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

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Brief Title

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

Official Title

A Phase II Trial of Reduced Intensity Allogeneic Stem Cell Transplantation With Fludarabine, Melphalan and Low Dose Total Body Irradiation

Brief Summary

      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

Detailed Description


      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).


      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.


      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.


      Patients undergo allogeneic PBSCT on day 0.


      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

Study Phase

Phase 2

Study Type


Primary Outcome

Transplant Related Mortality (TRM)

Secondary Outcome

 Clinical Response


Accelerated Phase Chronic Myelogenous Leukemia


fludarabine phosphate

Study Arms / Comparison Groups

 Treatment (reduced intensity allogeneic PBSCT)
Description:  PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV over 30 minutes on days -5 to -2 and melphalan IV over 30 minutes on day -2. Patients undergo low-dose TBI BID on day -1. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. GvHD PROPHYLAXIS: Patients receive tacrolimus IV or 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 to 30 minutes on days 1, 3, and 6.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

February 28, 2012

Completion Date

August 29, 2019

Primary Completion Date

May 28, 2015

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of a histology documented hematologic malignancy or marrow disorder


          -  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


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

          -  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 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


          -  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

          -  Secondary MDS with any IPSS scores

          -  Chronic myelomonocytic leukemia


          -  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


          -  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

          -  Female of childbearing potential with a positive pregnancy test




3 Years - 75 Years

Accepts Healthy Volunteers



George Chen, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID

I 177110

Secondary IDs


Responsible Party


Study Sponsor

Roswell Park Cancer Institute

Study Sponsor

George Chen, Principal Investigator, Roswell Park Cancer Institute

Verification Date

September 2019