Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies

PRIMARY OBJECTIVES:

I. To assess feasibility and tolerability of OSMI based hematopoietic stem cell transplant
(HSCT) as defined by transplant-related mortality (TRM) at day 30 as well as rate of grade
II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to
conditioning occurring within 30 days.

SECONDARY OBJECTIVES:

I. Day 100 transplant-related mortality (TRM). II. Donor chimerism assessment at day 100 (to
assess failure of engraftment rate).

III. Incidence of acute graft-versus-host disease (aGVHD) by day 100. IV. Incidence of
chronic GVHD at one year. V. Cumulative incidence of grade II organ toxicity through day 100.
VI. Rate and kinetics of hematopoietic recovery. VII. Incidence of graft failure (primary and
secondary). VIII. Rate of infectious complications. IX. Cumulative incidence of relapse,
overall survival, and progression-free survival at 1 year.

OUTLINE:

CONDITIONING REGIMEN: Patients undergo organ-sparing marrow irradiation twice daily (BID) on
days -6 to -4 and receive cyclophosphamide intravenously (IV) over 1-2 hours every 24 hours
on days -3 to -2. Patients with an unrelated donor also receive anti-thymocyte globulin every
24 hours on days -4 to -2.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV or orally (PO) beginning on day -1 and
continuing for at least 6 months and methotrexate IV on days 1, 3, 6, and 11.

TRANSPLANT: Patients undergo allogeneic peripheral blood progenitor cell or bone marrow
transplant on day 0.

After completion of study treatment, patients are followed up weekly for 12 weeks, at day
100, and then at 6 and 12 months.

Inclusion Criteria:

- Patients with a diagnosis of acute myeloid leukemia (AML), acute lymphoblastic
leukemia (ALL), or myelodysplastic syndromes (MDS) with fewer than 10% myeloblasts or
lymphoblasts in the bone marrow and no blasts in the peripheral blood on morphologic
analysis performed within 30 days of start of the conditioning regimen; if remission
bone marrow is available beyond 30 days a new bone marrow evaluation is required to
assess remission status

- The diagnosis of AML, ALL, or MDS will be based on World Health Organization
(WHO) criteria

- Pre-transplant bone marrow sample must be evaluable for assessment of remission
status (i.e. aspirate smear containing particles and/or evaluable bone marrow
core biopsy)

- Patients with leukemia infiltration in the central nervous system (CNS) are
eligible if cerebrospinal fluid (CSF) cytospin is negative for myeloblasts or
lymphoblasts at time of enrollment

- If the patient has an intra-abdominal chloroma on presentation, and has a partial
response or complete response to treatment (size reduction of chloroma and marrow
blast < 10%), the patient is eligible; however the chloroma must be included as
part of the treatment target

- For patients receiving treatment of their AML, MDS or ALL prior to transplantation:

- Interval between the start of a cycle of conventional cytotoxic chemotherapy and
the start of conditioning regimen must be at least 30 days

- Interval between completing treatment with a hypomethylating agent or other
non-cytotoxic chemotherapy and the start of conditioning regimen must be at least
10 days

- Hematopoietic Cell Transplantation-Specific Comorbidity Index score (HCT-CI) =< 4 for
patients in Cohort 1 and > 4 for Cohort 2

- Patient must be able to lie still in full body cast for 45 minutes

- Must have a suitable donor defined as a sibling matched at 5/6 or 6/6 antigens (human
leukocyte antigen [HLA]-A, B, and DRB1) or an unrelated volunteer matched at 7/8 or
8/8 HLA alleles (HLA-A, B, C, and DRB1)

- Signed informed consent

- DONOR: "High resolution" typing at HLA-A, B, C and DRB1 alleles

- Single antigen mismatch for siblings and single allele mismatch for volunteer
unrelated donors is acceptable

- Donors must be >= 17 years of age

Exclusion Criteria:

- Circulating peripheral blood myeloblasts or lymphoblasts on morphologic analysis from
time of last treatment to time of enrollment

- Prior allograft or prior autograft

- Active CNS disease as identified by positive CSF cytospin at time of enrollment

- Karnofsky performance score < 70

- Symptomatic uncontrolled coronary artery disease or ejection fraction < 40%

- Total bilirubin >= 2 x the upper limit of normal

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >= 3 x the upper
limit of normal

- Diffusion capacity of the lung for carbon monoxide (DLCO) < 40%

- Forced expiratory volume in one second (FEV1) < 50% (corrected for hemoglobin)

- Receiving supplementary continuous oxygen

- Creatinine clearance < 50 mL/min/1.73m^2

- Patients with active uncontrolled bacterial, viral or fungal infections (undergoing
appropriate treatment and with progression of clinical symptoms)

- Patients seropositive for the human immunodeficiency virus (HIV)

- Females who are pregnant or breastfeeding

- Fertile men and women unwilling to use contraceptive techniques during and for 12
months following treatment

- Patients who had prior radiation to more than 20% bone marrow containing areas or to
any areas exceeding 2000 cGy

- DONOR:

- Donors will be excluded if they are an identical twin of the recipient

- Females who are pregnant (positive serum beta human chorionic gonadotropin beta
[β HCG]) or uninterruptible breastfeeding

- HIV seropositive

- Donors receiving experimental therapy or investigational agents unless approved
by the protocol chair