Chemotherapy, Total Body Irradiation, and Post-Transplant Cyclophosphamide in Reducing Rates of Graft Versus Host Disease in Patients With Hematologic Malignancies Undergoing Donor Stem Cell Transplant

PRIMARY OBJECTIVES:

I. To determine the cumulative incidence of extensive chronic graft versus host disease
(GVHD) at 1 year after transplantation utilizing the novel conditioning/GVHD prophylactic
regimen for patients undergoing allogeneic hematopoietic cell transplantation, in patients
who do not progress before day 100.

SECONDARY OBJECTIVES:

I. To evaluate clinical response, engraftment rate, progression-free survival (PFS) at one
year and, overall survival (OS).

II. To determine the cumulative incidence of relapse. III. To evaluate the day 100
transplant-related mortality rate. IV. To determine the cumulative incidence of grade III-IV
acute GVHD.

OUTLINE: This is a dose-escalation study of melphalan hydrochloride.

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30
minutes on days -5 to -2 and melphalan hydrochloride IV over 30 minutes on day -2. Patients
undergo total body irradiation (TBI) on day -1.

STEM CELL INFUSION: Patients undergo allogeneic hematopoietic stem cell transplant on day 0.

GVHD PROPHYLAXIS REGIMEN: Patients receive cyclophosphamide IV over 2 hours on days 3-4,
mycophenolate mofetil IV over 2 hours on days 5-35, and tacrolimus IV and then orally (PO)
once tolerated on days 5-180 with a taper beginning on day 100.

After completion of study treatment, patients are followed up for 12 months and then annually
thereafter.

Inclusion Criteria:

- The patient must have a diagnosis of one of the following (one must be yes):

- Acute myeloid leukemia (AML)

- Acute lymphoblastic leukemia (ALL)

- Chronic myelogenous leukemia (CML) (chronic phase intolerant or unresponsive to
tyrosine kinase inhibitors, accelerated phase, history of blast crisis)

- Myelodysplastic syndrome (MDS)

- Myeloproliferative neoplasm (MPN)

- Chronic myelomonocytic leukemia (CMML)

- Non-Hodgkin lymphoma (NHL)

- Hodgkin lymphoma (HL) (received and failed frontline therapy or failed autologous
transplantation or inability to collect enough peripheral blood stem cells [PBSC]
for autologous hematopoietic cell transplant [auto-HCT])

- Multiple myeloma (MM)

- Waldenstrom's macroglobulinemia

- Severe aplastic anemia

- Histocompatible donor identified:

- Related donor or unrelated donor matched 5/6 or better (A, B, DRB1)

- Patients with benign hematological disorders such as severe aplastic anemia do not
have disease requirements. Patients with malignant hematologic disorder must be in CR
(MRD is allowed) with the exception of the following:

- Patients with MDS/MPN only require <5% myeloblast on bone marrow evaluation.

- Patients with AML or ALL may be in CRi, patients with MM may be in VGPR

- Have a Karnofsky performance status score of > 50%

- Diffusing capacity of the lung for carbon monoxide (DLCO) > 40% predicted, corrected
for hemoglobin and/or alveolar ventilation

- Left ventricular ejection fraction > 40%

- Bilirubin =< 3 x upper limit of normal

- Liver alkaline phosphatase =< 3 x upper limit of normal

- Serum glutamic-oxaloacetic transaminase (SGOT) or serum glutamate pyruvate
transaminase (SGPT) =< 3 x upper limit of normal

- Calculated creatinine clearance > 40 cc/min by the modified Cockroft-Gault formula

- Patient must be cleared pre-transplant by Radiation Oncology to be able to receive 400
cGy

- Participants of child-bearing potential must agree to use adequate contraceptive
methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study
entry; should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately

- Patients who have failed a prior autologous or allogeneic transplant are eligible;
however, at least 6 months must have elapsed between the start of this reduced
intensity conditioning regimen and the last transplant if patient had a prior
autologous or myeloablative allogeneic bone marrow transplant (BMT)

- At least 2 weeks since prior chemotherapy, radiation treatment and/or surgery

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Bone marrow failure disorders:

- Paroxysmal nocturnal hemoglobinuria (PNH)

- Hereditary bone marrow failure disorders include Diamond-Blackfan anemia,
Shwachman- Diamond syndrome, Kostmann syndrome, and congenital amegakaryocytic
thrombocytopenia

- Other non-malignant hematologic or immunologic disorders that require
transplantation:

- Quantitative or qualitative congenital platelet disorders (including but not
limited to congenital megakaryocytopenia, absent-radii syndrome, Glanzmann?s
thrombasthenia)

- Quantitative or qualitative congenital neutrophil disorders (including but
not limited to chronic granulomatous disease, congenital neutropenia)

- Congenital primary immunodeficiencies (including but not limited to severe
combined immunodeficiency syndrome, Wiskott-Aldrich syndrome, CD40 ligand
deficiency, T-cell deficiencies)

- Hemoglobinopathies (including sickle cell disease and thalassemia)

- Presence of human leukocyte antigen (HLA) antibodies

- Uncontrolled central nervous system (CNS) disease (for hematologic malignancies)

- Child-Pugh class B and C liver failure

- Patients who in the opinion of the treating physician are unlikely to comply with the
restrictions of allogeneic stem cell transplantation based on formal psychosocial
screening. (i.e., serious, uncontrolled psychiatric illness/social situations that
would limit compliance with study requirements)

- Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or
other condition which, in the opinion of treating physician, would make this protocol
unreasonably hazardous for the patient

- Known human immunodeficiency virus (HIV) positive

- Pregnant or nursing female participants

- Unwilling or unable to follow protocol requirements

- Any condition which in the Investigator?s opinion deems the participant an unsuitable
candidate to receive study drug