Lupus Erythematosus, Graft-versus-host Disease
Conditions
Brief summary
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
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.
Interventions
DRUGCyclophosphamide
14.5 mg/kg/day on Days -6 and -5. 50 mg/kg/day on Days 3 and 4.
DRUGFludarabine
30 mg/m\^2/day on Days -6 through -2.
DRUGTacrolimus
Starting on Day 5. Dose will be adjusted according to blood levels.
DRUGMycophenolate Mofetil
15 mg/kg three times per day from Day 5 to Day 35.
0.5 mg/kg on Day -9. 2 mg/kg/day on Days -8 and -7.
RADIATIONTotal body irradiation
200 centigray on Day -1.
BIOLOGICALAllogeneic bone marrow transplant
Infusion on Day 0.
Sponsors
Maryland Stem Cell Research Fund
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Feasibility of the Conditioning Regimen and Post Transplantation Cyclophosphamide in Refractory SLE Patients With Donors Having Various Degrees of Matching | 1 year | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival | 1 year | Number of patients alive and alive without relapse, respectively. |
| Graft Failure | 60 days | Number of participants with primary and/or secondary graft failure. |
| RIFLE Score | 1 year | 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 |
| Acute Graft Versus Host Disease (GVHD) | Up to 2 years | 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+). |
| Chronic Graft Versus Host Disease (GVHD) | Up to 2 years | 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nonmyeloablative Conditioning and BMT Nonmyeloablative Conditioning and Bone Marrow Transplant in Systemic Lupus Erythematosus patients
Cyclophosphamide: Cyclophosphamide (alkylating agent) conditioning regimen and post transplantation cyclophosphamide with matched, partially matched, haplo-identical or unrelated donors
Sodium-2-mercapto ethane sulphonate: Antineoplastic detoxifying agent
Fludarabine monophosphate: Purine antimetabolite
Tacrolimus: Calcineurin inhibitor
Mofetil: Immunosuppressant
Rabbit antithymocyte globulin: Selective immunosuppressant | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Nonmyeloablative Conditioning and BMT |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 1 Participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 0 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
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.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nonmyeloablative Conditioning and BMT | The Feasibility of the Conditioning Regimen and Post Transplantation Cyclophosphamide in Refractory SLE Patients With Donors Having Various Degrees of Matching | 1 Participants |
Secondary
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+).
Time frame: Up to 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nonmyeloablative Conditioning and BMT | Acute Graft Versus Host Disease (GVHD) | Grades II-IV acute GVHD | 0 Participants |
| Nonmyeloablative Conditioning and BMT | Acute Graft Versus Host Disease (GVHD) | Grades III-IV acute GVHD | 0 Participants |
Secondary
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).
Time frame: Up to 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nonmyeloablative Conditioning and BMT | Chronic Graft Versus Host Disease (GVHD) | 0 Participants |
Secondary
Graft Failure
Number of participants with primary and/or secondary graft failure.
Time frame: 60 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nonmyeloablative Conditioning and BMT | Graft Failure | Primary graft failure | 0 Participants |
| Nonmyeloablative Conditioning and BMT | Graft Failure | Secondary graft failure | 0 Participants |
Secondary
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
Time frame: 1 year
Population: The only enrolled participant on this study was never assessed for a follow-up RIFLE scale, so no data was collected for this outcome measure.
Secondary
Survival
Number of patients alive and alive without relapse, respectively.
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nonmyeloablative Conditioning and BMT | Survival | Overall Survival | 1 Participants |
| Nonmyeloablative Conditioning and BMT | Survival | Event Free Survival | 1 Participants |