Add-on sirolimus in refractory iMCD-TAFRO: a TAFRO-enriched 8-patient case series with paired single-cell profiling

Anti-IL-6 therapy with tocilizumab (TCZ) is ineffective in a proportion of patients with idiopathic multicentric Castleman disease (iMCD), particularly the TAFRO subtype, and rescue options remain limited. Evidence for mTOR inhibition comes mainly from cohorts in which iMCD-TAFRO was underrepresented.

Eight Japanese patients with refractory iMCD (iMCD-TAFRO, n=6; iMCD-NOS, n=1) or TAFRO syndrome without iMCD (n=1) received add-on sirolimus (1-2 mg/day). Five had active refractory iMCD-TAFRO at initiation and formed the efficacy set; Case 5 (sirolimus for glucocorticoid sparing), Case 1 (iMCD-NOS) and Case 3 (TAFRO syndrome without iMCD) are reported descriptively. Response was defined as improvement in at least one refractory feature (CRP <0.3 mg/dL, platelets >15×10⁴/µL, improvement of anasarca, or a ≥50% rise in eGFR) at 3 and 12 months.

In the efficacy set, 4/5 responded at 3 months (80%; 95% CI 28-99) and 3/4 evaluable at 12 months (75%; 95% CI 19-99); a prespecified TAFRO-phenotype analysis (n=6, including Case 3) gave 5/6 (83%; 95% CI 36-100) and 4/5 evaluable (80%; 95% CI 28-99). Under a prespecified stringent definition additionally requiring CRP normalization and no escalation of concomitant immunosuppression, proportions fell to 3/5 (60%) and 2/4 evaluable (50%), each reclassification resting on a single criterion. All six responders eventually discontinued sirolimus without relapse during available follow-up. Glucocorticoids were withdrawn in all four responders receiving prednisolone, TCZ intervals were extended to ≥5 weeks in three patients, and both patients with dialysis-dependent active disease stopped hemodialysis. Exploratory paired single-cell RNA sequencing in one TAFRO-phenotype patient showed reductions in inflammatory monocytes and B cells with lower cytotoxic and proliferative programs.

Given the very small sample, wide confidence intervals and the sensitivity of the estimates to the response definition, add-on sirolimus should be regarded as a hypothesis-generating adjunctive rescue option on top of standard treatment, not a substitute, in refractory iMCD-TAFRO.