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Peer-reviewedCC BY 4.0Frontiers in Immunology

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

  • Remi Sumiyoshi1,2
  • Tomohiro Koga1
  • Toru Michitsuji1
  • Masataka Umeda1
  • Ayuko Takatani1
  • Yoshito Nishimura3
  • David C Fajgenbaum4
  • Frits van Rhee5
  • Atsushi Kawakami2,6,7
7 affiliations
  1. 1Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences
  2. 2Clinical Research Center, Nagasaki University Hospital
  3. 3Division of Hematology, Mayo Clinic
  4. 4Division of Translational Medicine and Human Genetics, University of Pennsylvania
  5. 5Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences
  6. 6DEJIMA Infectious Disease Research Alliance (DIDA), Nagasaki University
  7. 7Biomedical Research and Career Support Office, Nagasaki University
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Abstract

Introduction: 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.

Methods: 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 >15×10 ⁴ /µL, improvement of anasarca, or a ≥50% rise in eGFR) at 3 and 12 months.

Results: 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.

Discussion: 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.

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Cite

BibTeXRIS
BibTeX
@article{sumiyoshi2026addon,
  title = {{Add-on sirolimus in refractory iMCD-TAFRO: a TAFRO-enriched 8-patient case series with paired single-cell profiling}},
  author = {Remi Sumiyoshi and Tomohiro Koga and Toru Michitsuji and Masataka Umeda and Ayuko Takatani and Yoshito Nishimura and David C Fajgenbaum and Frits van Rhee and Atsushi Kawakami},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1963440},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1963440/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Add-on sirolimus in refractory iMCD-TAFRO: a TAFRO-enriched 8-patient case series with paired single-cell profiling
AU  - Remi Sumiyoshi
AU  - Tomohiro Koga
AU  - Toru Michitsuji
AU  - Masataka Umeda
AU  - Ayuko Takatani
AU  - Yoshito Nishimura
AU  - David C Fajgenbaum
AU  - Frits van Rhee
AU  - Atsushi Kawakami
PY  - 2026
DA  - 2026/10/16
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1963440
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1963440/full
AB  - Introduction: 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.  Methods: 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 >15×10 ⁴ /µL, improvement of anasarca, or a ≥50% rise in eGFR) at 3 and 12 months.  Results: 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.  Discussion: 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.
SN  - 1664-3224
ER  -