Page 190 - Haematologica Vol. 109 - July 2024

ARTICLE - Disease burden of idiopathic MCD Discussion
iMCD is a rare, heterogeneous disorder, and its full impact on patients’ lives is still not well understood. Since the consensus diagnostic criteria for iMCD are relatively new, long-term epidemiological and medical data from patients with confirmed iMCD are sparse. The ACCELERATE natural history registry is ideally suited to better understand the burden of disease as the most extensive source of longi- tudinal clinical data (median 3.4 years of follow-up after diagnosis) for these patients. ACCELERATE also provides independent adjudication about the accuracy of diagnosis for each patient through a panel of clinicians and hema- topathologists who are experienced in diagnosing and treating iMCD.18 We found that patients with iMCD require extensive use of the healthcare system and experience long-term effects in terms of iMCD-related morbidities and comorbidities, time in disease flare, and QOL.
There are distinct clinical subtypes of iMCD and, important- ly, we found differences in the burden of disease between these subtypes. Patients with TAFRO required significantly longer stays in hospital and disproportionately required interventions such as dialysis, mechanical ventilation, and transfusions, illustrating the severe, life-threatening nature of this disease. NOS patients, however, spent a significantly greater proportion of time following diagnosis in a state of flare compared to TAFRO patients. These data reveal the challenges iMCD patients experience across the spectrum of clinical subtypes and severity. The patient-reported out- come data from our study indicate that patients with both subtypes continue to experience an impact on their QOL even years after diagnosis and that persistent iMCD-related symptoms lower QOL significantly. Notably, QOL scores re- flect the state of patients who have thus far survived their disease and may, therefore, be biased towards a healthier subset of the disease population.
Although NOS patients spent significantly less time in hos- pital, we found that 51.3% met criteria for severe disease at presentation. This remains lower than the 93.4% of TAFRO patients who presented with severe disease. A recent study from China characterizing 418 iMCD-NOS patients applied the same definition of severity and found that only 87 (21%) patients met criteria for severe disease at presentation.13 The researchers also noted a lower 3-year overall survival rate among NOS patients with severe (76%) compared to mild/moderate (94%) disease and found that severity at diagnosis was associated with death. Notably, our study showed high proportions of patients in both younger (<30 years) and older (>60 years) age groups who presented with severe disease. In our study, patients under 30 years old were significantly more likely to present with severe disease, and nearly all patients <18 years presented with severe disease. This may be associated with the median age of the TAFRO subtype of patients being 31 years, compared to 39 years for patients with iMCD-NOS, and with the fact
M. Sarmiento Bustamante et al.
that 93% of TAFRO patients presented with severe disease. The relatively young age at diagnosis, burden of disease, and availability of disease-controlling therapies highlight the importance of rapid diagnosis and treatment.
This study found that iMCD patients experienced a greater degree of hospitalization than the general population ex- periences in a given year, with this being primarily due to the increased rates of hospitalization among iMCD-TAFRO patients.20 Our observation that patients required extensive hospital care in the year surrounding diagnosis is consis- tent with the findings of a recent claims-based study.17 We found that 4 weeks after the first-administered treatment regimen, the proportion of hospitalized patients decreased significantly, including patients treated with siltuximab ± corticosteroids (34% vs. 6%), which is the current consen- sus first-line recommendation.15
We also found that the conditions most frequently diag- nosed in our cohort prior to the diagnosis of iMCD were similar to those among the general USA population. A report from the Agency for Healthcare Research and Quality found that hypertension, diabetes, and chronic respiratory disease were among the most common conditions associated with inpatient stays and that depression was present in 10% of patients requiring admission to hospital,22 which is similar to the findings in our cohort prior to the diagnosis of iMCD. We did not identify a condition present in a large proportion of iMCD patients prior to the iMCD diagnosis that might suggest a predisposition or trigger to iMCD, which has an as-yet-unknown etiology. Following the diagnosis of iMCD, patients in both the TAFRO and NOS subtypes developed life-threatening morbidities, most commonly acute renal failure. Consistent with previous reports, we found a high degree of both renal and hepatic dysfunction.17
In this cohort, few patients developed a malignancy following the diagnosis of iMCD. In fact, only one patient developed a myeloid malignancy (myelodysplastic syndrome), which contrasts with a key finding from a systematic literature review and a claims-based study that found an increase in myeloid and solid malignancies.17,23 No patients developed diffuse large B-cell lymphoma despite previous reports of its association with MCD, though predominantly in human herpes virus 8-positive MCD.24-26 We found that our rate of malignancies was comparable to that in the control population in the claims-based study.17 This discrepancy may be due to insufficient follow-up time to detect sub- sequent malignancies or to more rigorous validation of the iMCD diagnosis in our cohort and recent formalization of exclusion criteria for iMCD. Specifically, iMCD diagnostic criteria preclude patients from being concurrently diag- nosed with iMCD and a number of malignancies, given the overlapping histopathology and the fact that malignancies can cause reactive lymph node changes that resemble iMCD. It is, therefore, possible that some patients in the claims-based study who should have only been classi- fied as having a malignancy were incorrectly classified as
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