Page 187 - Haematologica Vol. 109 - July 2024

ARTICLE - Disease burden of idiopathic MCD
both subtypes in the context of a general population and given that most of our cohort were from the USA, we accessed the NHIS 2018 survey data20 and identified a control population of 408 individuals matched for age (±1 year), sex, and race. In a 12-month period, control patients were hospitalized for a median (IQR) of 0 (0-0) days. The number of days hospitalized differed between the general population and both TAFRO (W=47.5; P<2.2x10-16) and NOS (W=5,638; P=8.3x10-13) patients. This demonstrates that compared to the general population, patients with iMCD require substantially greater use of the healthcare system and frequently need to be admitted to hospital.
We hypothesized that initiating a course of treatment for iMCD would result in a reduction in the time spent in hospi- tal. To test this hypothesis, we first compared the proportion of patients hospitalized at the initiation of the first iMCD treatment regimen, excluding corticosteroid monotherapy, to the proportion hospitalized 4 weeks after initiating a treatment regimen. Four weeks after initiation was select- ed to allow sufficient time for the respective treatment regimen to have an effect. Among the 99 patients who re- ceived treatment with at least one regimen, 49 (49.5%) were hospitalized at the time of starting the treatment regimen. After 4 weeks of treatment, the number hospitalized had been reduced to 20 (20.2%) patients (X=17.4; P=3.0x10-5). We stratified the patients by type of treatment regimen, considering the regimens most frequently administered as first-line therapy, including siltuximab ± corticosteroids, tocilizumab ± corticosteroids, rituximab ± corticosteroids, chemotherapy-based regimens, and immunomodulator(s) ± corticosteroids. Corticosteroid monotherapy was not included in this analysis given that this approach is not recommended and patients often receive a short course while awaiting a correct diagnosis. We found that among the 32 patients treated with siltuximab ± corticosteroids as first-line therapy, 11 (34.3%) were hospitalized at the time of regimen initiation, and two (6.3%) were hospitalized 4 weeks after starting the treatment regimen (P=0.01). While fewer patients were hospitalized 4 weeks after starting treatment with each of the other regimens, we did not find any other statistically significant differences, although small sample sizes limit interpretation (Online Supplemen- tary Table S4). Overall, these data demonstrate the clear burden of hospitalizations early in the course of iMCD and the importance of administering targeted therapy at the time of diagnosis.
Patients with idiopathic multicentric Castleman disease often require urgent interventions and demonstrate multisystem organ involvement
Considering the degree of hospitalization burden, we next investigated the distribution of organ system involvement among iMCD patients ± 365 days from diagnosis (Online Supplementary Methods). Cytopenias were the most com- mon laboratory abnormalities, experienced by 97.1% (n=99)
M. Sarmiento Bustamante et al. of the cohort. This most frequent abnormality was anemia,
which was present in 87 (85.3%) patients. We also found large proportions of patients experiencing symptoms or laboratory abnormalities related to other organ systems, such as respiratory (n=90, 88.2%), gastrointestinal (n=86, 84.3%), hepatic (n=76, 74.5%), neurological (n=68, 66.7%), renal (n=63, 61.8%), cardiovascular (n=63, 61.8%), and ocular (n=27, 26.5%) systems (Figure 3A, Online Supplementary Tables S5 and S6).
Next, we looked at life-sustaining interventions related to organ system involvement. We found that 27 (26.5%) pa- tients required dialysis and 17 (16.7%) patients required a ventilator during at least one iMCD-related hospitalization. Additionally, 47 (46.0%) patients required paracentesis, 42 (41.1%) patients received a red blood cell transfusion, and 22 (21.6%) patients received a platelet transfusion (Figure 3B). These interventions, including all platelet transfusions, were mostly required for TAFRO patients.
We also quantified the proportion of time patients spent in a state of flare. We found that NOS patients spent a significantly greater proportion of time in flare from pre- sentation until last known follow-up (median [IQR]: 52.3% [21.0-99.6]) compared to TAFRO patients (18.9% [10.8-52.5], W=1,673; P=0.004) (Figure 3C, D). Of the eight deceased patients in this cohort, six had TAFRO and five of these TAFRO patients died within 2 years of diagnosis. These data suggest that while TAFRO patients experience a greater degree of organ failure and more hospital interventions, NOS patients experience a longer continuation of milder, chronic symptoms.
Patients with idiopathic multicentric Castleman disease develop severe disease-related morbidities and comorbidities following diagnosis
We next sought to identify and quantify the morbidities and comorbidities occurring both before and after the diagnosis of iMCD. Prior to the iMCD diagnosis, we found that the most common conditions diagnosed among the full cohort were hypertension (n=26, 25.5%), obesity (n=23, 22.5%), asthma (n=21, 20.6%), gastroesophageal reflux disease (n=14, 13.7%), and depression (n=11, 10.8%) (Figure 4A). Stratification by iMCD subtype did not reveal apparent differences in conditions identified before the diagnosis of iMCD (Online Supplementary Figure S1).
Following the iMCD diagnosis, 48% (n=49) of the cohort developed acute renal failure, 15.7% (n=16) developed chron- ic kidney disease, 13.7% (n=14) developed iron deficiency anemia, 10.7% (n=11) developed pneumonia, 6.9% (n=7) developed sepsis, and 6.9% (n=7) developed thrombotic microangiopathy (Figure 4B). Acute renal failure was the most common iMCD-related morbidity diagnosed follow- ing disease onset in both subtypes (Online Supplementary Figure S2). Sepsis and thrombotic microangiopathy were, however, primarily diagnosed in TAFRO patients. We al- so stratified the top three morbidities arising for the full
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