Reduced-Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

PRIMARY OBJECTIVE:

1. To compare the rate of disease-free survival (DFS) at 1 year post hematopoietic stem cell
transplant (HSCT) in patients undergoing HSCT treated on this successor Thomas Jefferson
University (TJU) 2 Step reduced intensity conditioning (RIC) haploidentical regimen and
compare it with that of the initial 2 Step RIC regimen.

SECONDARY OBJECTIVES:

1. To assess the 100 day regimen-related mortality (RRM) in patients undergoing HSCT on
this treatment protocol.

2. To determine the incidence and severity of graft-versus-host disease (GVHD) in patients
undergoing treatment on this regimen.

3. To evaluate engraftment rates and lymphoid reconstitution in patients treated on this
trial.

4. To assess overall survival at 1 and 3 years past HSCT in patients treated on this trial.

OUTLINE:

REDUCED INTENSITY CONDITIONING: Patients receive fludarabine phosphate intravenously (IV)
over 60 minutes on days -15 to -12, thiotepa IV over 2 hours on days -15 to -13, donor
lymphocyte infusion (DLI) on day -6, and cyclophosphamide IV over 2 hours on days -3 and -2.
Patients also undergo total-body irradiation (TBI) on day -10.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) on day
0.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV on days -1 to 42 followed by taper and
mycophenolate mofetil IV twice daily (BID) on days -1 to 28.

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

Inclusion Criteria:

1. Any patient with a high-risk hematologic or oncologic diagnosis in which allogeneic
HSCT is thought to be beneficial, and in whom front-line therapy has already been
applied. High risk is defined as:

1. Acute myeloid leukemia with high risk features as defined by:

- Age greater than or equal to 60

- Secondary AML (prior therapy or hematologic malignancy)

- Normal cytogenetics but FLT3/ITD positive

- Any relapse or primary refractory disease

- Greater than 3 cytogenetic abnormalities or any one of the following
cytogenetic abnormalities: -5/del(5q), -7/del(7q),
Abn(9q),(11q),(3q),(21q),(17p),t(6;9), t(6;11), t(11;19),
+8,del(12p),inv(3),t(10;11),-17, 11q 23

- Any single autosomal monosomy

2. Acute lymphoid leukemia in 1st or 2nd morphological remission. ALL with any
morphological evidence of disease will not be eligible.

3. Myelodysplasia (MDS) other than refractory anemia (RA), refractory anemia with
rare sideroblasts (RARS), or isolated 5q- syndrome subtypes.

4. Hodgkin's or Non-Hodgkin's lymphoma in 2nd or greater remission or with
persistent disease.

5. Myeloma with evidence of persistent disease after front-line therapy.

6. Chronic myeloid leukemia (CML) resistant to signal transducer inhibitor (STI)
therapy

7. Myelofibrosis and CMML

8. Essential Thrombocytopenia or Polycythemia Vera with current or past evidence of
evolution to acute leukemia

9. Any hematological malignancy not cited above which is thought to be high-risk
with increased chance of post HSCT relapse. Patients in this category require
specific approval of the PI and the TJU BMT attending physician group for
entrance.

10. Any hematological malignancy or dyscrasia not cited above which is thought to be
high-risk with increased chance of post HSCT relapse.

11. Any patient who has an aggressive disease that would normally be treated on a
myeloablative study, but is prevented from doing so by factors in their past
medical history. Examples are patients with previous treatment with radiation
therapy precluding TBI, or a past history of myeloablative therapy, precluding a
2nd myeloablative regimen.

12. Patients with aplastic anemia may be treated on this protocol, with outcomes
reported descriptively.

2. Patients must have a related donor who is at least a 4 antigen match at the Human
Leukocyte Antigen (HLA)-A; B; C; DR loci. Patients with only a 1 out of 8 mismatch in
the GVH direction will be classified in the matched related category

3. Patients must adequate organ function:

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

2. Diffusion Lung Capacity of Oxygen (DLCO) >50% of predicted corrected for
hemoglobin

3. Adequate liver function as defined by a serum bilirubin <1.8, aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5X upper limit of
normal

4. Creatinine Clearance of ≥ 60 mL/min 4) Patients must have adequate KPS and HCT-CI
scores:

1. Patients < age 60 years must have a KPS of ≥80% and an HCT-CI score of 5 or less

2. Patients aged 60 to 65 years must have a KPS of ≥80% and an HCT-CI score of 4 or
less

3. Patients aged 66 to 69 years must have a KPS of 90% and an HCT-CI score of 3 or
less

4. Patients aged 70 years or more must have a KPS of 90% and an HCT-CI score of 2 or
less (Patients with greater than the allowable HCT-CI points for age can be
enrolled for trial with approval of the PI and at least 1 Co-I not on the primary
care team of the patient). This is an adjustment to account for healthy patients
who meet the spirit of the protocol but have histories that result in higher than
guideline HCT-CI points. An examples is a patient with a solid tumor malignancy
in their remote history (adds 3 points to HCT-CI total) where the treatment for
the malignancy occurred years to decades before and there has been complete
recovery of toxicities 5) Patients must be willing to use contraception if they
have childbearing potential 6) Patient or patient's guardian is able to give
informed consent

Exclusion Criteria:

1. HIV positive

2. Active involvement of the central nervous system with malignancy

3. Pregnancy

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

5. Patients who have received alemtuzumab or ATG within 8 weeks of the transplant
admission.

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