Nonmyeloablative Conditioning and Transplantation for Patients With Refractory Systemic Lupus Erythematosus (SLE)

Study Overview
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Brief Summary
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The main goal of the study is to determine if bone marrow transplant (BMT) from a less specific pool of donors in combination with high dose cyclophosphamide can induce remission of refractory systemic lupus erythematosus.

Detailed Description
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Systemic lupus erythematosus (SLE) is a devastating systemic autoimmune disease that predominantly affects young women, is more common in African-Americans than in whites, and results in poor quality of life. Lupus has no cure, and up to 90% of patients require corticosteroids for disease control. More than half of patients with lupus have permanent organ damage, much of which is either directly due to or increased by corticosteroids. To satisfactorily manage moderate-to-severe SLE, the investigators need effective treatments that will allow corticosteroid-sparing. High-dose chemotherapy followed by autologous BMT or peripheral blood progenitor transplantation (PBSCT) has been proposed as a novel approach to treat severe autoimmune diseases. Allogeneic BMT is not currently utilized for the routine treatment of SLE because of the significant morbidity (GVHD) and mortality associated with the procedure. The investigators have recently developed an approach to BMT using post-transplant cyclophosphamide that allows us to safely perform allogeneic BMT from matched, mismatched, unrelated or haploidentical donors. Transplant-related mortality, graft-failure and risk of GVHD have been very low with this approach. Furthermore, this approach allows us to greatly expand the donor pool since any patient shares exactly one HLA haplotype with each biological parent or child and half of siblings, an eligible haploidentical donor can be identified rapidly in nearly all cases. This trial will employ a fludarabine + cyclophosphamide conditioning along with posttransplantation cyclophosphamide on for patients with refractory SLE. The purpose of this trial is to improve the salvage rate for patients with refractory SLE through a reformatting of the immune system.

Official Title
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A Phase I/II Study of Nonmyeloablative Conditioning and Transplantation of Human Leukocyte Antigen (HLA)-Matched, Partially HLA-mismatched, HLA-haploidentical or Matched Unrelated Bone Marrow for Patients With Refractory SLE

Conditions
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Lupus Erythematosus, Graft-versus-host Disease

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Tacrolimus
* Drug: Mycophenolate Mofetil
* Drug: Rabbit antithymocyte globulin
* Radiation: Total body irradiation
* Biological: Allogeneic bone marrow transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Four or more American College of Rheumatology (ACR) criteria for the classification of SLE or 4 or more of the SLICE criteria Involvement of one or more of the following organ systems: renal, neurologic, hematologic, cardiac, pulmonary, gastrointestinal A lack of response to corticosteroids in moderate-to-high doses, and to either an equivalent degree of immunosuppression with azathioprine, methotrexate, cyclosporin, tacrolimus, belimumab, rituximab, mycophenolate mofetil, and/or appropriate other treatment Patients should be eligible for transplantation according to the BMT Policy Manual Exclusion Criteria: Age less than 18 years and over 75 years Any risk of pregnancy Patients who are preterminal or moribund

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nonmyeloablative Conditioning and BMT<br>Nonmyeloablative conditioning with rabbit antithymocyte globulin, cyclophosphamide, fludarabine, and total body irradiation. Allogeneic bone marrow transplant on Day 0. Graft versus host disease (GVHD) prophylaxis with cyclophosphamide, mycophenolate mofetil, and tacrolimus. | Drug: Cyclophosphamide<br>* 14.5 mg/kg/day on Days -6 and -5. 50 mg/kg/day on Days 3 and 4.<br>* Other names: Cy;Drug: Fludarabine<br>* 30 mg/m^2/day on Days -6 through -2.<br>* Other names: Fludara;Drug: Tacrolimus<br>* Starting on Day 5. Dose will be adjusted according to blood levels.<br>* Other names: Prograf;Drug: Mycophenolate Mofetil<br>* 15 mg/kg three times per day from Day 5 to Day 35.<br>* Other names: MMF;Drug: Rabbit antithymocyte globulin<br>* 0.5 mg/kg on Day -9. 2 mg/kg/day on Days -8 and -7.<br>* Other names: Thymoglobulin;Radiation: Total body irradiation<br>* 200 centigray on Day -1.<br>Biological: Allogeneic bone marrow transplant<br>* Infusion on Day 0.<br>* Other names: BMT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Feasibility of the Conditioning Regimen and Post Transplantation Cyclophosphamide in Refractory SLE Patients With Donors Having Various Degrees of Matching | Number of participants who were alive at 1 year after transplant and who had not suffered graft rejection, acute or chronic GVHD, or Grade 3 or higher (CTCAE V4.0) adverse events. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RIFLE Score | Change in Responder Index for Systemic Lupus Erythematosis (RIFLE) assessment. This is a qualitative assessment of organ function. The 12 month response will be assessed as: complete= complete or partial resolution in more than one organ, partial= complete or partial resolution in at least one organ, the same= no change or no worsening in any organ, worse= worsening in any organ | 1 year | 
| Survival | Number of patients alive and alive without relapse, respectively. | 1 year | 
| Graft Failure | Number of participants with primary and/or secondary graft failure. | 60 days | 
| Acute Graft Versus Host Disease (GVHD) | Percentage of participants who developed grades II-IV and grades III-IV acute GVHD. Acute GVHD is defined by the Przepiorka criteria, which stages the degree of organ involvement in the skin, liver, and gastrointestinal (GI) tract, based on severity, with Stage 1+ being least severe and stage 4+ being the most severe. Grading of acute GVHD is as follows: Grade I (skin involvement stages 1+ to 2+, with no liver or GI involvement), Grade II (skin involvement stages 1+ to 3+, liver 1+, GI tract 1+), Grade III (skin involvement stages 2+ to 3+, liver 1+, GI tract 2+ to 4+), Grade IV (skin involvement stages 4+, Liver 4+). | Up to 2 years | 
| Chronic Graft Versus Host Disease (GVHD) | Percentage of participants who developed chronic GVHD as defined by the NIH consensus criteria. This system gives scores from 0 to 3 for Karnofsky performance score, skin, mouth, eyes, gastrointestinal, liver, lungs, joints, and genitals, as well as an overall severity (mild, moderate, or severe). Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung), with no clinically significant functional impairment (maximum of score 1 in all affected organs or sites). Moderate chronic GVHD involves 1) at least 1 organ or site with clinically significant but no major disability (maximum score of 2 in any affected organ or site) OR 2) 3 or more organs or sites with no clinically significant functional impairment (maximum score of 1 in all affected organs or sites). Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in any organ or site). | Up to 2 years |