Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning for Patients With Severe Systemic Sclerosis
Overview
- Phase
- Phase 1
- Intervention
- fludarabine phosphate
- Conditions
- Systemic Scleroderma
- Sponsor
- Fred Hutchinson Cancer Center
- Enrollment
- 3
- Locations
- 2
- Primary Endpoint
- Event-free Survival (EFS)
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of the study is to examine the safety and effectiveness of a reduced intensity conditioning regimen and allogeneic bone marrow transplant for people with systemic sclerosis. In an allogeneic bone marrow transplant procedure, bone marrow is taken from a healthy donor and transplanted into the patient. Bone marrow can be donated by a family member or an unrelated donor who is a complete tissue type match.
Participants will receive the chemotherapy and low dose radiation conditioning regimen consisting of the following: Fludarabine will be given intravenously for 5 days. Cyclophosphamide will be given intravenously on the first and second day. After completing the fludarabine and cyclophosphamide, patients will receive a single low dose of total body irradiation. The next day, patients will receive the allogeneic bone marrow transplant. On the third and fourth day after the transplant, patients will receive high dose intravenous cyclophosphamide. This is given to help prevent two complications: (1) graft rejection, which occurs when the body's immune system rejects the donor bone marrow, and (2) graft-versus-host disease (GVHD), which is when the donor immune cells attack the patient's normal tissues. On the fifth day after the transplant, patients will start receiving two additional medications: tacrolimus and mycophenolic acid (MPA, Myfortic), to help prevent GVHD. Patients will receive mycophenolic acid for about 5 weeks and tacrolimus for about 6 months. Also beginning on the fifth day after the transplant, patients will receive daily injections of a growth factor called granulocyte-colony stimulating factor (G-CSF), which is a protein that increases the white blood cell count; G-CSF will be continued until the patient's white blood cell count has returned to normal levels.
Patients will remain closely monitored either in the outpatient clinic setting or in the hospital for approximately 2-3 months after the transplant, but possibly longer if there are complications. Follow-up study visits will occur at 6 months and then at 1, 2, 3, 4, and 5 years after the transplant. Study researchers will keep track of the patient's medical condition after leaving the transplant center by phone calls or mailings to patients and their doctors once a year for the rest of the study participants' lives.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety and potential efficacy of reduced intensity conditioning with fludarabine/cyclophosphamide/low-dose total body irradiation (TBI) and allogeneic hematopoietic cell transplantation (HCT) for the stabilization or regression of disease manifestations of severe systemic sclerosis (SSc). SECONDARY OBJECTIVES: I. To determine whether stable allogeneic donor engraftment can be safely established with reduced intensity conditioning followed by matched sibling or unrelated donor bone marrow transplantation in patients with severe SSc. OUTLINE: Patients receive fludarabine phosphate intravenously (IV) on days -6, -5, -4, -3 and -2 and Cyclophosphamide IV on days -6, -5, and undergo 2 Gray TBI on day -1. Patients receive human leukocyte antigen (HLA)-matched donor bone marrow transplantation on day 0. Patients then receive cyclophosphamide IV on days +3 and +4, and beginning day +5 they start tacrolimus orally (PO) and enteric coated mycophenolic acid. After completion of initial study treatment, patients are followed up at 6 months and then annually for 5 years.
Investigators
George Georges
Principal Investigator
Fred Hutchinson Cancer Center
Eligibility Criteria
Inclusion Criteria
- •Patients eligible for the study must have a human leukocyte antigen (HLA)-identical sibling or HLA-matched unrelated bone marrow donor available and willing to donate.
- •Patients with severe SSc as defined by the American College of Rheumatology and at high-risk for a fatal outcome based on the following prognostic factors in groups 1-5:
- •Group 1: Patients must have 1) both a and b below; and 2) at least one of c, d or e:
- •a. diffuse cutaneous scleroderma with skin score of greater than or equal to 16 (modified Rodnan scale \[mRSS\]).
- •b. duration of systemic sclerosis less than or equal to 7 years from the onset of first non-Raynaud's symptom.
- •c. presence of interstitial lung disease (either forced vital capacity \[FVC\] or corrected diffusing capacity of the lung for carbon monoxide \[DLCOcorr\] less than 70 % of predicted) and evidence of alveolitis (abnormal bronchoalveolar lavage (BAL) or high resolution chest computed tomography \[CT\] scan) after treatment with intravenous cyclophosphamide greater than or equal 2 grams given over at least a 3 month period; for patients not able to adequately complete pulmonary function tests (PFT), there must be evidence of progressive disease on chest CT.
- •d. left heart failure with left ventricular ejection fraction (LVEF) \< 50% (that has responded to treatment targeted to scleroderma); 2nd or 3rd atrioventricular (AV) block with other evidence of cardiomyopathy related to SSc; myocardial disease not secondary to SSc must be excluded by a cardiologist.
- •e. history of SSc-related renal disease that is not active at the time of screening; history of scleroderma hypertensive renal crisis is included in this criterion.
- •Group 2: Progressive pulmonary disease as defined by a decrease in the FVC or DLCOcorr by 15 percent or greater compared to a prior FVC or DLCOcorr in the previous twelve month period; in addition, patients may have either less skin involvement than group 1 (mRSS less than 16) and the FVC or DLCOcorr is less than 70% or both FVC and DLCOcorr greater than or equal to 70% if they have diffuse cutaneous disease (mRSS greater than 16) at screening for the study; patients must also have evidence of alveolitis as defined by abnormal chest CT or BAL; for patients not able to adequately complete PFT, there must be evidence of progressive disease on chest CT.
- •Group 3: Have progressive active SSc after prior autologous transplant based on the presence of progressive pulmonary disease; this will be defined by a decrease in the FVC or DLCO adjusted since prior autologous transplant of 15 percent or greater of the pre-transplant percent predicted value, in addition to evidence of alveolitis as defined by chest CT changes or BAL. If patients had prior autologous HCT on the "Scleroderma: Cyclophosphamide Or Transplantation" (SCOT) clinical trial, they must have failed based on the defined study endpoints and be approved by the protocol principal investigator (PI).
Exclusion Criteria
- •Fertile men or women unwilling to use contraceptive techniques during and for 12 months following transplant
- •Evidence of ongoing active infection
- •Pregnancy
- •Patients with a creatinine clearance \< 60 ml/min/1.73 m\^2 body surface area
- •Uncontrolled clinically significant arrhythmias
- •Clinical evidence of significant congestive heart failure (CHF) (New York Heart Association \[NYHA\] Class III or IV)
- •LVEF \< 45% by echocardiogram
- •Severe pulmonary dysfunction with a hemoglobin corrected DLCO \< 30% or FVC \< 40% of predicted or O2 saturation \< 92% at rest without supplemental oxygen
- •Significant uncontrolled pulmonary hypertension defined as: Pulmonary artery peak systolic pressure \> 55 mmHg by echocardiogram, or pulmonary artery peak systolic pressure 45-55 mmHg by echocardiogram and mean pulmonary artery pressure by right heart catheterization exceeding 25 mmHg at rest (or 30 mmHg with exercise); or NYHA/World Health Organization (WHO), Class III or IV
- •Active hepatitis or liver biopsy evidence of cirrhosis or periportal fibrosis; liver function tests: total bilirubin \> 2 x the upper limit of normal and/or serum glutamic pyruvate transaminase (SGPT) and SGPT \> 4 x the upper limit of normal
Arms & Interventions
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: fludarabine phosphate
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: Mycophenolic Acid
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: tacrolimus
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: total-body irradiation
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: bone marrow transplantation
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: reduced intensity allogeneic hematopoietic stem cell transplantation
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: quality-of-life assessment
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: laboratory biomarker analysis
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: flow cytometry
Treatment: allogeneic UCB after reduced intensity conditioning
Patients receive fludarabine phosphate IV on days -4, -3 and -2, cyclophosphamide IV over 1-2 hours on days -6, -5, 3, and 4, and undergo low-dose TBI on day -1. Patients receive hematopoietic cell transplantation on day 0.
Intervention: biopsy
Outcomes
Primary Outcomes
Event-free Survival (EFS)
Time Frame: 2 years
The events will be defined as any one of the following: death; respiratory failure; renal failure, as defined by chronic dialysis \> or = 6 months or kidney transplantation; occurrence of cardiomyopathy, confirmed by clinical CHF (New York Class III or IV) or LVEF \< 30% by echocardiogram, sustained for at least 3 months despite therapy; organ dysfunction specific events must be documented on at least two occasions \> or = 3 months apart, or sustained for a 3-month period (documented from the first occurrence).
Secondary Outcomes
- EFS(5 years)
- Overall Survival(Up to 5 years)
- Treatment-related Mortality(From time of transplant to 5 years)
- Regimen-related Toxicity (Greater Than or Equal to Grade III) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0(Up to 5 years)
- The Percent of Participants With Definite and Probable Viral, Fungal, and Bacterial Infections(Up to 5 years)
- Quality of Life as Assessed by the Modified Scleroderma Health Assessment Questionnaire (SHAQ)(Up to 5 years)
- Quality of Life as Assessed by the Medical Outcome Short Form (36) Health Survey Instrument (SF-36)(Up to 5 years)
- Skin Score(Up to 5 years post-transplant)
- Incidence of Graft Rejection(Up to day +56)
- Incidence and Severity of Graft-versus-host Disease (GVHD)(Up to 5 years post-transplant)
- Incidence of Disease-modifying Antirheumatic Drugs (DMARDs) Initiated Post Transplant to Modify Disease(Up to 5 years post-transplant)