Intensity Modulated Total Marrow Irradiation, Fludarabine Phosphate, and Melphalan in Treating Patients With Relapsed Hematologic Cancers Undergoing a Second Donor Stem Cell Transplant

PRIMARY OBJECTIVES:

I. The determine the maximum tolerated dose (MTD) of intensity-modulate total marrow
irradiation (IMTMI) in combination with fludarabine (fludarabine phosphate)/melphalan as
conditioning for second allogeneic stem cell transplantation for patients with hematologic
malignancies.

SECONDARY OBJECTIVES:

I. To determine the overall toxicity and day 100 transplant related mortality after second
allogeneic hematopoietic stem cell transplantation conditioned with increasing doses of
intensity-modulate total marrow irradiation (IMTMI) in combination with
fludarabine/melphalan.

II. To determine the time to neutrophil and platelet engraftment after second allogeneic
hematopoietic stem cell transplantation conditioned with increasing doses of
intensity-modulate total marrow irradiation (IMTMI) in combination with
fludarabine/melphalan.

III. To determine the overall survival (OS) and event-free-survival (EFS) in patients with
hematologic undergoing second allogeneic hematopoietic stem cell transplant (HSCT) after
conditioning with fludarabine/melphalan and IMTMI.

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

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30
minutes daily on days -7 to -3 and melphalan IV on day -2. Patients also undergo IMTMI twice
daily (BID) for 2 to 5 days between days -7 to -3.

TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell transplant (PBSCT) or bone
marrow transplant (BMT) on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive tacrolimus IV continuously
over 24 hours or orally (PO) BID on days -2 to 180 with taper thereafter and mycophenolate
mofetil IV every 8 hours or PO on days 0-28 (for matched donors) or days 0-40 (for
alternative donors) with taper to day 60.

After completion of treatment, patients are followed up periodically for 1 year and then
yearly for 2 years.

Inclusion Criteria:

- Patients with the following diseases: acute myeloid leukemia (AML) and high risk
myelodysplastic syndrome (MDS) undergoing second allogeneic (allo)-stem cell
transplant (SCT) using the same donor or different donor for disease relapse; patients
with other hematologic malignancies, including acute lymphoblastic leukemia (ALL),
will be at the discretion of the investigators

- Karnofsky performance status of 70 or above

- Life expectancy is not severely limited by concomitant illness

- Adequate cardiac and pulmonary function; patients with decreased left ventricular
ejection fraction (LVEF) =< 40% or diffusion capacity of carbon monoxide (DLCO) =< 50%
of predicted will be evaluated by cardiology or pulmonary prior to enrollment on this
protocol

- Serum creatinine =<1.5 mg/dL or creatinine clearance > 50 ml/min; some patients with
minor deviations may be accepted on protocol after discussion with the principal
investigator (PI)

- Serum bilirubin =< 2.0 mg/dl; some patients with minor deviations may be accepted on
protocol after discussion with the PI

- Serum glutamic oxaloacetic transaminase (SGPT) < 5 x upper limit of normal; some
patients with minor deviations may be accepted on protocol after discussion with the
PI

- No evidence of chronic active hepatitis or cirrhosis

- Human immunodeficiency virus (HIV)-negative

- Patient is not pregnant

- Patient or guardian able to sign informed consent

- DONOR: Since these patients already had first allo-SCT; in the majority time, the same
matched donor has been used for second allo-SCT; if the patients have multiple donors,
alternative matched (8/8 or 10/10) donor could be used for the second allo-SCT; the
donor could be matched related donors or matched unrelated donors from registry

- DONOR: If more than one potential volunteer unrelated donor is considered suitable,
further selection of the most suitable donor will be prioritized as follows or will
follow our institutional guideline from our stem cell transplant standard operating
procedure (SOP):

- Age of donor (18-24 > 25-34 > 35-44 > 45+)

- Sex of donor (male > female, nulliparous female > parous, multiparous female)

- Cytomegalovirus (CMV) status, if recipient is CMV seronegative (CMV- > CMV+