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

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