• Plasma concentration and exposure time required for cyclosphosphamide to produce optimal immunosuppressive activity with minimal toxicity [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  

• Pharmacokinetics of a second dose in Arm 2 after initial cyclophosphamide exposure [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Effect of high dose cyclophosphamide regimen on myelosuppression [ Time Frame: At Hours 24 and 48 after dosage in Arm 1 ] [ Designated as safety issue: No ]
  

The purpose of this study is to determine the plasma concentration and exposure time required for cyclosphosphamide to produce optimal immunosuppressive activity with minimal toxicity in subjects with severe systemic sclerosis.

Secondary objectives are:

1. To determine whether the initial cyclophosphamide exposure affects the pharmacokinetics of a second dose in the cyclophosphamide arm.
2. To evaluate the effect of this high dose cyclophosphamide regimen on myelosuppression as assessed by total white cell count and that of polymorphic mononuclear cells at approximately 24 and 48 hours post-dose in the transplant arm.

Recruitment for this study will be limited to participants who have elected to participate in the SCOT study and have been randomized to one of the SCOT treatment arms. Participants will be recruited after randomization to ensure balance on the two arms for this mechanistic study and must agree to participate and sign an informed consent for this mechanistic study prior to initiation of treatment on either arm. Fifty participants, 25 from each arm, will be recruited for this sub-study. It will be conducted at the participating SCOT transplant and rheumatology centers.

In Arm 1 (the transplant arm), as part of the conditioning regimen, cyclophosphamide at a dose of 60 mg/kg will be infused over 1 to 2 hours (on 2 consecutive days), and blood collection will occur prior to dosing and at Hours 2, 4, 6, 8, 10, and 23 after completion of the first infusion for measurement of 4-OH-CP pharmacokinetics. Additionally, blood collection will occur at approximately 24 and 48 hours in the transplant arm to obtain white cell count and differential (including polymorphic mononuclear cell counts).

In Arm 2 (the high-dose cyclophosphamide arm), an initial cyclophosphamide dose of 500 mg/m2 will be infused over 1 to 2 hours, and blood collection will occur prior to dosing and at Hours 0.5, 1, 2, and 24 after completion of drug infusion for measurement of 4-OH-CP pharmacokinetics. For the second monthly infusion, a cyclophosphamide dose of 750 mg/m2 will be infused with blood collection occurring at the same time points as those for the first dose.