Page 183 - Haematologica Vol. 109 - July 2024

ARTICLE - Disease burden of idiopathic MCD
M. Sarmiento Bustamante et al.
phenotype.7 A subset of NOS patients have thrombocytosis and hyper-gammaglobulinemia and have historically been de- scribed as having idiopathic plasmacytic lymphadenopathy.8 A recent epidemiological study based on USA insurance claims found that approximately 1,000 patients were di- agnosed with iMCD each year.9 Making a diagnosis of iMCD is challenging because it is based on non-specific clinical features and characteristic lymph node histopathology. Underdiagnosis is likely as diagnostic criteria were not developed until 2017, and there is no known diagnostic serum biomarker.10 Challenges with diagnosis and limited understanding of the disease burden may contribute to poor outcomes. Data from the USA before 2012 suggested 5- and 10-year mortality rates of 35% and 60% for iMCD patients whereas more recent data from electronic medical records suggest 25% mortality at 5 years.11,12 Three-year sur- vival estimates based on a recent large cohort of patients in China were 65.7% for TAFRO patients, 87.2% for NOS patients without the characteristics of idiopathic plasma- cytic lymphadenopathy, and 98.5% for NOS patients with the features of idiopathic plasmacytic lymphadenopathy.13 In the USA and Europe, siltuximab, a monoclonal antibody directed against interleukin 6, is the only approved treat- ment and first-line recommended therapy.14,15 Tocilizumab, a monoclonal antibody directed against the interleukin 6 receptor, is recommended when siltuximab is not available and is approved for use in iMCD in Japan.16 For patients with severe disease who do not respond to first-line treatment with interleukin 6 blockade, multiagent cytotoxic chemo- therapy is recommended.15
Due to its rarity and heterogeneous nature, the natural history and long-term burden of iMCD are not well under- stood. In light of the limited understanding of the burden of disease and the significant consequences of underes- timating the risks of iMCD,17 we sought to investigate the burden of iMCD on patients and the healthcare system. ACCELERATE (NCT02817997), a longitudinal natural his- tory study of Castleman disease, is ideally positioned to characterize the natural history and burden associated with iMCD. Herein, we present data from ACCELERATE to demonstrate that iMCD patients face a high burden of disease with severe multisystem organ involvement, the onset of life-threatening iMCD-related morbidities, long periods of hospitalizations during which interventions are frequently required, and extensive periods of time spent with flares of active disease.
Methods
Study population
Patients with a pathology report suggestive of Castleman disease were invited to enroll into ACCELERATE beginning in October 2016.18 Enrollment is open to patients in the USA and globally. Given that the registry website is written
in English and records from institutions in English-speak- ing countries are more feasibly obtained, there is a bias towards enrollment of English-speaking patients. After enrollment, all available medical data from the time of symptom onset to the time of analysis were collected from each patient’s treating institution(s). Data were re- viewed and abstracted into the study database, and each case underwent a rigorous, systematic review by three hematopathologists and four hematologist-oncologists to confirm the accuracy of the iMCD diagnosis. While it is impossible to know the exact number of patients in this study who have been investigated previously, it is possible that some patients have been included in prior case reports/small series.
Outcome definitions
Diease severity at diagnosis was classified according to the iMCD treatment guidelines and at least two criteria had to be met for a diagnosis of severe iMCD: an Eastern Cooper- ative Oncology Group performance status ≥2 or hospital- ization, fluid retention, hemoglobin ≤8.0 g/dL, pulmonary involvement/interstitial pneumonitis with dyspnea, or stage IV renal dysfunction within 90 days of the diagnosis made by lymph node biopsy.15
To ensure standardization, we defined a new flare as the onset of at least two new iMCD disease symptoms or the clinical worsening of previously stable signs or symptoms. Flares also required at least one laboratory finding from the iMCD diagnostic minor criteria that was previously normal to become abnormal. A flare ended when a patient achieved at least 50% reduction of symptoms (minor criteria from the iMCD diagnostic criteria).10
The Systematized Nomenclature of Medicine – Clinical Terms (SNOMED-CT) ontology was used to categorize iMCD-related morbidities and comorbidities.
Patient-reported outcomes
Patients enrolled in ACCELERATE were given outcome surveys every 3 months throughout the duration of their enrollment. Data were analyzed from patients who com- pleted the survey at least once. Response data from Eu- roQoL five-dimension, five-level (EQ-5D-5L), a validated quality-of-life (QOL) questionnaire, and from the MCD symptom score, a validated MCD symptom survey devel- oped for the phase II siltuximab clinical trial, were analyzed for each patient’s most recent survey completion date.14 The EQ-5D-5L captures health on the day of the survey, as well as ease with each of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The MCD symptom survey captures 16 symptoms on a scale scored from 1 to 6 with 1 being the least severe (did not experience) and 6 being the most severe (very severe). The sum of the responses yields the total MCD symptom score. The 16 symptoms assessed included cough, short- ness of breath, loss of appetite, fatigue, lack of energy,
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