosteroids at least once throughout their treatment course. The plot is sequentially ordered with the earliest enrollees at the bottom and the most recent enrollees at the top. Regimens administered before confirmed diagnosis are represented to the left of the vertical bar, and regimens administered on, or after, diagnosis are represented to the right of the vertical bar. (B) Given variability in presentation and the time until accurate diagnosis, some regimens are administered before confirmed diagnosis. In this cohort, 49% of the corticosteroid regimens were administered before confirmed diagnosis, whereas only 1.7% of the siltuximab w/wo corticosteroids regimens were administered before confirmed diagnosis. In this figure, regimens defined as immunomodulator(s) w/wo corticosteroids, anti-IL6 therapy + rituximab w/wo other treatments, anti-IL6 therapy + immunomodulator(s) w/wo corticosteroids, anti-IL6 therapy + procedure w/wo corticosteroids, procedure + drug therapy, procedure, and no medical treatment have been combined into an “Other” category. CS, corticosteroids.

Figure 3.

Regimen response by severity, and relationship between severity and clinical subtype. (A) Best response by regimen category stratified by disease severity at the start of the regimen. Each dot represents a given patient within a regimen category and severity status colored by best response (responder status indicated by blue, and non-responder status indicated by gold). Within each regimen category, there was a higher number of regimens initiated in mild/moderate compared with severe disease. A comparable proportion of patients achieved a response to siltuximab w/wo corticosteroids during both mild/moderate (57%) and severe (42%) disease. Corticosteroids alone was associated with response in 1 patient during mild/moderate disease only. (B) Severe disease was strongly associated with TAFRO status (ꞵ = 3.14; 95% CI, 2.00-4.27; P < .001). The majority (91.2%) of regimens initiated in severe disease occurred in patients with TAFRO subtype, but regimens initiated in mild/moderate disease occurred equally among patients with TAFRO (50.3%) and NOS (49.7%) subtypes.

Figure 4.

Laboratory parameters indicate that some regimen categories outperform others. Mean and standard error of (A) hemoglobin (red) and albumin (blue) and (B) CRP at the initiation of a given regimen category (closest value within ± 7 days) and at the time of best response (closest value within ± 7 days). Anti-IL6–directed therapies show the most dramatic improvements in laboratory parameters, whereas corticosteroids show limited improvement. Slope between time points shown; available data points contributing to plots provided below plots. Only statistically significant results are marked, and statistical significance is defined by the number of asterisks: ∗P ≤ .05, ∗∗P ≤ .01, ∗∗∗P ≤ .001, and ∗∗∗∗P < .00001.

Figure 5.

Time-to-event analysis highlights the durability of anti-IL6–directed therapies. (A) Survival curve showing time to event by regimen category. Event is defined as disease progression or start of new regimen. (B) Results from a Cox proportional hazards model comparing siltuximab w/wo corticosteroids, tocilizumab w/wo corticosteroids, rituximab w/wo corticosteroids, and chemotherapy-based regimens, stratified by severity and controlled for age, sex, and clinical subtype. Siltuximab w/wo corticosteroids demonstrated stronger durability over rituximab w/wo corticosteroids (hazard ratio, 2.72; 95% CI, 1.50-4.91; P = .001).