Stem Cell Transplantation in Idiopathic Inflammatory Myopathy Diseases

Conditioning Regimen (In order to assure sterility testing, a minimum of 14 days will be required between stem cell collection and starting the conditioning regimen).

The conditioning regimen is outlined in below:

Cyclophosphamide 50 mg/kg/day will be given IV over 1 hour in 250 cc of normal saline on day -5, -4, -3, and -2. If actual weight is < ideal weight, cyclophosphamide will be given based on actual weight. If actual weight is > ideal weight, cyclophosphamide will be given as adjusted ideal weight. Adjusted ideal weight = ideal weight + 40% (actual weight minus ideal weight).

Mesna 50mg/kg/day will be given IV over 24 hours in 250 cc of normal saline or D5W starting at 10AM each dose. Weight base is calculated same as cyclophosphamide as above.

1ATG (rabbit) 0.5 mg/kg on day -6 and 1mg/kg on day -5, -4, -3, -2 and -1 (total 5.5mg/kg, no dose adjustment) will be given IV over 10 hours in 250 cc of normal saline beginning at least 1 hour after infusion of cyclophosphamide. Premedicate with acetaminophen 650 mg po and diphenhydramine 25 mg po/IV 30 minutes before the infusion.

Methylprednisolone- A suggested dose of 250mg IV should be administered 30 minutes before each ATG infusion.

Hydration- A suggested rate of 125 cc/hr NS should be given starting 6 hours before the first cyclophosphamide dose and continued until 24 hours after the last cyclophosphamide dose. The rate of hydration will be aggressively adjusted. BID weights will be obtained. Amount of fluid can be modified based on patient's fluid status. Minimum target urine output is 2 liters/m2/day

G-CSF 5 mcg/kg/day will be given subcutaneously and continued until the absolute neutrophil counts reaches at least 500/µl.

Rituxan 500 mg will be given IV on the day before the first dose of ATG and the day after stem cell infusion.

• Hematopoietic stem cell transplantation (Biological): Autologous hematopoietic stem cell transplantation
• Cyclophosphamide (Drug), also known as Cytoxan
• Mesna (Drug)
• ATG(rabbit) (Drug)
• Methylprednisolone (Drug)
• G-CSF (Drug)
• Rituxan (Drug)

Primary outcomes

• Survival [up to 5 years]: Survival

Sex: All, ages: 16 Years to 65 Years

Inclusion Criteria:

1. Age ≥ 16 years and ≤ 65 years at the time of pretransplant evaluation.
2. An established diagnosis of polymyositis, dermatomyositis, juvenile polymyositis/dermatomyositis, and myositis associated with other collagen diseases. Diagnosis requires electrophysiological studies and histopathologic features. MRI evidence of muscle inflammation or histological evidence of active myositis is mandatory at entry. If patient had dermatomyositis/polymyositis associated with malignancy, the patient has to be free of malignancy for 5 years and considered to be cured.
3. Patients who failed conventional treatment of at least 3 months duration including high-dose corticosteroids (equivalent dosage of prednisone >1.0 mg/kg/day to start), and must also have failed two or more of the followings: cyclophosphamide, azathioprine, 6-MP, methotrexate, tacrolimus, cyclosporin A, mycophenolate mofetil, TNF inhibitor (e.g. etanercept), IVIG or any other immunosuppressive drugs or immune modulating drugs.
4. Failure is defined by (one or more of the following) (not caused by unrelated conditions):

   * Persistent muscle weakness (grade 4/5 or worse by MRC) with elevation of muscle derived enzymes (CPK, aldolase)
   * Worsening pulmonary function especially %VC or DLCo > 15% over 12 months indicating active alveolitis.
   * Abnormal EKG or echocardiographic evidence of cardiomyopathy.
   * Presence of progressive joint contracture, progressive calcinosis, vasculitis, or skin ulcers in juvenile dermatomyositis/polymyositis.

Exclusion Criteria:

1. Poor performance (PS) status (ECOG >2) at the time of entry, unless decline of PS is due to the disease itself.
2. Significant end organ damage such as (not caused by IIM):

   * LVEF <40% or deterioration of LVEF during exercise test on MUGA or echocardiogram.
   * Untreated life-threatening arrhythmia.
   * Active ischemic heart disease or heart failure.
   * DLCo <40% or FEV1/FEV < 50%.
   * Serum creatinine >2.5 or creatinine clearance <30ml/min.
   * Liver cirrhosis, transaminases >3x of normal limits or bilirubin >2.0 unless due to Gilbert disease.
3. HIV positive.
4. Uncontrolled diabetes mellitus, or any other illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive treatment.
5. Prior history of malignancy except localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgical therapy, such as (but not limited to) head and neck cancer, or stage I or II breast cancer will be considered on an individual basis.
6. Positive pregnancy test, inability or unable to pursue effective means of birth control, failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
7. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
8. Inability to give informed consent.
9. Major hematological abnormalities such as platelet count less than 100,000/ul, ANC less than 1000/ul.

Participant flow

Outcome results

• Survival (Primary), Count of participants, Participants: Hematopoietic Stem Cell Transplantation 7

Adverse events

Time frame: 6 months, 1 year, then yearly up to 5 years post transplant

Other adverse events by term

Limitations and caveats: Early termination leading to small numbers of subjects analyzed

• Richard Burt, MD, Principal investigator, Northwestern University