Treo/Flu/TBI With Donor Stem Cell Transplant for Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the better of two treosulfan-based conditioning regimens in patients with
myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), by comparing 6-month
progression-free survival.

SECONDARY OBJECTIVES:

I. Determine the effects of two conditioning regimens on changes in gene expression profiles,
and evaluate the association of gene expression profiles and disease relapse.

II. Determine the incidence of progression-free survival at 1 year and 2 years after
hematopoietic cell transplantation (HCT).

III. Evaluate overall survival (OS) at 6 months, at 1 year and at 2 years after HCT.

IV. Determine the incidence of grades II-IV acute graft-versus-host disease (GVHD).

V. Determine the incidence of chronic GVHD.

VI. Determine donor chimerism around days +28 and +84.

CONDITIONING REGIMEN:

Arm A: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and
fludarabine phosphate IV over 30 minutes on days -6 to -2.

Arm B: Patients receive treosulfan and fludarabine phosphate as in Arm A and undergo low-dose
total-body irradiation (TBI) on day 0.

TRANSPLANT: Patients in both arms undergo allogeneic peripheral blood stem cell (PBSC)
transplant or bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients with a related donor receive tacrolimus orally (PO) every 8 or 12
hours on days -3 to 56 with taper to day 180. Beginning 4-6 hours after PBSC infusion,
patients also receive mycophenolate mofetil PO every 12 hours to day 28. Patients with an
unrelated donor receive tacrolimus PO every 8 or 12 hours on days -3 to 100 with taper to day
180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO
every 8 hours to day 40 with taper to day 96.

NOTE: Patients with related donors eligible for FHCRC protocol 2545 may receive cyclosporine
IV, instead of tacrolimus, beginning on day -3 to day 50 with a taper to day 180.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- MDS, myelodysplastic syndrome/myeloproliferative neoplasia overlap disorders
(including chronic myelomonocytic leukemia [CMML], and MDS/myeloproliferative neoplasm
[MPN] unclassifiable syndromes)

- AML, other than acute promyelocytic leukemia (APL), in first or second remission or
with minimal residual disease

- With Karnofsky index or Lansky Play-Performance scale > 70% on pre-transplant
evaluation

- Able to give informed consent (if > 18 years), or with a legal guardian capable of
giving informed consent (if < 18 years)

- Patients with previous autologous or allogeneic HCT are allowed to enroll

- DONOR: Human leukocyte antigen (HLA)-identical related donors or

- DONOR: Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 as defined by high
resolution deoxyribonucleic acid (DNA) typing; mismatch for one HLA allele is allowed

- DONOR: Donors able to undergo peripheral blood stem cell collection or bone marrow
harvest

- DONOR: Donors in good general health, with a Karnofsky or Lansky play performance
score > 90%

- DONOR: Donors able to give informed consent (if > 18 years), or with a legal guardian
capable of giving informed consent (if < 18 years)

Exclusion Criteria:

- Receiving umbilical cord blood

- With impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable
to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency
requiring treatment or symptomatic coronary artery disease; patients with a shortening
fraction < 26% may be enrolled if approved by a cardiologist

- With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) < 70
mm Hg and carbon monoxide diffusing capability test (DLCO) < 70% of predicted or pO2 <
80 mm Hg and DLCO < 60% of predicted; (or, for pediatric patients unable to perform
pulmonary function tests, then oxygen (O2) saturation < 92% on room air), or receiving
supplementary continuous oxygen

- With impaired renal function as evidenced by creatinine-clearance < 50% for age,
weight, height or serum creatinine > 2 x upper limit of normal or dialysis-dependent

- With hepatic dysfunction as evidenced by total bilirubin > 2.0 x upper limit of normal
or evidence of synthetic dysfunction or severe cirrhosis

- With hepatic dysfunction as evidenced by aspartate aminotransferase (AST) > 2.0 x
upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis

- With active infectious disease requiring deferral of conditioning, as recommended by
an infectious disease specialist

- With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis

- With central nervous system (CNS) leukemic involvement not clearing with intrathecal
chemotherapy, cranial irradiation or both prior to initiating conditioning (day -6)

- Patients with active non-hematological malignancies (except non-melanoma skin cancers)
or those with non-hematological malignancies who have been rendered with no evidence
of disease, but have a greater than 20% chance of having disease recurrence within 5
years; this exclusion does not apply to patients with non-hematologic malignancies
that do not require therapy

- With life expectancy severely limited by diseases other than malignancy

- Women who are pregnant or lactating

- With known hypersensitivity to treosulfan or fludarabine (fludarabine phosphate)

- Receiving another experimental drug within 4 weeks before initiation of conditioning
(day -6)

- Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18
years) unable to give informed consent

- DONOR: Individuals deemed unable to undergo marrow harvesting or PBSC mobilization and
leukapheresis

- DONOR: Individuals who are HIV-positive

- DONOR: Individuals with active infectious hepatitis

- DONOR: Females with a positive pregnancy test

- DONOR: Persons unable to give informed consent (if > 18 years) or with a legal
guardian (if < 18 years) unable to give informed consent