NONSPECIFIC CYTOTOXIC IMMUNO-DEPLETION

Molecular Evidence (rationale) for non-specific cytotoxic immuno-depletion in iMCD patients:

Cytotoxic chemotherapy eliminates rapidly dividing cells, including all immune cells. The immune system is thought to be over-activated in iMCD, therefore weakening the immune system can bring the disease under control.

Case Reports of nonspecific cytotoxic immuno-depletion therapy for iMCD patients:

R-CHOP or CHOP or [R]-CHOEP (Rituximab, Cyclophosphamide, Hydroxydaunorubicin (also called Doxorubicin or Adriamycin), Oncovin (or Vincristine), Etoposide, Prednisone or Prednisolone). Ten iMCD patients received this cytotoxic chemotherapy alone with complete remission for 6 patients, partial remission for 1 patient, no response for 1 patient and unclear response in 1 patient. Six iMCD patients received this cytotoxic chemotherapy in addition to other treatments with complete remission achieved in 5 patients and partial remission in 1 patient. Please see patient descriptions below.

25-year-old male with iMCD-TAFRO received cytotoxic chemotherapy in combination with other drugs for complete response for 15 months then relapsed and complete response for 17 months then relapsed then 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 + 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 + 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 + 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 was treated with three cycles of R-CHOP with partial response complicated by severe bone marrow suppression. Due to severe bone marrow suppression the patient was switched to three cycles of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) with complete remission for 30 months without relapse. (Gatti-Mays et al)
50-year-old male with autoimmune hemolytic anemia and iMCD received 2nd-line R-CHOP with complete remission for unknown period of time and passed away from accident without relapse of CD. Patient was previously treated with corticosteroids (prednisolone) + IVIG + blood transfusions with no response for 10 days. (Tajima et al)
37-year-old female with iMCD with preceding symptoms of nephrotic syndrome received 6 cycles of R-CHOP with complete remission after 4 cycles for 6 months without relapse. (Li et al)
50-year-old male with erythrodermic psoriasis, iMCD and adenocarcinoma treated with CHOP with complete remission for 24 months then relapsed and received R-CHOP with partial response. First-line was 6 cycles of CHOP with complete remission for 24 months (dramatic improvement of the systemic symptoms, lymphadenopathy, and the dermatopathy), remained symptom free for 2 years but then presented with the same signs. 2nd-line 6 cycles of R-CHOP with partial response. Most symptoms resolved, but later found adenocarcinoma, condition deteriorated. MCD likely secondary to unidentified primary adenocarcinoma and cause of death was adenocarcinoma. (Megalakaki et al)
65-year-old male with history of pulmonary tuberculosis, tuberculosis lymphadenitis and iMCD with cutaneous involvement treated with 8 cycles of CHOP with complete remission (size and hypermetabolic activities of lymph nodes decreased, skin lesions improved) for 57 months, without documented relapse. (Park et al)
63-year-old man with a 20-year history of diabetes mellitus and iMCD with ophthalmic involvement treated with CHOP with partial response for 45 months without relapse. (Park et al)
17-year-old male with plasma cell variant MCD associated with autoimmune hemolytic anaemia and autoimmune thrombocytopenia (Evan’s syndrome) and complicated by mixed nephrotic-nephritic syndrome and acute renal failure due to an underlying glomerulopathy with microscopic and immunofluorescence findings suggestive of membranoproliferative glomerulonephritis (MPGN) type I was treated with CHOP with unclear response.(Gakiopoulou et al)
66-year-old female with hyaline vascular variant iMCD associated with B cell lymphoma, treated with CHOP plus radiation with complete remission for 24 months without relapse. (Erkurt et al)
43-year-old female with iMCD received CHOP with complete remission (fever subsided, lymphadenopathy resolved after initial course of treatment) for 52 months with no recorded relapse. (Seo et al)
70-year-old male with iMCD, presumed TAFRO, in the setting of multiple myeloma received 6 cycles of 2nd-line CHOP plus methylprednisone, but patient died from disease progression. Patient previously received 4 cycles of dexamethasone + bortezomib with partial remission (improved labs, 75% decrease in LN and splenomegaly) after two cycles for a total of 18 months. (Yuan et al)
48-year-old male of Mediterranean origin with plasma-cell variant iMCD with irreversible kidney damage received R-CHOP 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 1st-line high dose steroids without response. (Kahn et al)
73-year-old male with mixed-type iMCD and concomitant diffuse large B cell lymphoma received 2nd-line CHOP with no response for 6 months. Patient previously received first-line prednisone with partial remission for 4 months then readmitted with lower extremity edema, fever and weakness, anemia, remarkable lymphadenopathy of the chest, hypocalcemia, renal failure. Patient then received 2nd-line CHOP with no response for 6 months. Patient passed away at 6 months after diagnosis of lymphoma from complication of pneumonia and sepsis. (Venizelos et al)
24-year-old female with a history of connective tissue diseases and mixed-type iMCD received 2nd-line CHOP + Azothioprine maintenence with partial remission for 25 months without documented relapse. Patient previous received daily pulses of IV methylprednisolone followed by high dose steroids for less than 1 month with no response (got worse). (De Marchi et al)
57-year-old female with iMCD-TAFRO treated with 2nd-line CHEOP plus methylprednisolone with transient improvement then death secondary to septic shock. Patient had previously received corticosteroids (pulse therapy of methylprednisolone and prednisolone) for less than 1 month with worsening condition. (Masaki et al)
7-year-old male with plasmacytic-type iMCD received 2nd-line therapy of four courses of CHOP plus prednisolone was administered without response and relapse 3 months later. Patient had previously received pulse therapy of methylprednisolone with partial response for 9 months but discontinued preoperatively and patient relapsed within a few days with similar clinical and laboratory symptoms. After second relapse, patient resumed high-dose pulse methylprednisolone treatment, tapered dose in a month and continued with partial response for 18 months without relapse. (Karapinar et al)

Cyclophosphamide. Out of seven iMCD patients that received cyclophosphamide in combination with other drugs, four patients achieved partial remission and three patients achieved no response. Please see patient descriptions below.

6.5-year-old male with iMCD showed no response to cyclophosphamide, vinblastine and rituximab for 5 months. Patient achieved partial remission for 27 months without relapse to 2nd-line anakinra. At 16.5 years old, patient started 3rd-line tocilizumab (8mg/kg every 2 weeks) and achieved 36 months complete remission without relapse. (Galeotti et al)
71-year-old male with hepatic amyloidosis and mixed-type iMCD treated with cyclophosphamide and prednisolone without response for 2 month period of treatment. Patient was then treated with 1 month of corticosteroid monotherapy without response, then patient died of unrelated cause. (Gianstefani et al)
48-year-old man Ghanan male with iMCD complicated by renal thrombotic microangiopathy was treated with cyclophosphamide plus prednisolone with partial response after several months (dramatic improvement in constitutional symptoms and kidney function). (Suneja et al)
48-year-old female with iMCD treated with 2nd-line cyclophosphamide plus corticosteroids without improved response and was poorly tolerated. Patient previously received 1st-line corticosteroids with partial response (Hyperimmunoglobulinemia and lymphadenopathy were moderately sensitive) for 132 months then relapsed. 3rd-line therapy was 6 cycles of bortezomib with IL-6 level reduced and general performance status improved. (Kreft et al)
53-year-old male with iMCD treated with cyclophosphamide, rituximab, dexamethasone and prednisolone with partial remission for 10 months (improved hemoglobin, decreased serum IgG, CRP, IL-6 and soluble IL-2R). Subsequent follow-up at 76 months, patient alive without improvement in presenting generalized lymphadenopathy and eruption. (Ide et al)
53-year-old female with plasmacytic-type iMCD received 2nd-line methyl-prednisolone pulse therapy (1 g/day for 3 days) followed by oral prednisolone (25 mg/day) and cyclophosphamide (CPA at 100 mg/day) with partial response for 48 months without relapse. Patient had previously received 1st-line received oral prednisolone (60 mg/day tapering to 25 mg/day by 4 months, then maintained at 25mg/day) with partial response (symptoms disappeared and elevated levels of CRP, IL6, IL2R, and LDP showed improvement) for five months, then relapsed and (Iyongaga et al)
25-year-old male with classical Hodgkin’s lymphoma co-occurring with plasma cell type-iMCD was initiated on cyclophosphamide in combination with other drugs for partial response for 12 months. 1st-line cyclophosphamide, corticosteroid, tocilizumab and methotrexate achieved partial response for 12 months, then the patient experienced a Hodgkin Lymphoma relapse (treated with adriamycin, bleomycin, vinblastine, and dacarbazine). Patient then received one course of CHASE (Cyclophosphamide, Cytarabine, Etoposide and Dexamethasone) with complete remission and one course of DeVIC (Dexamethasone, Etoposide, Ifosfamide, Carboplatin) then 5th-line was 3 courses of GCD (Gemcitabine, Carboplatin and Dexamethasone). Subsequently added 40Gy doses of radiation to his mediastinum with partial response for 7 months without relapse. (Momoi et al)

CVP or COP or R-CVP (Rituximab, Cyclophosphamide, Vincristine (Oncovin), and Prednisone). Of five iMCD patients who received this chemotherapy, two patients achieved complete remission and three patients achieved partial remission. Two patients received this chemotherapy in combination with additional corticosteroids with complete remission for one patient and partial remission for the other patient. Please see patient descriptions below.

70-year-old male with iMCD and autoimmune pancreatitis received three cycles of 2nd-line R-CVP with complete remission for 30 months without relapse. Patient was previously treated with three cycles of R-CHOP with partial response, which was discontinued due to severe bone marrow suppression. (Gatti-Mays et al)
40-year-old male with hyaline-vascular iMCD and membranoproliferative glomerulonephritis received 2nd-line CVP 3 times in 3 months with resolution of anemia and renal function. Patient previously received with 6 months of prednisone with no response (improved edema, early low-grade fever, hyperglobulinemia, urinalysis, but persistent anemia and renal function changes). 3rd-line therapy was splenectomy and regional retroperitoneal lymphadenectomy with no response for 44 months. (Zhang et al)
64-year-old female with mixed-type iMCD and membranoproliferative glomerulonephritis treated with CVP with partial response for 18 months, without relapse. (Zhang et al)
52-year-old male with iMCD (presenting as anorexia, persistent diarrhea, weight loss, and liver enzyme elevations, with no hematologic laboratory abnormalities) who achieved complete remission for 22 months following 6 cycles of R-CVP and prednisolone. Relapse treated with vinblastine and rituximab 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)
33-year-old man with plasmacytic-type iMCD, presumed TAFRO, with crescentic glomerulonephritis received 2nd-line CVP chemotherapy with partial response for 20 months then restarted another course of chemotherapy. Patient had previously received corticosteroids plus plasma exchange with complete remission for 6 months then relapsed (anti-GBM antibodies normalized by 2 weeks and indirect Coombs test became negative, lymphadenopathy, splenomegaly, generalized edema, anemia, thrombocytopenia, and anemia resolved). (Yv et al)
34-year-old male with a remote history of pulmonary tuberculosis and mixed-type iMCD treated with CVP plus prednisolone with partial relief of symptoms, but did not tolerate well. Patient was switched to the MP regimen (melphalan 2 mg three times daily and prednisone 50 mg once daily for seven consecutive days) for the second cycle of chemotherapy. After two cycles, MP was combined with the COX2 inhibitor celecoxib (200 mg daily) and patient had complete remission for 3 months to 2nd-line therapy without relapse. (Liu J. et al)
28-year-old female with plasma-cell type iMCD associated with advanced systemic amyloidosis who received 2 cycles of cyclophosphamide, vinblastine plus corticosteroids with partial response for less than 1 month then relapsed. 2nd-line was 2 cycles rituximab, with partial response for 3 months but died from end-stage cardiac and digestive amyloidosis. (Gholam et al)

CAV, CVAD or hyper-CVAD (Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone). One iMCD patient achieved complete remission to this chemotherapy regimen. One iMCD patient achieved partial remission to this chemotherapy in combination with other drugs. A third iMCD patient achieved no response then a partial remission when the chemotherapy was combined with other therapies. Please see patient descriptions below.

67-year-old male with a history of labile hypertension, viral hepatitis, remote myocardial infarction with plasmacytic-type iMCD who received received 8 cycles of 2nd-line cyclophosphamide, doxorubicin, vinblastine and prednisolone for complete remission for 52 months (a nearly complete clearing of skin lesions with postinflammatory hyperpigmentation), when he died of gastric carcinoma. Patient was previously treated with prednisolone with partial remission for 6 months (partial resolution of skin lesions, complete regression of lymphadenopathy), then relapsed. (Haque et al)
51-year-old male with iMCD associated with Mantle cell lymphoma treated with one cycle of hyperCVAD, high-dose methotrexate and Ara-C therapy with partial remission (pleural effusion and ascites diminished, enlarged lymph nodes were reduced in size) for unclear time period. (Yoshida et al)
4-year-old girl with mixed-type iMCD, presumed TAFRO, was treated with CAV, prednisone and IVIG for four cycles with no response and then CAV and prednisone with partial remission for 36 months. Follow-up imaging at 30 months after completion of chemotherapy showed marked improvement in soft tissue swelling and ascites with small residual lymph nodes present without new large lymph masses. All laboratory abnormalities (anemia, thrombocytopenia, hypoalbuminemia, C-reactive protein, and renal function) normalized after starting chemotherapy. Currently free of disease at 36 months of follow-up. (Baserga et al)

ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine)

27-year-old female with nodular sclerosis Hodgkin’s lymphoma repeatedly relapsing in the context of plasma cell-hyaline vascular-type idiopathic MCD received 6 courses of ABVD with partial response for 8 months then relapsed (rapid normalization of laboratory abnormalities and complete regression of all pathological lymph nodes). Relapse was treated with radiation resulting in partial remission for 11 months. Radiation for the next relapse achieved partial response for 12 months. Final relapse was treated with rituximab resulting in complete remission for 21 months without relapse. (Falchi et al)

Vincristine. Two iMCD patients received vincristine plus prednisone with complete remission and partial remission, respectively, with subsequent relapses. Please see patient descriptions below.

65-year-old female with a history of idiopathic thrombocytic purpura with mixed-type iMCD, presumed TAFRO, who received vincristine and prednisone achieved complete remission, but was maintained on low-dose prednisone with recurrence in the lymph node at 6mo and 46 months, but was alive at 113 mo (Kojima et al)
65-year-old female with mixed-type iMCD-presumed TAFRO received vincristine and prednisone with partial remission for 6 months, then had recurrence in lymphadenopathy at 6 months and 46 months. No treatment information about 2nd-line therapy. (Kojima et al)

Etoposide. Seven iMCD patients received etoposide plus corticosteroids. Five patients achieved complete remission, while two patients achieved a partial remission. Please see patient descriptions below.

41-year-old female HTN and iMCD was treated with corticosteroids and etoposide with complete response for 180 months without recorded relapse. (El Karoui et al)
42-year-old female with HTN with hyaline vascular-type iMCD received corticosteroids and etoposide with partial response for 92 months without recorded relapse. (El Karoui et al)
79-year-old female with HTN and hemolytic uremic syndrome with iMCD received corticosteroids and etoposide with complete response for 50 months then relapsed. Patient passed away from metastatic gastric cancer. (El Karoui et al)
38-year-old male with HTN with iMCD treated with corticosteroids and etoposide achieved complete response for 2 months without recorded relapse. (El Karoui et al)
17-year-old male with HTN with iMCD received corticosteroids and etoposide with complete response for 50 months then relapsed. (El Karoui et al)
18-year-old female with HTN with iMCD received corticosteroids and etoposide with complete response for 105 months without recorded relapse. (El Karoui et al)
56-year-old male with HTN and tubulo-interstitial disease with iMCD received corticosteroids and etoposide with partial response for 92 months without recorded relapse. (El Karoui et al)

Other non-specific cytotoxic immunodepletion regimens. Please see patient descriptions below for regimens and responses.

63-year-old male with plasmacytic-type iMCD received vincristine, adriamycin, high-dose dexamethasone without response for 3 months, at which point patient died from neutropenic fever and sepsis. (Kwon et al)
61-year-old female with hyaline-vascular type-iMCD status-post splenectomy for iMCD treatment received 1st-line cytotoxic chemotherapy with no response for 2 months. Patient initially presented with nearly-fatal myocarditis associated with a 2009 pandemic H1N1 influenza virus infection. 2nd-line therapy included antibiotics, oseltamivir, furosemide, and spironolactone with improvement of all clinical parameters. Three years later, 3rd-line treatment IVIFGand rituximab and daily steroids with no response, the patient’s condition deteriorated and she died of paraneoplastic pemphigus. (Roca et al)
61-year-old female with iMCD received 3rd-line consecutive plateletpheresis for thrombocytosis and then cladribine for 5 days (non-cytoxin-based chemotherapy) with no response. Patient previously received 1st-line siltuximab achieved partial remission (improved blood counts, lymphadenopathy resolved, but intermittent fever and rash persisted) for 36 months. Second-line treatment at 36 months included corticosteroids and etanercept with 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 cyclophosphamide, vinblastine plus rituximab with partial response for 7 months, then symptoms recurred. 2nd-line with anakinra plus corticosteroids (and colchicine) with 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)
46-year-old male with plasmacytic-type iMCD received 3 cycles of 2-chloro-deoxyadenosine (2-CDA) resulting in complete clinical and radiological remission for 26 months, but relapsed and was found to have diffuse, large, B-cell lymphoma, CS IIIB. 2nd-line was 6 cycles of cytotoxic chemotherapies (anthracyclin-based) with partial remission. 3rd-line was 3 cycles of salvage therapy DHAP (dexametasone, cytarasine and cisplatin) + MINE (mesna, ifosfamide, mitoxantrone) with no response. Patient received cytotoxic chemotherapy, then died secondary to sepsis and disease progression. (Colleoni et al)
55-year-old male with iMCD, presumed TAFRO, associated with Acute Myelogenous Leukemia M5b received 2nd-line cytotoxic chemotherapies (cytarabine, etoposide, and mitoxantrone) without response, but developed invasive pulmonary aspergillosis and died. Patient had previously received prednisolone at an initial dose of 50 mg/day then gradually tapered with partial response (pancytopenia, skin rash, and cervical lymph node enlargement subsequently resolved) for 27 months then relapsed. After 2nd-line therapy, patient subsequently developed invasive pulmonary aspergillosis and received amphotericin B from day 12 after chemotherapy, developed massive pulmonary hemorrhage that resulted in his death from respiratory failure on day 76 after chemotherapy. (Tomonari et al)
61-year-old male with hyaline-vascular-type iMCD and non-Hodgkin’s lymphoma received cytotoxic chemotherapy (NOS) and radiation therapy with with partial response for 120 months without relapse, but died of unrelated cause. (Larroche et al)
39-year-old male with mixed-type iMCD and non-Hodgkin’s lymphoma received cytotoxic chemotherapy (NOS) and radiation therapy. Patient was alive, but no length or quality of survival listed. (Larroche et al)
26-year-old female with plasmacytic iMCD received cytotoxic chemotherapies (endoxan, vincristine) and corticosteroids (prednisolone) with no response for unclear months, then relapsed. (Nishi et al)

Azathioprine is an immunosuppressant.

24-year-old female with a history of connective tissue diseases and mixed-type iMCD received 2nd-line CHOP plus Azathioprine maintenance with partial remission for 25 months without documented relapse. 1st-line therapy was daily pulses of IV methylprednisolone followed by high dose steroids for less than 1 month with no response (got worse). (De Marchi et al)
11-year-old male with a history of Klinefelter syndrome, systemic lupus erythematosus phenotype and plasma cell-type iMCD-TAFRO was treated with tumor removal, maintenance steroids and azathioprine with complete response for 6 months, then interferon-alpha with partial response (dramatic improvement in patient’s condition) for unknown number of months without relapse. (Simko et al)

Clinical Trials of non-specific cytotoxic immuno-depletion in iMCD:

No clinical trials of non-specific cytotoxic immuno-depletion in iMCD patients have been conducted.