Donor Stem Cell Transplant in Treating Patients With High Risk Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To assess the feasibility of cytarabine based chemotherapy and human leukocyte antigen
(HLA)-mismatched allogeneic cellular therapy (HMMACT) in patients with high risk acute
myeloid leukemia (AML), with feasibility measured by induction mortality (IM) and complete
response rate.

SECONDARY OBJECTIVES:

I. To obtain preliminary estimates of clinical outcome following cytarabine based
chemotherapy and HMMACT in patients with high risk AML, as measured by event free survival
(EFS) and overall survival (OS).

II. To further evaluate the safety outcomes of induction and consolidation of cytarabine and
HMMACT in terms of serious infections (grade 4), time to recovery of absolute neutrophil
counts and platelets and incidence of graft versus host disease (GvHD).

III. To further evaluate the feasibility of this approach in terms of identifying a suitable
donor in this elderly population.

IV. To compare in preliminary manner the clinical outcomes of cytarabine and HMMACT in
patients with high risk AML as measured by complete response rate (CRR), event free survival
(EFS) and overall survival (OS) by donor/recipient HLA-C1 vs C2 pairs.

V. To characterize in a preliminary manner, the numbers of suppressor regulatory T cells
(Tregs), T helper 17 cells (Th17), and cytotoxic T cells during pre and post HMMACT
treatment, and with clinical outcomes in leukemia.

OUTLINE:

INDUCTION CHEMOTHERAPY: Patients receive mitoxantrone hydrochloride intravenously (IV) on
days 1-3 and cytarabine IV on days 1-7.

HMMACT: Patients receive filgrastim (G-CSF) mobilized peripheral blood stem cells (G-PBSC) on
day 9. After completion of study treatment, patients are followed up monthly for 3 years.

Inclusion Criteria:

- Patients must have a histologically and cytological confirmed acute myeloid leukemia,
high risk AML defined as:

- Age > 60, or

- Presence of complex cytogenetic abnormalities (with > 3 cytogenetic
abnormalities), del (7q, -5, -7), t(9,22), 11q(23) or high risk mutations by FISH
eg MLL, FLT-3 +

- Secondary AML, or

- A white blood cell count of > 50 x10^9/L

- Patients must be medically ineligible for allogeneic stem cell transplant (alloSCTx)
or not have a known fully HLA matched sibling for planned sibling transplant.

- Patients must have measurable or evaluable disease

- Diagnosis of AML according to World Health Organization (WHO) diagnostic criteria (at
least 20% blasts in the peripheral blood or bone marrow), with French-American-British
Cooperative group (FAB) classification other than M3 (acute promyelocytic leukemia),
documented by bone marrow aspiration and biopsy performed within 14 days prior to
administration of 1st dose of remission induction chemotherapy; if a bone marrow
aspirate and biopsy were obtained within 28 days prior to the first dose of remission
induction therapy then these tests may be submitted for review at University of
Southern California (USC) and a repeat screening bone marrow does not need to be
conducted;

- Cohort A: newly diagnosed AML, no prior cytotoxic chemotherapy

- Cohort B: newly diagnosed AML, failed to achieve Complete remission (CR) with
single standard Induction chemo.

- Patient has at least one medically fit family member expected to be HLA mismatched at
1-9/10; more commonly and preferred: 4-6/10 loci (parent, sibling, niece/nephew, etc
but adult children preferred)

- Absolute neutrophil count (ANC) > 1500, unless due to direct bone marrow involvement
of disease

- Platelets > 75,000, unless due to direct bone marrow involvement of disease

- Hemoglobin > 8.0 gm/dL, transfusion allowed

- Serum creatinine < 2.0 x the upper limits of institutional normal (ULN)

- Total bilirubin < 1.5 x the upper limits of institutional normal

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT )< 2.5 x the upper
limits of institutional normal (=< 5 x ULN for patients with liver involvement of
leukemia)

- Cardiac left ventricular ejection fraction (LVEF) > 45%

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

- Estimated survival of at least 3 months

- Patients must be able to understand and agree to sign an Institutional Review Board
(IRB)-approved informed consent form

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control) prior to study entry, for the duration
of study, and for two months after study participation

- DONOR: Donor screening; all donors will meet the standard blood donor criteria
established by the participating local blood center, American Association of Blood
Banks (AABB)

- DONOR: Donors will be selected from among the subject's relatives, adult children
preferred

- DONOR: Infectious disease testing will be done per Hemacare policy and AAAB guidelines

- DONOR: Donor and intended recipient red cell type and compatibility will be determined

- DONOR: Donors will be pre-selected on the basis of HLA haploidentity

- DONOR: If patient is cytomegalovirus (CMV)-negative, donors who are CMV-negative will
be preferred; CMV serology of the donor will be tested prior to the allogeneic cell
donation; donations from CMV-positive donors to CMV-negative recipients will be given
if no CMV negative donor is available, and CMV surveillance and pre-emptive treatment
given

Exclusion Criteria:

- Cohort A: Patients who have received prior cytotoxic chemotherapy, such as
anthracyclines and cytarabine not permitted; but prior treatment with demethylating
agents (azacytidine or decitabine, lenalidomide, etc) ALLOWED.

- Cohort B: Patients who have received prior fludarabine, clorarabine or drugs known to
target T cells not permitted; but prior standard induction with anthracylines and
cytarabine ALLOWED including after demethylating agents.

- Have uncontrolled systemic infections, coagulation disorders, or other major medical
illnesses of the cardiovascular or respiratory systems

- Pregnant and/or lactating

- Patients who have had non-biopsy surgery in the last 10 days

- Active central nervous system (CNS) disease; patients with previously treated
leptomeningeal disease without evidence of remaining leukemia cells by spinal fluid
will be eligible

- Known active autoimmune disorder

- Known to be human immunodeficiency virus (HIV)-positive or have active hepatitis B or
C

- Patients concurrently taking the following drugs are excluded: mycophenolate,
cyclosporine, prednisone > 20mg/day, or immunosuppressive agents

- DONOR: Personal or family history of severe sickle cell disease or variant (unless
donor has tested negative); testing for the presence of hemoglobin S is not required

- DONOR: Positive infectious disease test as dictated by blood collection center's
standard operating procedure (SOP)

- DONOR: Current uncontrolled hypertension

- DONOR: Diabetes mellitus

- DONOR: Active peptic ulcer disease

- DONOR: Pregnant or breast-feeding

- DONOR: Currently taking lithium therapy

- DONOR: History of autoimmune disease

- DONOR: History of coronary disease