Molecular Evidence (rationale) for Calcineurin targeted therapy in iMCD patients:
- Calcineurin lowers T cell activity and immune response by binding to cyclophilin, a multifunctional protein that facilitates protein folding, acts as a protein chaperone, and regulates the activity of other proteins. The resulting ciclosporin/cyclophilin complex inhibits the phosphatase activity of calcineurin which in turn is required for the activation of transcription factors that up-regulate the expression of inflammatory cytokines. (Matsuda et al)
- 20 out of 21 iMCD patients had increased soluble IL-2 receptor, which is a marker of T cell activation (Liu et al), therefore inhibition of calcineurin prevents T cell activation.
Case Reports of anti-calcineurin therapy for iMCD patients:
Cyclosporin is a calcineurin inhibitor which prevents T cell activation and therefore acts to suppress the immune system. Three iMCD patients that have received cyclosporin have been described in published case reports. Cyclosporin monotherapy achieved complete remission in an iMCD-TAFRO patient. Cyclosporin in combination with other drugs achieved partial response in one iMCD patient and complete remission in a iMCD-TAFRO patient. Please see patient descriptions below.
- 49-year-old female status-post C-section with iMCD-TAFRO received 2nd-line cyclosporin A with complete remission for 1 month. Prior therapy included corticosteroid (dexamethasone, prednisolone) with partial response for 1 month. On the 36th day, patient was treated with cyclosporin A (5 mg/kg) with complete remission for 1 month without relapse. Prednisolone was stopped on the 53rd day after tapering. (Inoue et al)
- 30-year-old female with iMCD and paraneoplastic pemphigus vulgaris received 2nd-line daily cyclosporin A, corticosteroids and thalidomide with partial response for 36 months. Patient then had surgical resection of tumor, after which, the steroid dose was decreased to 8 mg daily, together with the initial dose of thalidomide and cyclosporin A and patient remained on thalidomide daily with no tumor progression. 1st-line therapy was steroids with partial response for 12 months. (Miltenyi et al)
- 25-year-old male with iMCD-TAFRO received 5th-line cyclosporine, rituximab, IVIG and cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin, cyclophosphamide and etoposide) with maintenance therapy of IVIG and sirolimus with complete response for 39 months. 1st-line therapy of corticosteroids achieved partial response for 2 months and then the patient relapsed. 2nd-line treatment with rituximab achieved partial response for 2 months and then the patient relapsed. 3rd-line siltuximab, corticosteroids, rituximab, IVIG, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin, cyclophosphamide and etoposide) and maintenance therapy of thalidomide, bortezomib, dexamethasone, rituximab (for 3 months) and ongoing siltuximab achieved a complete remission for 15 months and then the patient relapsed. 4th-line therapy of rituximab, tocilizumab, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin, cyclophosphamide and etoposide) with maintenance therapy of thalidomide (daily), bortezomib (weekly), dexamethasone (weekly), and siltuximab (every 3 weeks) for full response and then relapsed at 17 months. 5th-line therapy of rituximab, cyclosporine, IVIG, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin, cyclophosphamide and etoposide) with maintenance therapy of IVIG and sirolimus with complete response for 39 months. (Patient reported in Fajgenbaum et al with subsequent data collected.)
Clinical Trials targeting calcineurin in iMCD:
No clinical trials targeting calcineurin in iMCD patients have been conducted.