MTOR

Molecular Evidence (rationale) for mTOR targeted therapy in iMCD patients:

• mTOR blocks lymphocyte proliferation, angiogenesis and lymphocyte activation (Thomson et al), which are three hallmarks of Castleman disease.

Case Reports of anti-mTOR therapy for iMCD patients:

Sirolimus (Rapamycin) is an mTOR inhibitor (and therefore also blocks VEGF expression). One iMCD-TAFRO patient on sirolimus has been published in a systematic literature review and in a case series. See below for patient details. No case studies on patients treated with sirolimus have been published.

• One seriously ill iMCD-TAFRO patient achieved complete remission for 39 months on maintenance sirolimus and IVIG. Patient was previously refractory to corticosteroids, rituximab, and siltuximab therapy, responded well to a cycle of VDT-ACER, but relapsed 15 months later while on siltuximab maintenance administered every 3 weeks. The patient then responded to another cycle of VDT-ACE-R, but relapsed 16 months later while on siltuximab every 3 weeks and weekly VDT maintenance. The patient received a third round of VDT-ACE-R, which induced another complete remission. He was then started on maintenance IVIG and sirolimus. (The patient was reported in Iwaki et al. Subsequent data was collected from the patient.)
• “The combination of the mTOR inhibitor sirolimus with intravenous immunoglobulin…has led to extended remission in a patient with idiopathic multicentric Castleman’s disease with TAFRO features refractory to many other treatments”. (Liu et al)

Clinical Trials targeting mTOR in iMCD:

No clinical trials targeting mTOR in iMCD patients have been conducted.

• For non-responders to anti-IL-6 therapy, various alternative drugs exist, including sirolimus, “with little data or prognostic guidance with respect to which patients will respond to treatment. Agents that warrant further investigation include…the combination of the mTOR inhibitor sirolimus with intravenous immunoglobulin”. (Liu et al)