INTERLEUKIN-6 (IL-6)

Molecular Evidence (rationale) for IL-6 targeted therapy in iMCD patients:

Excess IL-6 causes “episodic systemic inflammatory symptoms, reactive proliferation of morphologically benign lymphnocytes, and multiple organ system impairment.” (Blood 2014)
“Rare cases of cytogenetic aberrations and light chain restriction have been described, including 1 report describing a translation involving the IL-6 gene.” (blood 2014)
“Human and animal studies have demonstrated IL-6’s role as a common mediator of iMCD symptomatology, histopathology, and pathogenesis. Symptoms typically wax and wane in accordance with serum IL-6 levels, which are often highly elevated in iMCD. Interruption of the IL-6 signaling cascade with anti-IL-6 or anti-IL-6 receptor monoclonal antibodies (mAb) often amerliorates iMCD symptoms and can lead to lymph node involution.” (Blood 2014)
There are also a portion of patients who do not have elevated IL-6 and do not improve with anti-IL-6 therapy.
After any anti-IL-6 treatment is administered, you should disregard all measured IL-6 levels. If anti-IL-6 therapy is discontinued, you should disregard all measured IL-6 levels up to a year after anti-IL-6 therapy is stopped.

Case Reports of anti-IL-6 therapy for iMCD patients:

Over the last decade, treatments directly targeting IL-6 have been employed.
Siltuximab is an anti-IL-6 monoclonal antibody. Three patients that have received siltuximab have been written up in case reports. Siltuximab monotherapy resulted in partial remission for 1 patient. Two patients achieved complete remission with siltuximab in combination with other drugs. See patient descriptions below.

56-year-old female with iMCD achieved 72 months complete response without relapse when treated with siltuximab plus steroids (Kwon et al)
61-year-old female with iMCD achieved partial remission for 36 months while on 1st-line siltuximab (improved blood counts, lymphadenopathy resolved, but intermittent fever and rash persisted). 2nd-line treatment at 36 months included corticosteroids and etanercept with no response. 3rd-line consecutive plateletpheresis for thrombocytosis and then cladribine for 5 days achieved no response. The patient was then treated with repeated courses of steroids, and later was started on naprosyn for possible neoplastic fever. She also received a weekly dose of rituximab for 8 weeks with persistence of disease flare up. Patient achieved a complete remission of 7 months on 5th-line anakinra. (El-Osta et al)
25-year-old male with iMCD-TAFRO received siltuximab in combination with other drugs for complete response for 15 months then relapsed and complete response for 17 months then relapsed. 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.)

Tocilizumab is an anti-IL-6 receptor monoclonal antibody. Nineteen patients that have received tocilizumab have been described in published case reports. Tocilizumab monotherapy achieved complete remission in 9 patients, partial remission in 3 patients and no response in 1 patient. Tocilizumab in combination with other drugs achieved complete remission in 5 patients and partial response in 1 patient. See patient descriptions below.

54-year-old male with iMCD with abundant IgG4-positive cells achieved 13 months complete remission on tocilizumab (disappearance of lymph node swelling and multiple lung nodules, improved laboratory data). (Sato et al)
Four iMCD patients had 38 months in complete remission without recorded relapse when treated with tocilizumab plus steroids. Five iMCD patients had 38 months in complete remission without recorded relapse when treated with tocilizumab alone. (Song et al)
35-year-old Japanese male with plasma cell-type iMCD with cutaneous involvement accompanied by IgA nephropathy achieved 74 months of complete remission without relapse when treated with tocilizumab. (Komatsuda et al)
7-year-old female with iMCD achieved partial response on 2nd-line tocilizumab for 8 months without relapse. Patient was previously treated with infusions of immunoglobulins with no response. (Galeotti et al)
16.5-year-old male with iMCD received 3rd-line tocilizumab with 36 months complete remission without relapse. At 6.5 years old, patient had no response to rituximab plus cytotoxics (Cyclophosphamide, vinblastine) for 5 months and partial response for 27 months without relapse to Anakinra. (Galeotti et al)
37-year-old Japanese female with iMCD received 2nd-line tocilizumab with partial response (alleviated generalized fatigue, pyrexia, anemia, hypoalbuminemia, hypergammaglobulinemia, and increased C-reactive protein) for 4 months without relapse, but was ultimately discontinued due to concern for DIC. Patient had previously received 1st-line corticosteroids with partial response for 5 months then relapsed. (Matsuyama et al)
21-year-old Japanese female with iMCD complicated by cardiomyopathy and congestive heart failure achieved partial response to 2nd-line tocilizumab for 2 months. Patient was previously unresponsive to 1st-line corticosteroids for 36 months. (Kanda et al)
78-year-old female with Sarcoidosis and mixed-type iMCD-TAFRO achieved complete remission for 15 months while on 2nd-line tocilizumab (improved DIC, complete resolution of ascites and pleural effusion), but died from unknown cause (DIC or progression of disease state). Patient was unresponsive to first-line corticosteroids. (Awano et al)
46-year-old male with medication-resistant plasma-cell-type iMCD had no response to 3 months of 3rd-line tocilizumab. Prior therapies included 1st-line cytotoxic chemotherapies (CHOP), rituximab and corticosteroids for 3 months with no response; 2nd-line cytotoxic chemotherapies (cyclophosphamide, dexamethasone) plus thalidomide resulted in partial response (tumor shrinkage by 50%) for 10 months. 4th-line thalidomide achieved no response in 3 months. 5th-line lenaldimide achieved complete remission for 36 months without relapse. (Szturz et al)
25-year-old male with iMCD-TAFRO received tocilizumab in combination with other drugs for complete response for 17 months then relapsed. 1st-line corticosteroids achieved partial response for 2 months and then the patient relapsed. 2nd-line 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.)
43-year-old female with ulcerative colitis status-post colonic resection and hyaline-vascular type-iMCD-TAFRO treated with tocilizumab, corticosteroid (methylprednisolone), and rituximab with partial response for 2 months. (Iwaki et al)

Approved Clinical Therapies targeting IL-6 in iMCD:

Siltuximab (Sylvant)

Siltuximab was the first approved treatment in the US for iMCD patients. It was approved for iMCD by the US Food & Drug Administration and European Medicines Agency in 2014 after a clinical trial was conducted.
Siltuximab is an anti-IL-6 monoclonal antibody that has “demonstrated durable tumor and symptomatic response at a significantly higher rate compared with placebo (34% vs 0%, p=0.0012) in the first randomized Phase II study in MCD (34% vs 0%; P = 0.0012)” (Blood 2014)
However, patients “require lifelong administration and are not effective in all patients.” (Blood 2014)

Tocilizumab

Tocilizumab is an anti-IL-6 receptor monoclonal antibody approved for MCD treatment in Japan. It has “demonstrated effectiveness at inducing and maintaining remission.” (Blood 2014)
Similar to siltuximab, patients “require lifelong administration and are not effective in all patients.” (Blood 2014)