A Two Step Approach to Allogeneic Hematopoietic Stem Cell Transplantation for Patients With Hematologic Malignancies-Increasing GVT Effects Without Increasing Toxicity

Primary Objective:

1. To assess 2 year probability of OS in high risk patients undergoing a myeloablative 2 step
HSCT utilizing strategies to decrease relapse.

Secondary Objective:

1. To assess relapse incidence at 2 years post-HSCT of patients undergoing treatment on
this protocol.

2. To assess regimen related toxicity and GVHD incidence at 2 years post-HSCT and severity
in patients undergoing treatment on this protocol.

3. To assess the consistency and pace of engraftment.

4. To assess the pace of T cell and B cell immune recovery.

Inclusion Criteria:

This treatment is for patients with high risk hematologic malignancies. High risk is
defined as:

- Any patient with a hematologic malignancy in which allogeneic HSCT is pursued with the
expectation of cure. Patients may have post-treatment residual disease, but the
disease should be stable or minimally progressive and must be responsive to
chemotherapy.

- Any patient with an untreated hematologic malignancy in which allogeneic HSCT is
thought to be the sole or the best option for cure and in Patients without morphologic
evidence of disease but with high risk features which would predict for relapsed
despite remission at HSCT such as adverse cytogenetics, 3rd or greater CR, or failure
to recover peripheral blood counts to normal ranges. While these patients do not have
detectable disease by current methods, like all patients they have non-detectable
disease which in their case is highly aggressive.

- Patients must have one related donor who is HLA mismatched in the GVHD direction at
two or more HLA loci (except as described below)

- Patients must have adequate organ function:

- Left Ventricular Ejection Fraction (LVEF) of ≥50%

- DLCO (adjusted for hemoglobin) ≥50% of predicted and FEV-1 ≥50%

- Adequate liver function as defined by a serum bilirubin ≤1.8, Aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 x Upper Limit of Normal
(ULN)

- Creatinine clearance of ≥ 60ml/min

- Karnofsky Performance Status (KPS) of ≥80% on the modified KPS tool (see Appendix)

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

- Able to give informed consent

- Age ≥ 18 years of age

Exclusion Criteria:

- Modified KPS of <80%

- > 5 Comorbidity Points on the Hematopoietic Cell Transplant Co-Morbidity Index (HCT
CI) (See Appendix) (Patients with greater than 5 points will be allowed 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 this
protocol but have histories that result in higher than HCT-CI 5 points. An example 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.

- Human Immunodeficiency Virus (HIV) positive

- Active involvement of the central nervous system with malignancy

- Psychiatric disorder that would preclude patients from signing an informed consent

- Pregnancy, or unwillingness to use contraception if they have childbearing potential

- Patients with life expectancy of ≤ 6 months for reasons other than their underlying
hematologic/oncologic disorder

- Alemtuzumab treatment within 8 weeks of HSCT admission

- ATG within 8 weeks of HSCT administration

- Patients with active inflammatory processes including T max >101 or active tissue
inflammation are excluded up to and including the day of admission

- Inability to tolerate cyclophosphamide or undergo total body irradiation at the doses
specified in the treatment plan.