Pentostatin in Treating Patients With Refractory Chronic Graft-Versus-Host Disease

OBJECTIVES:

Primary

- Determine the response rate in patients with refractory chronic graft-versus-host
disease treated with pentostatin.

Secondary

- Determine the time to next immunosuppressive agent (i.e., the time to progression from
best response) in patients treated with this drug.

- Determine the toxicity of this drug in these patients.

- Determine the infection rate in patients treated with this drug.

- Determine the pharmacokinetics of this drug in these patients.

- Determine the changes in lymphocyte populations in patients treated with this drug.

- Determine the survival of patients treated with this drug.

OUTLINE: This is a multicenter study.

Patients receive pentostatin IV over 20-30 minutes on day 1. Treatment repeats every 14 days
for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients who achieve a complete response after 6 courses receive 4 additional courses.
Patients who achieve a partial response, minor response, or stable disease after 6 courses
may receive up to 6 additional courses.

Patients are followed every 4 weeks for 1 year, every 3 months for 2 years, and then annually
for 5 years.

PROJECTED ACCRUAL: Approximately 37 patients will be accrued for this study.

1. Histologic documentation of chronic GvHD following allogeneic HCT or donor lymphocyte
infusion.

2. Patients may have progressive, quiescent, or de novo onset chronic GvHD.

3. Patients with extensive stage chronic GvHD requiring systemic immunosuppressive
therapy are eligible. Patients with limited stage disease are excluded. Extensive
stage is defined according to Seattle criteria (9) as either:

- Generalized skin involvement or

- Limited skin involvement or hepatic involvement with any one of the following:

- Liver histology showing chronic progressive hepatitis, bridging necrosis or
cirrhosis

- Eye involvement (Schirmer's test with < 5 mm wetting)

- Involvement of minor salivary glands or oral mucosa

- Involvement of any other organ

4. Patients must have failed treatment with, or experience progression after, prior
corticosteroids for extensive stage chronic GvHD, as defined below.

4.1 Patients will be considered to have failed corticosteroids if they have any one of
the following criteria:

- Progressive disease or less than a minor response in any organ system despite 2
weeks on corticosteroid treatment at least 1 mg/kg methylprednisolone or
equivalent.

- Failure to achieve at least a minor response after at least 4 weeks of treatment
with a dose of ≥ 0.5 mg/kg methylprednisolone or equivalent.

- Achievement of less than a partial response at 8 weeks of corticosteroid
treatment despite use of a dose ≥ 0.5 mg/kg methylprednisolone or equivalent.

- Requirement of ≥ 0.5 mg/kg methylprednisolone or equivalent to maintain a partial
response or better at 12 weeks of corticosteroid treatment.

- Requirement of > 10 mg/kg methylprednisolone or equivalent to maintain a partial
response or better at 18 weeks of corticosteroid treatment.

4.2 Patients with progression of extensive stage chronic GvHD after a prior history of
treatment with at least 18 weeks of corticosteroids, now requiring the reintroduction
of corticosteroids (> 10 mg/day methylprednisolone or equivalent) or an additional
agent (including photopheresis, PUVA) for treatment.

5. Patients with established chronic GvHD not improving or progressing on other
immunosuppressive agents are also eligible if steroid refractoriness has been
established previously.

6. Age ≥ 18 years

7. Performance Status 0-3

8. Patients on mechanical ventilation are excluded.

9. No active infection. Patients with active infection requiring antibiotic therapy are
not eligible until infection is controlled.

10. No HIV infection. Patients with HIV infection are excluded because of safety concerns
in this patient population.

11. Non-pregnant and non-nursing. Women and men of reproductive potential should agree to
use an appropriate method of birth control throughout their participation in this
study due to the teratogenic potential of the therapy utilized in this trial (although
it is unlikely that successful pregnancy will occur in patients with chronic GvHD).
Appropriate methods of birth control include oral contraceptives, implantable hormonal
contraceptives (Norplant®), or double barrier method (diaphragm plus condom).

12. Required Initial Laboratory Values:

- Calc. Creatinine Clearance ≥ 30 mL/min/1.73 m^2

- ANC > 1000/μL

- Platelets > 50,000/μL without transfusion