Thiotepa Plus Fludarabine+ Melphalan as the Preparative Regime for Alternative Donor Transplantation

Primary Objective:

To assess the effectiveness of Thiotepa, Fludarabine, and Melphalan in alternative donor
transplants as measured by leukemia free survival.

Secondary Objective:

To assess the 1- year OS, Relapse, TRM, aGVHD and cGVHD rates and the rates of neutrophil and
platelet engraftment.

Study Design This is a Phase II study of Thiotepa, Fludarabine, and Melphalan in alternative
donor transplants.

Subjects will be assessed for safety and tolerability (including adverse events, serious
adverse events, and clinical/laboratory assessments) using a continuous monitoring approach.
Subjects will be followed for up to 1 year or until progression of disease, relapse, or
death.

Inclusion Criteria:

- Patients with the following hematologic malignancies:

- Acute myelogenous leukemia (AML): High-risk AML including:

- Antecedent hematological disease (e.g., myelodysplasia (MDS))

- Treatment-related leukemia

- Complete Remission (CR1) with poor-risk cytogenetics or molecular markers
(e.g. Flt 3 mutation, 11q23, del 5, del 7, complex cytogenetics)

- Second complete remission (CR2) or third complete remission (CR3)

- Induction failure or 1st relapse with ≤ 10% blasts in the marrow

- Acute lymphoblastic leukemia (ALL)

- High-risk CR1 including:

- Poor-risk cytogenetics (e.g., Philadelphia chromosome t(9;22)or 11q23
rearrangements)

- Presence of minimal disease by flow cytometry after 2 or more cycles of
chemotherapy

- No CR within 4 weeks of initial treatment

- Induction failure with ≤ 10% blasts in the marrow

- CR2 or CR3

- Myelodysplastic syndromes (MDS), Intermediate, High or Very High Risk by the
revised international prognostic scoring system (IPSS-R)

- Chronic Myelogenous Leukemia (CML) in second chronic phase after accelerated or
blast crisis.

- Myelofibrosis (MF):

- Intermediate-2 or high risk by Dynamic International Prognostic Scoring
System (DIPSS-plus) or

- Monosomal karyotype or

- Presence of inv(3)/i(17q) abnormalities or

- Other unfavorable karyotype OR leukocytes ≥40 × 10(9) /L and

- Circulating blasts ≤ 9%

- Relapsed or Refractory Lymphoid Malignancies (including non-Hodgkin Lymphoma,
Hodgkin Lymphoma and Chronic Lymphocytic Leukemia) meeting the following
criteria:

- Disease status: Stable Disease, Partial Remission or 2nd and 3rd Complete
Remission.

- Have relapsed after autologous transplant or who have failed to collect for
an autologous transplant.

- Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2

- Patients without a matched related or unrelated donor

- Patient with either one or both:

- Two 5/8 human leukocyte antigen (HLA) high resolution matched umbilical cord
blood (UCB) grafts with a cell dose of 2.0x10^7 total number of nucleated cells
per kilogram (TNC/kg) each, or

- A related haplo-identical donor

- Concurrent Therapy for Extramedullary Leukemia or central nervous system (CNS)
Lymphoma: Concurrent therapy or prophylaxis for testicular leukemia, CNS leukemia, and
CNS lymphoma including standard intrathecal chemotherapy and/or radiation therapy will
be allowed as clinically indicated. Such treatment may continue until the planned
course is completed. Subjects must be in CNS remission at the time of protocol
enrollment if there is a history of CNS involvement. Maintenance therapy after
transplant is allowed.

- Subjects must have the ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

- Patients with inadequate Organ Function as defined by:

- Creatinine clearance < 30ml/min

- Bilirubin > twice institutional upper limit of normal

- aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) ≥
twice institutional upper limit of normal

- Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) ≥ twice
institutional upper limit of normal

- Pulmonary function: diffusing capacity of the lung for carbon monoxide corrected
for hemoglobin (DLCOc) < 40% normal

- Cardiac: left ventricular ejection fraction < 35%

- Patients with uncontrolled inter-current illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.

- Pregnant or breastfeeding women are excluded from this study because chemotherapy
involved with Reduced Intensity Conditioning (RIC) have the significant potential for
teratogenic or abortifacient effects.

- Any condition that would, in the investigator's judgment, interfere with full
participation in the study, including administration of study drug and attending
required study visits; pose a significant risk to the subject; or interfere with
interpretation of study data.

- Known allergies, hypersensitivity, or intolerance to any of the study medications,
excipients, or similar compounds

- Presence of donor-specific antibodies against chosen graft source.