Total Marrow and Lymphoid Irradiation Before Donor Transplant and Cyclophosphamide in Treating Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To evaluate the safety/feasibility of combining a total marrow and lymphoid irradiation
(TMLI) transplant conditioning regimen with a post-transplant high dose cyclophosphamide
(PTCy)-based graft versus host disease (GvHD) prophylaxis strategy, through the assessment
of: adverse events: type, frequency, severity, attribution, time course, duration and
complications: including acute GvHD, infection and delayed neutrophil/platelet engraftment.

SECONDARY OBJECTIVES:

I. To estimate the cumulative incidence (CI) of acute GvHD at 100 days post allogeneic
hematopoietic cell transplantation (alloHCT).

II. To estimate the CI of chronic GvHD at 6 months, 1- and 2-years post alloHCT.

III. To estimate GVHD-free relapse-free survival (GRFS) at 1- and 2-years post alloHCT.

IV. To describe the kinetics of immune reconstitution and T cell repertoire in the first year
post alloHCT.

V. To estimate overall survival (OS), relapse-free survival (RFS) and CI of relapse, and
non-relapse mortality (NRM) at 100 days, 1- and 2-years post alloHCT.

VI. To characterize quality of life using 36-Item Short Form Health Survey (SF-36),
Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and M. D. Anderson
Symptom Inventory (MDASI) or Pediatric Quality of Life Inventory (PedsQL) at 100 days, 6
months, 1- and 2-years post alloHCT.

VII. To assess bone marrow cellularity from bone marrow samples. VIII. To assess the
clonogenic potential of cells from bone marrow samples. IX. To assess stromal damage from
bone marrow samples. X. To evaluate cytokines and oxidative stress markers.

OUTLINE: This is a dose-escalation study of TMLI.

Patients undergo TMLI twice daily (BID) on days -4 to 0, then undergo bone marrow or
peripheral blood stem cell transplant on day 0. Patients receive cyclophosphamide
intravenously (IV) over 2 hours on days 3 and 4, tacrolimus given by continuous intravenous
infusion (CIV) on days 5-90, and filgrastim beginning on day 5 until absolute neutrophil
count (ANC) 1,500/mm^3 for 3 consecutive days.

After completion of study treatment, patients are followed for up to 24 months.

Inclusion Criteria:

- This study is open to patients with acute myeloid leukemia (AML) evaluated within 30
days of the start of conditioning regimen and in first or second complete remission
(CR)

- Karnofsky performance status (KPS) >= 70%

- The effects of radiation on the developing fetus are known to be teratogenic; for this
reason, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control or abstinence) prior to
study entry and for six months following duration of study participation; should a
woman become pregnant or suspect that she is pregnant while participating on the
trial, she should inform her treating physician immediately

- Patients with acute myelogenous leukemia (AML) who are in first or second complete
remission

- All candidates for this study must have a human leukocyte antigen (HLA) (A,B,C,DR)
identical sibling who is willing to donate primed blood stem cells (preferred) or bone
marrow, or have a 10/10 allele matched unrelated donor; all ABO blood group
combinations of the donor/recipient are acceptable

- A cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal
rhythm and an ejection fraction of >= 50% established by multi-gated acquisition scan
(MUGA) or echocardiogram

- Patients must have a serum creatinine of less than or equal to 1.3 mg/dL or creatinine
clearance > 70ml/min as calculated by the Cockcroft-Gault formula

- A bilirubin of less than or equal to 1.5mg/dL, excluding patients with Gilberts
disease

- Patients should also have a serum glutamic-oxaloacetic transaminase (SGOT) and serum
glutamate pyruvate transaminase (SGPT) less than 5 times the upper limit of normal

- Pulmonary function tests including diffusing capacity of the lung for carbon monoxide
(DLCO) will be performed; forced expiratory volume in 1 second (FEV 1) and DLCO should
be greater than 50% of predicted normal value

- All subjects must have the ability to understand and the willingness to sign a written
informed consent; signed informed consent form approved by the Institutional Review
Board (IRB) is required; the patient, family member, and transplant staff physician
(physician, nurse, and social worker) meet at least once prior to starting the
transplant procedure; during this meeting, all pertinent information with respect to
risks and benefits to the donor and recipient will be presented; alternative treatment
modalities will be discussed

- The time from the end of last induction, re-induction, or consolidation regimen should
be greater than or equal to 14 days

- Prior therapy with etoposide and cyclophosphamide is allowed

- DONOR: donor evaluation and eligibility will be assessed as per current City of Hope
standard operating procedure (SOP)

Exclusion Criteria:

- Patients should not have any uncontrolled illness including ongoing or active or
poorly controlled infection

- Patients may not be receiving any other investigational agents, or concurrent
biological, chemotherapy, or radiation therapy; maintenance therapy with Food and Drug
Administration (FDA)-approved targeted therapies (e.g. tyrosine kinase inhibitors for
Philadelphia chromosome [Ph] positive [+] acute lymphoblastic leukemia [ALL], and FLT
inhibitors for FLT3+ patients) will be allowed after day 60 disease assessment

- Prior radiation therapy that would exclude the use of TMLI

- Relapsed patients who have undergone autologous or allogeneic hematopoietic stem cell
transplantation previously

- Patients with psychological or medical condition that patient's physician deems
unacceptable to proceed to allogeneic hematopoietic stem cell transplantation

- Electrocardiogram (EKG) showing ischemic changes or abnormal rhythm and/or an
echocardiogram or MUGA scan showing abnormal wall motion or ejection fraction < 50%

- Patients who have been treated with chemotherapy or radiation for the purpose of
induction, re-induction or consolidation, within two weeks of planned study enrollment

- Patients with other active malignancies are ineligible for this study, other than
localized malignancies

- Patients that are pregnant or breastfeeding

- Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns or compliance
with clinical study procedures, including but not limited to, infection/inflammation,
intestinal obstruction, unable to swallow medication, social/ psychological issues,
etc