Tafro Syndrome without Pathological Evidence Consistent with Castleman Disease: A Subtype of Tafro or a Distinct Disease Entity?

Introductions: TAFRO syndrome, characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly, was primarily considered a distinct subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO). Patients often experience severe cytokine storm, leading to multiorgan failure (even death) if not treated adequately and promptly. According to CDCN (Castleman Disease Collaborative Network), the diagnostic criteria for iMCD-TAFRO require pathological evidence consistent with Castleman disease (CD). However, obtaining lymph node biopsies is challenging for TAFRO patients (TAFRO without pathological evidence, TAFRO-w/op-iMCD) (Am J Hematol 2021, 96:1241-1252) due to the unapparent lymphadenopathy and high-risk of bleeding caused by thrombocytopenia. Even with significant effort, biopsies may not yield conclusive pathological findings consistent with iMCD spectrum (TAFRO-w/o-iMCD) (Am J Hematol 2021, 96:1241-1252). Without a definite pathological diagnosis of Castleman disease for patients with TAFRO-w/o-iMCD and TAFRO-w/op-iMCD, treatment might be delayed which would bring poor diagnosis. Thus, it is crucial to figure out whether these patients should be also treated as iMCD-TAFRO. Previous studies demonstrated that TAFRO-w/op-iMCD patients showed no significant differences in clinical presentation, laboratory findings, and treatment efficacy compared with iMCD-TAFRO patients and could be regarded as a subtype of TAFRO syndrome. However, it remains unclear whether TAFRO-w/o-iMCD should be treated as a subtype of TAFRO syndrome.

Methods: This retrospective, single-center study included patients diagnosed with iMCD-TAFRO and TAFRO-w/o-iMCD from May 2015 to April 2024. The diagnostic criteria for TAFRO syndrome require all three major categories and at least two of four minor categories and failing to satisfy any of the suggested exclusion criteria (Int J Hematol 2020, 111:155-158). Patients with TAFRO syndrome were categorized into iMCD-TAFRO, TAFRO-w/op-iMCD, and TAFRO-w/o-iMCD and we included patients with iMCD-TAFRO and TAFRO-w/o-iMCD for further analysis. Treatment response (symptomatic response and biochemical response) was evaluated according to the CDCN guidelines, with primary outcomes being response rates at 3 months, 6 months, and the best overall response. Secondary outcomes included 3-year estimated progression-free survival (PFS), overall survival (OS) rates, and 3-month mortality rate. Chi-square and t-tests were used for dichotomous and continuous variables, respectively. Kaplan-Meier method depicted survival curves and log-rank test was utilized to compare. Univariate logistic regression analyzed potential progression factors.

Results: A total of 61 patients were included, comprising 50 iMCD-TAFRO and 11 TAFRO-w/o-iMCD. Both groups showed no significant differences in clinical presentations (fatigue, anasarca, fever, organomegaly, and skin involvement) and laboratory data (including hemoglobin, platelets, creatinine, hypersensitive C-reactive protein, and interleukin-6). Each group had one patient who achieved spontaneous remission, while the remaining 59 patients were treated with iMCD-targeted strategies addressing cytokine storm. With a median follow-up time of 21.4 (range, 0.5-107.0) months, there were no significant differences between iMCD-TAFRO patients to TAFRO-w/o-iMCD patients in terms of the 3-month response rate (72.1% vs. 88.9%, P=0.525), 6-month response rate (70.0% vs. 83.3%, P=0.849), and best overall response rate (77.6% vs. 90.0%, P=0.645). Additionally, the 3-month mortality rate (12.0% vs. 0%, P=0.515), estimated 3-year PFS rate (65.8% vs. 90.0%, log-rank P=0.163), and estimated 3-year OS rate (77.0% vs. 100%, log-rank P=0.145) were also not significantly different. Decreased eGFR level (< 60ml/min/1.73m²) was associated with an increased risk of disease progression (OR=5.556, 95%CI: 1.653-18.672, p=0.006) in our entire patient cohort.

Conclusions: iMCD-TAFRO and TAFRO-w/o-iMCD patients could be considered as the same disease entity and should be treated promptly, targeting the cytokine storm using similar treatment strategies.

No relevant conflicts of interest to declare.