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 nocturnalhemoglobinuria (PNH) * Primary allogeneic HSCT is appropriate for selected patientswith severe aplastic anemia; however, patients with aplastic anemia must have failedat least one cycle of standard immunosuppressive therapy with calcineurin inhibitorplus anti-thymocyte globulin (ATG) if a fully matched donor is available * Patientswith PNH should not be eligible for a myeloablative HSCT

• Hereditary bone marrow failure disorders include Diamond-Blackfan Anemia,Shwachman-Diamond Syndrome, Kostmann Syndrome, congenital AmegakaryocyticThrombocytopenia; Fanconi Anemia or related chromosomal breakage syndrome,Dyskeratosis Congenital are excluded from this study die to their poordeoxyribonucleic acid (DNA) repair capacity * Fanconi anemia or related chromosomalbreakage syndrome: positive chromosome breakage analysis using diepoxybutane (DEB) ormitomycin C if applicable * Dyskeratosis Congenita: diagnosis is supported by usingeither telomerase RNA component (TERC) gene mutation in autosomal dominantDyskeratosis 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 limitedto congenital amegakaryocytopenia, absent-radii syndrome, Glanzmann's thrombasthenia)
• Quantitative or qualitative congenital neutrophil disorders (including but notlimited to chronic granulomatous disease, congenital neutropenia) *Congenital primaryimmunodeficiency syndrome, Wiskott-Aldrich syndrome, CD40 ligand deficiency, T-celldeficiencies) ACUTE LEUKEMIAS:

• Subjects must be ineligible for or unable to receive a conventional myeloablativetransplantation

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

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

• high or standard risk ALL CHRONIC MYELOID LEUKEMIA (CML):

• Chronic phase (intolerant or unresponsive to imatinib and/or other tyrosine kinaseinhibitors), second chronic phase or accelerated phase who are ineligible forconventional 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 severeneutropenia 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 orpersistent) fludarabine refractory or with less than 6 months duration or completeremission (CR) between courses of conventional therapy

• Multiple myeloma (progressive disease after autologous stem cell transplant, tandemallogeneic 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 mantlecell lymphoma HODGKIN LYMPHOMA:

• Received and failed front-line therapy

• Failed or were not eligible for autologous transplantation DONOR: Permissible humanleukocyte 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 levelmismatch at A, B, V or DRB1

• Minimum goal for peripheral blood stem cells (PBSC) dose is 2 x 10^6 CD34+ cells/kg ofrecipient weight; minimum goal for the marrow dose is 1 x 10^8 nucleated cells/kg ofrecipient 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 shouldagree 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 reducedintensity conditioning regimen and the last transplant if patient had a priorautologous 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 transplantoutcomes; the A, B, C and DRB1 loci comprise 8 possible alleles (a haplotype beinginherited from each parent); one additional locus, HLA-DQ, is also typed to ascertainhaplotypes and assist in the search for a compatible donor; however mismatching at DQ hasnot been shown to be associated with adverse outcomes; high resolution molecular typing (atthe allele level) is now the standard of care for unrelated donor searches and allowsgreater 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 associatedwith a higher risk of GVHD but similar overall survival when compared to full identity atthese 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, thelower risk of GvHD; the A, B, C, DRB1 and DQB1 loci, comprising 10 possible antigen (withalleles), will be typed for all unrelated transplants; given the higher risk of TRM inmismatched transplants, RIT is often the best way to mitigate the risk; data from theNational Marrow Donor Program makes it possible to estimate the risk of donor-recipient HLAmismatch at the allele or antigen level; the higher risk from HLA-mismatching must bebalanced against the clinical urgency and the patient's risk by the transplant team; atthis time, antigen level mismatches at DQB1 do not affect outcomes and will not be used formatching 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, withor without additional single allele level mismatch may participate in this protocol forvoluntary unrelated donors (blood or marrow) DONOR: Donor must be healthy and havenon-reactive test results for all infectious disease assays as required by state andfederal regulations; donors who screen seropositive for hepatitis an/or syphilis must becleared by infectious disease consultation DONOR: Donor must have no uncontrolledcardiopulmonary, renal, endocrine, hepatic or psychiatric disease to render donation unsafeDONOR: The donor (or parent in minor) must give informed consent for peripheral blood stemcell collection or bone marrow collection DONOR: Syngeneic donors are not eligible DONOR:Donors who have poor peripheral venous access, may require central venous line placementfor 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, correctedfor 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 foradults or the Schwartz formula for pediatrics

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

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

• Uncontrolled diabetes mellitus, cardiovascular disease, active serious infection orother condition which, in the opinion of treating physician, would make this protocolunreasonably hazardous for the patient

• Human immunodeficiency virus (HIV) positive

• Patients who in the opinion of the treating physician are unlikely to comply with therestrictions of allogeneic stem cell transplantation based on formal psychosocialscreening

• Female of childbearing potential with a positive pregnancy test