Fludarabine and 400 CGY Total Body Irradiation for Recipients of HLA-Matched or Mis-Matched Family or Unrelated Donor Hematopoietic Stem Cell Transplants Who Have Rejected Their First Allogeneic Stem Cell Transplant

This protocol will evaluate the use of Fludarabine (150mg/m2) with TBI (400cGy) as
pre-transplant conditioning for a second allogeneic stem cell transplant after initial graft
rejection. Preliminary data suggest that the combination of Flu/TBI at the proposed doses is
safer and more effective than prior second transplantation regimens published to date. As we
perform more non-myeloablative transplantations we expect that this issue to arise more
frequently. The preliminary data available indicate that the proposed regimen is the safest
and most effective to instill donor hematopoiesis after the initial graft has been rejected.

We also wish to evaluate the safety and effectiveness of Tacrolimus and MMF as GVHD
prophylaxis in patients receiving a second transplant. Tac/MMF is our current GVHD
prophylaxis regimen. It has proven to be well tolerated and provide good protection against
GVHD, even in heavily pretreated patients. We propose to use this standard first transplant
GVHD prophylaxis to prevent GVHD after second transplantation. DLI may be given in the
presence of disease progression or for mixed chimerism as clinically indicated.

Inclusion Criteria:

Any patient who has rejected a previous allogeneic transplant (related or unrelated)
rejection based on chimerism data from peripheral blood specimens showing loss of donor T
Cells.

1. Available HLA-identical, a one-antigen mis-matched sibling donor, a phenotypically
HLA-matched family member, a phenotypically matched unrelated donor, or a 9/10
matched unrelated donor with a negative cross-match.

2. Age ≤ 75 years.

3. Patients who fail to engraft or have signs of early relapse after an autologous
transplant may be considered for this protocol as salvage treatment if they are
presented to the RMBMTP Clinical Care meeting and the majority of the group agrees
that this a reasonable treatment option.

Exclusion Criteria:

1. Patients whose low donor chimerism is felt to be due to rapidly progressive
hematological malignancies, unless they can be treated into a minimal disease state
with additional treatment.

2. Patients with active uncontrolled CNS involvement with malignancy.

3. Fertile men or women unwilling to use contraceptive techniques during and for 12
months following treatment.

4. Females who are pregnant.

5. Patients who are HIV positive

6. Organ dysfunction felt to be due to the conditioning for the first transplant
including the following:

- Left ventricle ejection fraction < 35%.

- DLCO <35% of predicted, or receiving continuous supplementary oxygen.

- Karnofsky score <50 for patients < 60 years, or <70 for patients aged 60 - 69
years (see appendix B).

- Creatinine clearance < 40 ml/min.

- Patients with these end-organ toxicities may be presented to the RMBMTP Patient
Care Conference. If the majority opinion is that this treatment is the safest
option for a patient who has rejected their first transplant, they will be
allowed to undergo the treatment, after informed consent has been signed.

- Patients with a positive PRA or anti-donor T or B cell (+) will be
considered for this treatment protocol only if no other option is
available. They should not be eligible for another research study. The
transplantation group must have a majority opinion that this is the best
available option for the patient in question. In patients with either
condition, the only acceptable stem cell source will be peripheral blood.