B CELLS

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

“B cells…are typically implicated as the pathologic overproducers of IL-6” (Blood 2014), but this may not be the case for all patients.

Case Reports of anti-B cell therapy for iMCD patients:

Rituximab (Rituxan) is an anti-CD20 antibody that binds to CD20 expressed on B cells resulting in increased elimination of B cells. “Rituximab, which is a frequent first- or second-line therapy in iMCD, is only partially effective and typically does not provide long-term disease control.” (Blood 2014) Rituximab is also effective in most cases of HHV-8-associated MCD. Eight patients received rituximab monotherapy for treatment of iMCD. Complete remission was achieved in 3 patients, partial remission in 4 patients and unclear response in 1 patient. Twenty patients received rituximab in combination with other drugs with complete remission achieved in 7 patients, partial remission in 4 patients and no response in 5 patients. Please see patient descriptions below.

61-year-old female with hyaline-vascular type-iMCD status-post splenectomy for iMCD received 3rd-line rituximab, IVIG plus daily steroids with no response and subsequently died of paraneoplastic pemphigus.Patient initially presented with nearly-fatal myocarditis associated with a 2009 pandemic H1N1 influenza virus infection. 1st-line cytotoxic chemotherapy achieved no response for 2 months. 2nd-line included antibiotics, oseltamivir, furosemide, and spironolactone with improvement of all clinical parameters. Three years later, 3rd-line IVIg, rituximab and daily steroids achieved no response. The patient’s condition deteriorated and she died of paraneoplastic pemphigus. (Roca et al)
25-year-old male with iMCD-TAFRO received rituximab alone for partial response for 2 months then relapsed. Patient received rituximab in combination with other drugs for complete response for 15 months then relapsed, for complete response for 17 months then relapsed and then for complete response for 39 months without relapse. 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 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 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.)
70-year-old male with iMCD and autoimmune pancreatitis received three cycles of rituximab, cyclophosphamide, vincristine and prednisone (R-CVP) with complete remission for 30 months without relapse. 1st-line therapy was three cycles of R-CHOP with partial response, but this was discontinued due to severe bone marrow suppression and R-CVP was initiated. (Gatti-Mays et al)
37-year-old female with iMCD with preceding symptoms of nephrotic syndrome received 6 cycles of R-CHOP and obtained complete remission after 4 cycles (completed all 6) for 6 months without relapse. (Yi et al)
6.5-year-old male with iMCD showed no response to rituximab, cyclophosphamide and vinblastine for 5 months. Patient achieved a partial response for 27 months without relapse to 2nd-line anakinra. At 16.5 years old, the patient started 3rd-line tocilizumab (8mg/kg every 2 weeks) and achieved 36 months complete remission without relapse. (Galeotti et al)
52-year-old male with iMCD treated with rituximab, thalidomide and dexamethasone with complete remission for 36 months without relapse. (Ramasamy et al)
46-year-old African American female with Rheumatoid Arthritis, Sjögren’s syndrome, leg ulcer, and iMCD was treated with rituximab with partial response for 12 months. For 2nd-line therapy, the patient restarted methotrexate for other autoimmune diseases; this treatment was not directed at MCD, and its impact on MCD is unclear. (Kerr et al)
46-year-old male with plasma-cell-type iMCD with splenomegaly and generalized lymphadenopathy received first-line R-CHOP plus prednisolone for 3 months with no response. Patient then received cyclophosphamide, dexamethasone and thalidomide with partial response (tumor shrinkage by 50%) for 10 months, then tocilizumab for 3 months with no response. 4th-line thalidomide achieved no response in 3 months and 5th-line lenaldimide achieved with complete remission for 36 months without relapse. (Szturz et al)
46-year-old male with a history of untreated hepatitis C, intravenous drug use and iMCD was treated with rituximab with unclear response. (Talukder et al)
52-year-old male with iMCD received rituximab in combination with other drugs for complete remission for 22 months then relapse and 2 months without a response. Patient presented with anorexia, persistent diarrhea, weight loss, and liver enzyme elevations, but with no hematologic laboratory abnormalities. 1st-line therapy was 6 cycles of rituximab, cytotoxic chemotherapies (CVP) and corticosteroids (prednisolone) with 22 months of complete remission, then the patient relapsed. Relapse was treated with rituximab plus cytotoxic chemotherapies (vinblastine) for 2 months without response. 3rd-line therapy was melphalan plus autologous Stem Cell Transplant with complete remission for 18 months, without relapse during follow-up period. (Tal et al)
25-year-old female with iMCD associated with hypercalcemia received rituximab plus corticosteroids with complete response (good control of eye and joint symptoms) for 10 months without relapse. 1st-line therapy of high dose corticosteroids achieved partial response (diminished conjunctival injection, joint swelling, and pain) for 8 months, then the patient relapsed. (Washington et al)
17-year-old female with a history of depression, treated left renal artery stenosis secondary to fibromuscular dysplasia and mixed variant iMCD with thrombocytopenia (presumed TAFRO) achieved complete remission for 31 months without relapse when treated with rituximab monotherapy. Patient previously received prednisone for 1 month without response (continued to have ongoing symptoms, lymphadenopathy, splenomegaly, and thrombocytopenia). (Mian et al)
61-year-old female with iMCD was unresponsive to 4th-line rituximab plus steroids during flare. Patient previously achieved partial remission (improved blood counts, lymphadenopathy resolved, but intermittent fever and rash persisted) for 36 months while on siltuximab, then relapsed. Second-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. 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)
13-year-old male with mixed-type iMCD received rituximab plus cytotoxic chemotherapies (cyclophosphamide, vinblastine) with partial response for 7 months, then symptoms recurred. 2nd-line anakinra plus corticosteroids (and colchicine) achieved complete remission (resolution of all clinical symptoms, although occasional fever peaks over a 6-month period, decreased lymph node size, CRP waxed and waned, hemoglobin levels, ESR values, and immunoglobulin levels stabilized) for 18 months without relapse. (Galeotti et al)
48-year-old male of Mediterranean origin with plasma-cell variant iMCD with irreversible kidney damage received 2nd-line R-CHOP (Rituximab, Vincristine, Doxorubicin, Cyclophosphamide and Prednisolone every 21 days) with partial response for 12 months. Patient’s general condition improved with serum albumin and systolic blood pressure normalized. After second course, the patient’s condition was complicated by pneumonia and multiorgan system failure. Patient had previously received first-line high dose steroids without response. (Kahn et al)
76-year-old male with autoimmune pancreatitis and iMCD associated with T-cell lymphoma received rituximab plus prednisone with complete remission for 9 months without relapse. Follow-up at 36 months, patient without relapse. (Maithel et al)
27-year-old female with nodular sclerosis Hodgkin’s lymphoma repeatedly relapsing in the context of plasma cell-hyaline vascular-type idiopathic MCD received 4th-line rituximab with complete remission for 21 months without relapse. Previous treatment included 6 courses of cytotoxic chemotherapies (adriamycin, bleomicin, vinblastine and dacarbazine) with partial response (rapid normalization of laboratory abnormalities and complete regression of all pathological lymph nodes) for 8 months, then the patient relapsed. Relapse was treated with radiation resulting in partial remission for 11 months, then the patient relapsed again and received radiation with partial response for 12 months then relapsed again. (Falchi et al)
61-year-old male with iMCD and orbital tumor received rituximab plus corticosteroids (prednisolone) with partial response for 40 months without relapse (orbital tumor and mediastinal lymphadenopathy were improved, serum IgG and c-globulin levels normalized). Subsequent follow-up at 106 months, patient without evidence of disease. (Ide et al)
26-year-old previously healthy female with iMCD received rituximab plus corticosteroids (methylprednisolone) with complete response for 16 months and discontinued therapy due to pregnancy. After initiation of rituximab, the patient’s fever remarkably improved and her pleural effusion, ascites, and generalized lymphadenopathy disappeared. CRP, IgG, IL-6 and soluble IL-2 levels normalized. Patient stopped rituximab due to pregnancy. Patient’s baby was healthy and patient had no sign of recurrence of MCD after pregnancy. She was started on oral prednisolone for maintenance therapy. Follow-up at 82 months, patient was alive with no evidence of disease. (Ide et al)
23-year-old male with Raynaud phenomenon without connective tissue disease, immune hemolytic anemia status-post splenectomy and aggressive form of iMCD associated with immune phenomena received rituximab with partial remission for 14 months without relapse. Four doses of rituximab treatment resulted in partial remission (abdominal masses diminished more than 50%, and gallium-67 scintigraphy positivity persisted, complete disappearance of the enlarged lymph nodes), but patient received 3 sets of rituximab treatments (4 courses each) and achieved partial remission for 14 months without record of relapse. (Ocio et al)
43-year-old female with ulcerative colitis status-post colonic resection and hyaline-vascular type-iMCD-TAFRO treated with rituximab in combination with corticosteroid (methylprednisolone) and tocilizumab achieved partial response (laboratory data and clinical findings improved) for 2 months without relapse. (Iwaki et al)
28-year-old female with plasma-cell type iMCD associated with advanced systemic amyloidosis received 2 cycles of second-line rituximab with partial response for 3 months, but died from end-stage cardiac and digestive amyloidosis. Patient previously received 2 cycles of cyclophosphamide, vinblastine plus corticosteroids with partial response for less than 1 month then relapsed. (Gholam et al)

Clinical Trials targeting B cells in iMCD:

No clinical trials targeting B cells in iMCD patients have been conducted.