Cyclophosphamide for Prevention of Graft-Versus-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation in Patients With Hematological Malignancies

PRIMARY OBJECTIVES:

I. The primary objective of this study is to assess outcomes when high-dose cyclophosphamide
(CY) is administered on days 3 and 4 followed by cyclosporine (CSP) after human leukocyte
antigen (HLA)-matched related or unrelated mobilized blood cell transplantation with
total-body irradiation (TBI) or busulfan (BU)-based conditioning.

SECONDARY OBJECTIVES:

I. The secondary objective of this study is to assess hematopoietic cell transplantation
(HCT) outcomes when withdrawal of CSP is accelerated in patients without acute
graft-versus-host disease (GVHD).

OUTLINE: Patients' conditioning regimens are determined by the Clinical Coordinator after
consultation with the attending physician. Based on disease, patients receive either TBI or
fludarabine and busulfan.

PREPARATIVE REGIMEN: Patients receive TBI twice daily (BID) on days -4 or -3 to -1. Some
patients also receive fludarabine intravenously (IV) daily on days -5 to -2 and busulfan IV
over 3 hours once daily (QD) or over 2 hours every 6 hours on days -5 to -2. Patients may
also undergo central nervous system (CNS) prophylaxis, testicular irradiation, and/or
involved field irradiation as per standard practice.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation
(PBSCT) on day 0 per standard practice.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 1-2 hours on days 3-4. Patients
also receive cyclosporine IV every 12 hours or every 8 hours beginning on day 5 with taper
on days 56-126.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at day 180 and then annually
for 5 years.

Inclusion Criteria:

- Acute lymphocytic leukemia (ALL) in morphologic first complete remission (CR1) with
high risk features defined as, but not limited to: evidence of adverse cytogenetics
such as t(9;22), t(1;19), t(4;11), or mixed-lineage leukemia (MLL) rearrangements;
presence of minimal residual disease; progenitor B-cell immunophenotype; high white
blood cells (WBC) at diagnosis (> 30,000/ul in B-ALL; > 100,000/ul in T-ALL); or
delayed attainment of CR (> 4 weeks) after induction therapy; additional clinical
characteristics deemed to confer a high relapse risk may be discussed with and
approved by the Principal Investigator (PI)

- Acute myeloid leukemia (AML) in CR1 EXCEPT patients with low-risk features defined
as:

- Inv 16 or t(8;21) in the absence of c-kit mutations

- Normal karyotype who are FLT3-ITD-negative and NPM1-positive in the absence of
c-kit mutations

- Patients with respective "low-risk" features are eligible, however, if (i) more
than 1 cycle of induction therapy was required to achieve CR1 (ii) the patient
had a preceding myelodysplastic syndrome (MDS) other than myelofibrosis, or
(iii) secondary AML

- Acute leukemia in 2nd or greater CR (CR >= 2)

- Refractory or relapsed AML with =< 10% bone marrow blasts and no circulating blasts
or proven extramedullary disease

- AML transformed from myelodysplastic syndrome (MDS) with < 10% bone marrow blasts

- MDS with following high risk features:

- High risk cytogenetics (including, but not limited to: 7q--, inv[3], t[3q],
del[3q] or complex karyotype)

- International Prognostic Scoring System (IPSS) intermediate (INT)-2 or greater

- Treatment-related MDS

- Any phase of MDS if patient is < 21 years of age

- Chronic myelogenous leukemia (CML) beyond 1st chronic phase or resistant or
intolerant to tyrosine kinase inhibitors (adults) or any phase (pediatric < 21 years)

- Chronic myelomonocytic leukemia

- Philadelphia-negative myeloproliferative disorder

- Lymphoma: relapsed chemotherapy-sensitive (complete or partial response) Hodgkin or
non-Hodgkin lymphoma

- Multiple myeloma-stage III

- The patient or legal representative must be able to understand and give written
informed consent

- DONORS: The donor must be a genotypically HLA-identical sibling, a phenotypically
HLA-matched first-degree relative, or an unrelated donor who is molecularly matched
with the patient at HLA-A, B, C, DRB1

- DONORS: Donors must meet the selection criteria for administration of G-CSF
(filgrastim) and apheresis defined by the Foundation for the Accreditation of Cell
Therapy (FACT) and will be screened per the American Association of Blood Banks
(AABB)

- DONORS: Donors must be capable of giving informed consent

Exclusion Criteria:

- Prior autologous or allogeneic stem cell transplant

- Performance status > 2 (Eastern Cooperative Oncology Group [ECOG]) or < 50 (Lansky;
for patients < 16 years old)

- Uncontrolled infection; the protocol principal investigator (PI) will be final
arbiter if there is uncertainty regarding whether a previous infection is under
adequate control to allow enrollment in the study

- Positive serology for human immunodeficiency virus (HIV)-1, 2 or human T cell
lymphotropic virus (HTLV)-1, 2

- Left ventricular ejection fraction < 45% or shortening fraction < 25%; no
uncontrolled arrhythmias or symptomatic cardiac disease

- Symptomatic pulmonary disease; forced expiratory volume in one second (FEV1), forced
vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO) =<
50% of predicted (corrected for hemoglobin); if pulmonary function tests cannot be
performed, an oxygen saturation < 92% on room air

- Calculated (Cockcroft-Gault or appropriate calculation for pediatric patients) serum
creatinine clearance =< 60 mL/min; if the calculated CrCl is 50-60 mL/min, but a
measured CrCl by 24 hour urine collection is > 60 mL/min, this measurement is
acceptable

- Total serum bilirubin more than twice upper normal limit

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3-fold
higher than laboratory upper normal limits

- Female patient must have negative serum pregnancy test (all women of child
bearing-potential must have test performed)

- DONORS: Potential donors who for psychological, physiological, or medical reasons
cannot tolerate administration of G-CSF or apheresis

- DONORS: Donors who are allergic to filgrastim or Escherichia (E.) coli-derived
proteins

- DONORS: Donor-related risks to recipients

- DONORS: Positive anti-donor lymphocytotoxic crossmatch

- DONORS: Donors who are positive for HIV