Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

PRIMARY OBJECTIVES:

I. To determine the transplant related mortality (TRM) of this reduced-intensity
transplantation (RIT) combination, fludarabine (fludarabine phosphate), melphalan, and TBI in
a patient population usually not eligible for a full a myeloablative allogeneic hematopoietic
stem cell transplantation (HSCT).

SECONDARY OBJECTIVES:

I. To evaluate clinical response, progression free survival (PFS) at one year, engraftment
rate, and graft-versus-host disease (GvHD) incidence with the proposed RIT regimen across a
variety of hematological conditions.

II. Correlative studies will include chimerism analysis by molecular analysis and evaluation
of immune reconstitution by cytomegalovirus (CMV) dextramer analysis using flow cytometry.

OUTLINE: PREPARATIVE REGIMEN:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -5 to -2
and melphalan IV over 30 minutes on day -2. Patients undergo low-dose TBI twice daily (BID)
on day -1.

TRANSPLANTATION:

Patients undergo allogeneic PBSCT on day 0.

GvHD PROPHYLAXIS:

Patients receive tacrolimus IV or orally (PO) BID on days -1 to 100 with taper over 4-6
months, MMF PO or IV every 6-8 hours on days -1 to 60, and methotrexate IV over 15-30 minutes
on days 1, 3, and 6. After completion of study treatment, patients are followed up
periodically.

Inclusion Criteria:

- Diagnosis of a histology documented hematologic malignancy or marrow disorder

BONE MARROW FAILURE DISORDERS:

- Acquired bone marrow failure disorders include aplastic anemia, paroxysmal nocturnal
hemoglobinuria (PNH) * Primary allogeneic HSCT is appropriate for selected patients
with severe aplastic anemia; however, patients with aplastic anemia must have failed
at least one cycle of standard immunosuppressive therapy with calcineurin inhibitor
plus anti-thymocyte globulin (ATG) if a fully matched donor is available * Patients
with PNH should not be eligible for a myeloablative HSCT

- Hereditary bone marrow failure disorders include Diamond-Blackfan Anemia,
Shwachman-Diamond Syndrome, Kostmann Syndrome, congenital Amegakaryocytic
Thrombocytopenia; Fanconi Anemia or related chromosomal breakage syndrome,
Dyskeratosis Congenital are excluded from this study die to their poor
deoxyribonucleic acid (DNA) repair capacity * Fanconi anemia or related chromosomal
breakage syndrome: positive chromosome breakage analysis using diepoxybutane (DEB) or
mitomycin C if applicable * Dyskeratosis Congenita: diagnosis is supported by using
either telomerase RNA component (TERC) gene mutation in autosomal dominant
Dyskeratosis Congenita or X-linked DKC1 gene mutation

- Other non-malignant hematologic or immunologic disorders that require transplantation
* Quantitative or qualitative congenital platelet disorders (including but not limited
to congenital amegakaryocytopenia, absent-radii syndrome, Glanzmann's thrombasthenia)
* Quantitative or qualitative congenital neutrophil disorders (including but not
limited to chronic granulomatous disease, congenital neutropenia) *Congenital primary
immunodeficiency syndrome, Wiskott-Aldrich syndrome, CD40 ligand deficiency, T-cell
deficiencies)

ACUTE LEUKEMIAS:

- Subjects must be ineligible for or unable to receive a conventional myeloablative
transplantation

- Resistant or recurrent disease after at least one standard combination chemotherapy OR
first remission patients at high risk of relapse * Acute myeloid leukemia (AML)

- antecedent myelodysplastic syndrome, secondary AML, high risk cytogenetic
abnormalities or normal cytogenetics with high-risk molecular mutations (e.g.,
fms-like tyrosine kinase3-internal tandem duplication [Flt3-ITD] mutation) * Acute
lymphocytic leukemia (ALL)

- high or standard risk ALL

CHRONIC MYELOID LEUKEMIA (CML):

- Chronic phase (intolerant or unresponsive to imatinib and/or other tyrosine kinase
inhibitors), second chronic phase or accelerated phase who are ineligible for
conventional myeloablative transplantation

MYELOPROLIFERATIVE AND MYELODYSPLASTIC SYNDROME (MDS):

- Myelofibrosis (with/without splenectomy) with intermediate to high risk features

- Advanced polycythemia vera nor responding to standard therapy

- MDS with lower International Prognostic Scoring System (IPSS) score of intermediate
(Int)-2 or higher

- MDS with lower IPSS score Int-1 or less with severe clinical features such as severe
neutropenia or thrombocytopenia or high risk chromosome abnormalities such as monosomy
7

- Secondary MDS with any IPSS scores

- Chronic myelomonocytic leukemia

LYMPHOPROLIFERATIVE DISEASE:

- Chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin lymphoma (NHL) (recurrent or
persistent) fludarabine refractory or with less than 6 months duration or complete
remission (CR) between courses of conventional therapy

- Multiple myeloma (progressive disease after autologous stem cell transplant, tandem
allogeneic transplant after prior autologous stem cell transplant)

- Waldenstrom's macroglobulinemia (failed one standard regimen)

- High grade NHL and diffuse large B-cell lymphoma (DLBCL)

- Not eligible for conventional myeloablative HSCT OR failed autologous HSCT

- First remission lymphoblastic lymphoma, or small, non-cleaved cell lymphoma or mantle
cell lymphoma

HODGKIN LYMPHOMA:

- Received and failed front-line therapy

- Failed or were not eligible for autologous transplantation DONOR: Permissible human
leukocyte antigen (HLA) matching: related donors

- single antigen mismatch at HLA A, B, or DRB1; unrelated donors

- a single antigen mismatch at HLA A, B, or C, +/- additional single allele level
mismatch at A, B, V or DRB1

- Minimum goal for peripheral blood stem cells (PBSC) dose is 2 x 10^6 CD34+ cells/kg of
recipient weight; minimum goal for the marrow dose is 1 x 10^8 nucleated cells/kg of
recipient weight

- No serious uncontrolled psychiatric illness

- No concomitant active malignancy that would be expected to require chemotherapy within
3 years of transplant (other than non-melanoma skin cancer)

- Non-pregnant and non-nursing woman; (women or men with reproductive potential should
agree to use an effective means of birth control)

- Patients who have failed a prior autologous or allogeneic transplant are eligible;
however, at least 90 days must have elapsed between the start of this reduced
intensity conditioning regimen and the last transplant if patient had a prior
autologous or myeloablative allogeneic bone marrow transplant (BMT)

- At least 2 weeks since prior chemotherapy, radiation treatment and/or surgery

- Informed consent

DONOR: Compatibility at the four most informative HLA loci:

A, B, C and DRB1 are important for reducing the risk of GVHD and successful transplant
outcomes; the A, B, C and DRB1 loci comprise 8 possible alleles (a haplotype being
inherited from each parent); one additional locus, HLA-DQ, is also typed to ascertain
haplotypes and assist in the search for a compatible donor; however mismatching at DQ has
not been shown to be associated with adverse outcomes; high resolution molecular typing (at
the allele level) is now the standard of care for unrelated donor searches and allows
greater refinement of the search strategy

DONOR: Matched related donor:

a single antigen mismatch at A, B, or the DR transplant from a family member is associated
with a higher risk of GVHD but similar overall survival when compared to full identity at
these 3 regions; related donor/recipient pairs must be matched at 5 of 6 HLA antigens (A,
B, DRB1)

DONOR: Unrelated Donor:

When evaluating patients for unrelated donor transplant, the higher degree of matching, the
lower risk of GvHD; the A, B, C, DRB1 and DQB1 loci, comprising 10 possible antigen (with
alleles), will be typed for all unrelated transplants; given the higher risk of TRM in
mismatched transplants, RIT is often the best way to mitigate the risk; data from the
National Marrow Donor Program makes it possible to estimate the risk of donor-recipient HLA
mismatch at the allele or antigen level; the higher risk from HLA-mismatching must be
balanced against the clinical urgency and the patient's risk by the transplant team; at
this time, antigen level mismatches at DQB1 do not affect outcomes and will not be used for
matching purposes for donor selection; thus, the matching required will be at the HLA A, B,
C and DRB1 (8 loci); for this protocol, a single antigen mismatch at the HLA A, B, C, with
or without additional single allele level mismatch may participate in this protocol for
voluntary unrelated donors (blood or marrow) DONOR: Donor must be healthy and have
non-reactive test results for all infectious disease assays as required by state and
federal regulations; donors who screen seropositive for hepatitis an/or syphilis must be
cleared by infectious disease consultation DONOR: Donor must have no uncontrolled
cardiopulmonary, renal, endocrine, hepatic or psychiatric disease to render donation unsafe
DONOR: The donor (or parent in minor) must give informed consent for peripheral blood stem
cell collection or bone marrow collection DONOR: Syngeneic donors are not eligible DONOR:
Donors who have poor peripheral venous access, may require central venous line placement
for stem cell apheresis

Exclusion Criteria:

- Uncontrolled central nervous system (CNS) disease (for hematologic malignancies)

- Karnofsky (adult) or Lansky (for =< 16 years) performance status < 50%

- Diffusing capacity of the lung for carbon monoxide (DLCO) < 40% predicted, corrected
for hemoglobin and/or alveolar ventilation

- Left ventricular ejection fraction < 40% - Bilirubin >= 3 X upper limit of normal

- Liver alkaline phosphatase >= 3 x upper limit of normal

- Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvate transaminase
(SGPT) >= 3 x upper limit of normal

- Child's class B and C liver failure

- Calculated creatinine clearance < 40 cc/min by the modified Cockroft-Gault formula for
adults or the Schwartz formula for pediatrics

- Patients who have received maximally allowed doses (given in 2 Gy fractionations, or
equivalent) of previous radiation therapy to various organs as follows: * Mediastinum:
adult -40, pediatric (=<18 yrs) - 21 * Heart: adult 36, pediatric - 26 * Whole
lung(s): adult - 12, pediatric - 10 * Small bowel: adult - 46, pediatric - 40 *
Kidneys: adult - 12, pediatric - 10 * Whole liver: adult - 20, pediatric - 20 * Spinal
cord: adult - 36, pediatric - 36 * Whole Brain: adult 30, pediatric - 30

- Patients who previously have received a higher than allowed dose of radiation to a
small lung, liver, and brain volume, will be evaluated by the radiation oncologist to
determine if the patient is eligible for study

- Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection or
other condition which, in the opinion of treating physician, would make this protocol
unreasonably hazardous for the patient

- Human immunodeficiency virus (HIV) positive

- Patients who in the opinion of the treating physician are unlikely to comply with the
restrictions of allogeneic stem cell transplantation based on formal psychosocial
screening

- Female of childbearing potential with a positive pregnancy test