• Overall mortality [ Designated as safety issue: Yes ]
• Transplant-related mortality [ Designated as safety issue: Yes ]
• Incidence of graft rejection [ Designated as safety issue: Yes ]
• Incidence of grades II-IV acute graft-vs-host disease (GVHD) [ Designated as safety issue: Yes ]
• Incidence of chronic extensive GVHD [ Designated as safety issue: Yes ]
• Incidence of life-threatening infections [ Designated as safety issue: Yes ]

RATIONALE: Giving low doses of chemotherapy, such as fludarabine, total-body irradiation, and antithymocyte globulin before a donor peripheral stem cell transplant or umbilical cord transplant helps stop the growth of abnormal cells. It also may stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining abnormal cells. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine together with total-body irradiation followed by a donor peripheral stem cell transplant works in treating patients with severe systemic sclerosis.

OBJECTIVES:

Primary

• To determine the efficacy of nonmyeloablative conditioning comprising fludarabine phosphate and low-dose total-body irradiation followed by allogeneic peripheral blood stem cell transplantation, in terms of stabilization or regression of disease manifestations, in patients with severe systemic sclerosis.

Secondary

• To determine whether stable allogeneic engraftment can be safely established in patients treated with this regimen.

OUTLINE: This is a multicenter study.

• Nonmyeloablative conditioning: Patients receive fludarabine phosphate IV on days -4, -3 and -2 and undergo total-body irradiation on day 0 or cyclophosphamide IV on day -6, fludarabine phosphate IV on days -6 to -2, anti-thymocyte globulin on days -6 to -4, and undergo total-body irradiation on day -1.
• Allogeneic peripheral blood stem cell transplantation (PBSCT) or umbilical cord blood transplantation (UCBT): Patients undergo allogeneic PBSCT or UCBT on day 0.
• Graft-versus-host disease prophylaxis: Patients receive oral tacrolimus twice daily beginning on day -3 and continuing until day 180, followed by a taper until day 365. Patients also receive mycophenolate mofetil IV or orally three times daily beginning on day 0 and continuing until day 100, followed by a taper until day 156.

Patients are followed periodically after transplantation.

• Biological: anti-thymocyte globulin
• Drug: fludarabine phosphate
• Drug: mycophenolate mofetil
• Drug: tacrolimus
• Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
• Procedure: peripheral blood stem cell transplantation
• Procedure: umbilical cord blood transplantation
• Radiation: total-body irradiation

DISEASE CHARACTERISTICS:

• Diagnosis of severe systemic sclerosis (SSc) as defined by the American College of Rheumatology

• At high-risk for a fatal outcome based on the following prognostic factors from any of the following groups as defined below:

  • Group 1: Patients must meet both of the first two criteria AND ≥ 1 of the last three criteria, including the following:

    • Diffuse cutaneous scleroderma with skin score of ≥ 16 (modified Rodnan Skin Score [mRSS])
    • Duration of systemic sclerosis ≤ 5 years from the onset of first non-Raynaud's symptom
    • Presence of interstitial lung disease (FVC or corrected DLCO ≤ 70% of predicted) and evidence of alveolitis (abnormal bronchoalveolar lavage [BAL] or high resolution chest CT scan) after treatment with intravenous cyclophosphamide (≥ 2 g) given over at least a 3 month period

    • Left heart failure with LVEF < 50% (that responds to treatment targeted to scleroderma), pericardial effusion (mild-moderate), or second- or third-degree atrioventricular block

      • Myocardial disease not secondary to SSc must be excluded by a cardiologist
    • History of SSc-related renal disease that is not active at the time of study screening, including history of scleroderma hypertensive renal crisis

  • Group 2: Patients must have progressive pulmonary disease as the primary indication for transplant, as defined by a decrease in the FVC or DLCO by ≥ 15% within the past 12 months AND evidence of alveolitis (abnormal chest CT scan or BAL)

    • May have either less skin involvement than group 1 (mRSS < 16) and FVC or corrected DLCO < 70% of predicted OR both FVC and corrected DLCO ≥ 70% of predicted provided there is diffuse cutaneous disease (mRSS ≥ 16) at study screening

  • Group 3: Patients must have progressive active SSc after prior autologous hematopoietic cell transplantation (HCT) based on the presence of progressive pulmonary disease

    • Progressive pulmonary disease is defined by a decrease in the FVC or DLCO by ≥ 15% since prior autologous HCT AND evidence of alveolitis (abnormal chest CT scan or BAL)
    • Patients who have undergone prior autologous HCT on FHCRC-1948 (SCOT clinical trial) must have failed the transplant based on the defined study endpoints and be approved by the study Principal Investigator
  • Group 4: Patients must meet the criteria for group 1, but may have FVC or DLCO-adjusted < 70% AND have had an adverse event on cyclophosphamide preventing its further use (specifically hemorrhagic cystitis, leukopenia with WBC of 2,000 or ANC < 1,000 or platelet count < 100,000)
  • Group 5: Patients must have diffuse scleroderma with disease duration ≤ 2 years since development of first sign of skin thickening AND modified Rodnan skin score ≥ 25 AND ESR > 25 mm/1st hour and/or hemoglobin < 11 g/dL, not explained by causes other than active scleroderma

• Failed one of the following oral or IV cyclophosphamide regimens (unless corrected DLCO < 45% of predicted):

  • IV cyclophosphamide administered for ≥ 3 months between first and last cyclophosphamide dose at a total cumulative IV dose of at least 2 g
  • Oral cyclophosphamide administered for > 4 months, regardless of dose
  • Combination of oral and IV cyclophosphamide administered for ≥ 6 months, independent of dose

• Ineligible for FHCRC-1948 (SCOT clinical trial)

  • Patients who are eligible for FHCRC-1948 (SCOT clinical trial) who refuse participation on the SCOT clinical trial secondary to concerns of loss of fertility and other potential toxicities of high-dose immunosuppressive therapy (HDIT) are eligible for this clinical trial
• No myelodysplastic syndromes

• HLA genotypically identical sibling or unrelated donor available

  • No identical twin donor
  • Unrelated donors are required to be matched by standard molecular methods at the intermediate resolution level at HLA-A, -B, -C and -DRB1 and the allele level at DQB1

PATIENT CHARACTERISTICS:

• ANC > 2,000/mm^3 (unless marrow cellularity > 40% with trilineage hematopoiesis by bone marrow biopsy)
• Platelet count > 120,000/mm^3 (unless marrow cellularity > 40% with trilineage hematopoiesis by bone marrow biopsy)

• No organ dysfunction as defined by any of the following criteria:

  • Creatinine clearance < 60 mL/min
  • Uncontrolled clinically significant arrhythmia
  • Clinical evidence of significant congestive heart failure (NYHA class III or IV congestive heart failure)
  • LVEF < 40% by echocardiogram
  • Severe pulmonary dysfunction, defined as hemoglobin corrected DLC0 < 30%, FVC < 45% of predicted, or O_2 saturation < 92% at rest without supplemental oxygen

  • Significant uncontrolled pulmonary hypertension, defined by any of the following:

    • Pulmonary artery peak systolic pressure > 55 mm Hg by echocardiogram
    • Pulmonary artery peak systolic pressure 45-55 mm Hg by echocardiogram and mean pulmonary artery pressure > 25 mm Hg at rest (or > 30 mm Hg with exercise) by right heart catheterization
    • WHO/NYHA class III or IV pulmonary hypertension
  • Active hepatitis or evidence of cirrhosis or periportal fibrosis by liver biopsy
  • Total bilirubin > 2 times upper limit of normal (ULN) and/or SGOT and SGPT > 4 times ULN
• No evidence of ongoing active infection
• No poorly controlled hypertension
• Life expectancy not severely limited by illness other than autoimmune disease
• No poorly controlled bleeding from gastric antral vascular ectasia (GAVE) or other gastrointestinal sites
• No untreated psychiatric illness
• No drug or alcohol abuse
• No demonstrated lack of compliance with prior medical care
• No HIV seropositivity
• No malignancies except squamous cell or basal cell carcinoma of the skin
• Not pregnant
• Fertile patients must use effective contraception during and for 12 months following transplant

PRIOR CONCURRENT THERAPY:

• Not specified