A Two-Step Approach to Reduced Intensity Bone Marrow Transplant for Patients With Hematological Malignancies

PRIMARY OBJECTIVES:

I. To compare the overall survival (OS) rate at 2 years post treatment using the Jefferson 2
step reduced intensity conditioning (RIC) approach in patients with haploidentical family
donors with hematological malignancies in morphological or radiographic remission or with
chemosensitive, indolent diseases to historical OS rates in similar populations after RIC
matched donor HSCT as reported in the literature.

SECONDARY OBJECTIVES:

I. To compare the treatment-related mortality (TRM) rate at 2 years for patients treated on
this study to the historical TRM rates of patients undergoing RIC matched-sibling HSCT as
reported in the literature.

II. To compare the 2 year relapse rates and relapse related mortality of patients with
myeloid diseases to that of patients with lymphoid diseases who are treated on this Thomas
Jefferson University (TJU) RIC 2 step approach.

III. To determine the incidence and severity of graft-versus-host disease (GVHD) in patients
undergoing treated on the TJU RIC 2 step approach.

IV. To evaluate engraftment rates and lymphoid reconstitution in patients treated on the TJU
RIC 2 step approach.

V. To evaluate the incidence of TRM at 100 days in patients treated on the TJU RIC 2 step
approach.

OUTLINE:

REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV)
over 60 minutes on days -11 to -8 and bulsufan IV over 3 hours on days -10 to -9. Patients
undergo total body irradiation (TBI) on day -6. Patients also receive cyclophosphamide IV
over 2 hours on days -3 and -2.

TRANSPLANTATION: Patients undergo donor lymphocyte infusion (DLI) on day -6 and cluster of
differentiation (CD)-34+ allogeneic peripheral blood stem cell transplantation (PBSCT) on day
0.

GVHD PROPHYLAXIS: Beginning on day -1, patients receive tacrolimus IV or orally (PO) with
taper beginning on day 42. Patients also receive mycophenolate mofetil IV twice daily (BID)
on days -1 to 28.

After completion of study treatment, patients are followed up periodically for 2 years.

Inclusion Criteria:

1. Any patient with hematologic or oncologic diagnosis in which allogeneic HSCT is
thought to be beneficial, and in whom front-line therapy has already been applied.
Patients treated on this protocol will be without morphological evidence of disease
(complete remission or "CR"), or if the patient has evidence of disease, the patient
must have had at least a good partial response (PR) to the most recent therapy and the
disease must be chemoresponsive.

2. Patients treated on this study will have:

- Acute leukemia in 1st or 2nd CR

- MDS (myelodysplastic syndrome), specific subtypes of RA (refractory anemia) or
RARS (refractory anemia with ringed sideroblasts) subtypes.

- Hodgkin or Indolent Non-Hodgkin's lymphoma with chemosensitive disease

- Myeloma without morphological evidence of disease, or a deep PR to the most
recent therapy

- Myeloproliferative disorders with at least a PR to current therapy

- Aplastic Anemia

- A hematological or oncological disease (not listed) that meets the criteria
reviewed above (in CR or with a good PR).

3. Patients must have a related donor who is HLA mismatched at 2, 3, or 4 antigens at the
HLA-A; B; C; DR loci in the GVHD direction. (Patients with related donors who are HLA
identical or are a 1-antigen mismatch may be treated on this therapeutic approach, but
will have their outcomes will not be part of the statistical aims of the study (see
Summary section).

4. Patients must adequate organ function:

- LVEF (Left ventricular end diastolic function) of >50%

- DLCO (Diffusing Capacity of the Lung for Carbon Monoxide ) ≥50% of predicted
corrected for hemoglobin

- Adequate liver function as defined by a serum bilirubin <1.8, AST or ALT < 2.5X
upper limit of normal

- Creatinine Clearance of ≥ 60 mL/min

5. Performance status ≥ 80% (TJU Karnofsky) for patients ≥ 60 years old or ≥70% for
patients < 60 years old.

6. HCT-CI Score ≤ 4 points for patients ≥ 60 years old or ≤ 5 points for patients < 60
years old.

7. Patients must be willing to use contraception if they have childbearing potential

8. Able to give informed consent

Exclusion Criteria:

1. Performance status < 80% (TJU Karnofsky) for patients ≥ 60 years old or <70% for
patients < 60.

2. Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) Score > 4 points for patients
≥ 60 years old or > 5 points for patients < 60.

3. HIV positive

4. Active involvement of the central nervous system with malignancy

5. Inability to obtain informed consent

6. Pregnancy

7. Patients with life expectancy of < 6 months for reasons other than their underlying
hematologic/oncologic disorder

8. Patients who have received alemtuzumab within 8 weeks of the transplant admission, or
who have recently received horse or rabbit anti-thymocyte globulin and have an
anti-thymocyte globulin level of > 2 ugm/ml

9. Patients with evidence of another malignancy, exclusive of a skin cancer that requires
only local treatment, should not be enrolled on this protocol