Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
This phase II trial studies how well giving fludarabine phosphate, melphalan, and low-dose
 total-body irradiation (TBI) followed by donor peripheral blood stem cell transplant (PBSCT)
 works in treating patients with hematologic malignancies. Giving chemotherapy drugs such as
 fludarabine phosphate and melphalan, and low-dose TBI before a donor PBSCT helps stop the
 growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting
 the donor's stem cells. When the healthy stem cells from the donor are infused into the
 patient they may help the patient's bone marrow make stem cells, red blood cells, white blood
 cells, and platelets. Sometimes the transplanted cell from a donor can make an immune
 response against the body's normal cells. Giving tacrolimus, mycophenolate mofetil (MMF), and
 methotrexate after transplant may stop this from happening
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