High Dose Immune Suppression With Hematopoietic Stem Cell Support in Refractory Vasculitis, Necrotizing Vasculitis, Neurovascular Behcet's Disease, and Sjogren's Syndrome

Northwestern University1 个研究点分布在 1 个国家目标入组 7 人开始时间: 2003年8月最近更新: 2018年8月2日

适应症

干预措施

试验速览

阶段: 1 期
状态: 终止
发起方: Northwestern University
入组人数: 7
试验地点: 1
主要终点: Survival

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

The systemic vasculitis is a wide-ranging group of diseases that are characterized by the presence of blood vessel inflammation (1). Despite this common feature, each type of vasculitis has a unique variety of clinical manifestations that influences its degree of disease severity and ultimately its management. Immunosuppressive therapy forms the foundation of treatment for almost all forms of systemic vasculitis.

The systemic necrotizing vasculitis (SNV) are a subset of vasculitis with significant morbidity and mortality (2). The SNV are Wegener's granulomatosis, allergic angiitis and granulomatosis (AAG) (also known as Churg-Strauss syndrome), polyarteritis nodosum (PAN), microscopic polyangiitis (MPA), and overlap syndrome. In spite of modern therapeutic immune suppressive agents, there remains a not inconsequential morbidity and mortality associated with SNV. The current standard therapy for SNV is chronic oral cyclophosphamide (1-3 mg/kg/day) and corticosteroids (3-6). Transplant doses of cyclophosphamide at 200 mg/kg infused over 4 days is the most common worldwide transplant regimen for systemic lupus erythematosus (SLE) (7). Like SLE, SNV are cyclophosphamide responsive disease. We, therefore, propose a trial of high dose cyclophosphamide with anti-thymocyte globulin (ATG) for patients with SNV.

详细描述

Selection of High Dose Immunosuppressive Therapy and Autologous HSCT Strategy for this Trial

Selection of the Regimen for High-Dose Immunosuppressive Therapy Cyclophosphamide with ATG (Cy/ATG) is a common conditioning regimen with two decades of experience in the treatment of aplastic anemia and has been used safely without reported mortality in the treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Cy/ATG not only has less acute toxicity, it has less chronic side effects. Cy/ATG is not associated with late malignancies or cataracts. Cyclophosphamide and anti-thymocyte globulin (horse or rabbit ATG) and rituximab are potent immunosuppressive agents. Rituximab and ATG contribute additional immunosuppression without additional cytotoxicity. Rituximab and ATG given shortly pre-transplant will contribute to the elimination of host T lymphocytes that survive cyclophosphamide or that contaminate the CD34+selected graft. SLE, an autoimmune disease responsive to cyclophosphamide, responds well to a Cy/ATG/rituximab conditioning regimen. For these reasons, Cy/ATG/rituximab will be the conditioning regimen utilized in this study.

To justify any new therapy such as HSCT, the risk of dying from the disease must be higher than that expected from its treatment, or the morbidities associated with the disease must justify the treatment risks. Autologous stem cell transplantation has a mortality of 1-3% in breast cancer patients using intense conditioning regimens with multiple alkylating agents, and up to 10-15% in patients with lymphomas and other malignancies. The latter patients usually have been heavily treated before transplant and the accumulation of treatment toxicities is thought to play a role in their increased transplant-related mortality. Cyclophosphamide and ATG/rituximab have been used to transplant of extremely ill patients with systemic lupus erythematosus and multiple organ dysfunction at Northwestern University without mortality.

Since patients in this study are earlier in the disease course, a conditioning regimen that has historically been associated with less toxicity will be employed. The regimen will be Cyclophosphamide at 200 mg/kg with ATG 5.5 mg/kg and rituximab 1000 mg divided over 2 doses. Cyclophosphamide 200mg/kg with or without ATG has been used safely and effectively in a variety of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and aplastic anemia. Rabbit ATG will be used instead of equine ATG due to the lower incidence of hypersensitivity and fever with rabbit ATG compared to equine.

Method of Harvesting Stem Cells Based on the experience of the pilot studies, the current protocol will mobilize stem cells with cyclophosphamide and granulocyte-colony stimulating factor (G-CSF), and collect stem cells by apheresis, with subsequent bone marrow harvest performed only if needed to supplement the peripheral blood stem cells (PBSC). Based on experience of autoimmune flares in patients receiving G-CSF alone for mobilization (56), patients will be mobilized with cyclophosphamide 2.0 g/m2 and G-CSF 10 mcg /kg.

研究设计

研究类型: Interventional
分配方式: Non Randomized
干预模型: Single Group
主要目的: Treatment
盲法: None

入排标准

年龄范围: 16 Years 至 60 Years（Child, Adult）
性别: All
接受健康志愿者: 否

入选标准

•Age 16 to 60 years old at the time of pretransplant evaluation.
•An established diagnosis of systemic necrotizing vasculitis (Wegener's granulomatous, polyarteritis nodosum (PAN), allergic angiitis granulomatous (AAG, also known as Churg Strauss syndrome), microscopic polyangiitis (MPA), or overlap syndrome)Temporal arteritis, or mixed cryoglobulinemia or primary central nervous system vasculitis AND failure of corticosteroids and any of the following at least 6 months of oral or IV cytoxan, rituximab, or cellcept. (Failure defined as: a) patients with a high disease activity and involvement of internal organs as measured by increased FFS > 2 and/or BVAS > 20, or b) patients who develop recurrent flares with subsequent progressive organ damage.)
•Neurovascular Behcets with recurrent oral and/or genital lesions confirmed by culture to be herpes negative, MRI findings consistent with CNS vasculitis, recurrent neurological symptoms, and clinical confirmation by a Neurologist (e.g., Dr. Rama Gourimeni) AND failure of at least 3 months of oral or IV cytoxan.
•Pulmonary or neurovascular Sjogrens with positive SSA/SSB confirmed by a rheumatologist and neurologist (if CNS involved) or pulmonologist (if lungs involved) and either recurrent neurologic attacks or progressive pulmonary compromise (dyspnea on exertion, decreased DLCO or CT findings of active disease) despite at least 6 months of intravenous monthly pulse cyclophosphamide.
•Patient eligibility must be confirmed by two Rheumatologists. For patients with neurovascular Behcets, eligibility need only be confirmed by a neurologist.
•A minimum CD34+ cell dose of 2.0 x 10e6/kg post-selection.

排除标准

•Significant end organ damage such as:
•LVEF <40% or deterioration of LVEF during exercise test on MUGA or echocardiogram unless due to active disease.
•Untreated life-threatening arrhythmia.
•Active ischemic heart disease or heart failure.
•DLCO < 40% of predicted value unless due to active disease.
•Serum creatinine > 2.5 mg/dl, unless due to active disease.
•Liver cirrhosis, transaminases >3x of normal limits, or bilirubin >2.0 unless due to Gilberts disease.
•HIV positive.
•Uncontrolled diabetes mellitus, or any other illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive treatment.
•Prior history of malignancy except localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgical therapy, such as (but not limited to) head and neck cancer, or stage I or II breast cancer will be considered on an individual basis.
•Positive pregnancy test, inability or unable to pursue effective means of birth control, failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
•Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
•Inability to give informed consent.
•Active infection, excluding asymptomatic bacteruria or vaginal candidiasis.
•Active hepatitis B (HBSAg positive) or active hepatitis C (PCR positive blood lymphocytes).

研究组 & 干预措施

Autologous Stem Cell Transplant

Experimental

Autologous Stem Cell Transplant will be performed on eligible patients

干预措施: Allogeneic Stem Cell Transplant (Biological)

Autologous Stem Cell Transplant

Experimental

Autologous Stem Cell Transplant will be performed on eligible patients

干预措施: Autologous Stem Cell Transplant (Biological)

Autologous Stem Cell Transplant

Experimental

Autologous Stem Cell Transplant will be performed on eligible patients

干预措施: Cyclophosphamide (Drug)

Autologous Stem Cell Transplant

Experimental

Autologous Stem Cell Transplant will be performed on eligible patients

干预措施: ATG (rabbit) (Drug)

Autologous Stem Cell Transplant

Experimental

Autologous Stem Cell Transplant will be performed on eligible patients

干预措施: G-CSF (Drug)

Autologous Stem Cell Transplant

Experimental

Autologous Stem Cell Transplant will be performed on eligible patients

干预措施: Mesna (Drug)