PRO#1278: Fludarabine and Busulfan vs. Fludarabine, Busulfan and Total Body Irradiation
Condition: Myeloid Malignancies; Acute Myelogenous Leukemia; Chronic Myelogenous Leukemia; Myeloproliferative Disorders; Myelodysplastic Syndrome
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders
Intervention: Fludarabine and Busulfan plus/minus Total Body Irradiation (low dose); Fludarabine and Busulfan + Low Dose Total Body Irradiation (LD TBI)
Intervention description: Fludarabine 40mg/m2 and Busulfan 130mg/m2 on days -6, -5, -4 and -3 of transplant.
rATG on days -3, -2 and -1; Fludarabine 40mg/m2 and Busulfan 130mg/m2 on days -6, -5, -4 and -3 of transplant.
rATG on days -3, -2 and -1 TBI 200cGY (as randomized) on day -1
Intervention MeSH terms: Vidarabine; Fludarabine; Fludarabine phosphate; Busulfan
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 53.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Allogeneic Stem Cell Transplant; AML; CML; MDS

Summary:

      This is a single institution study of fludarabine and busulfan versus fludarabine, busulfan
      and low dose total body irradiation in patients undergoing allogeneic stem cell
      transplantation. A study population of 80 subjects will be enrolled from The John Theurer
      Cancer Center at Hackensack University Medical Center. Subjects who are eligible to receive
      allogeneic hematopoietic stem cell transplantation according to the eligibility criteria will
      be consented and enrolled. Subjects will be randomly assigned to receive one of 2
      conditioning regimen: fludarabine and busulfan, or fludarabine busulfan and low dose total
      body irradiation (TBI). Subjects will be followed until 1 year post transplantation to assess
      the relapse rate in each arm and transplant-related toxicity.

      The combination of fludarabine and busulfan is the current standard of care for patients with
      myeloid malignancies (AML, CML and other myeloproliferative disorders, or MDS) undergoing
      allogeneic transplantation at HUMC. In this study we will be comparing in a randomized
      fashion the standard regimen to a regimen of fludarabine, busulfan and TBI.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of acute myelogenous leukemia, chronic myelogenous leukemia, other
             myeloproliferative disorder, or myelodysplastic syndrome

          -  Any stage of disease will be considered for transplantation

          -  Have a suitable related or unrelated donor (Section 3.3)

          -  Age ≥18 but <70 yrs

          -  KPS of ≥70%

          -  Recovery from all hematologic and non-hematology toxicities from previous therapies.

        Exclusion Criteria:

          -  Diagnosis other than acute myelogenous leukemia, myeloproliferative disorder, or
             myelodysplastic syndrome

          -  Chemotherapy or radiotherapy within 14 days of initiating treatment in this study with
             the exception of lenalidomide, decitabine, azacitidine, imatinib mesylate, dasatinib,
             nilotinib hydrochloride and hydroxyurea

          -  Prior dose-intense therapy requiring HSC support within 56 days of initiating
             treatment in this study

          -  Uncontrolled bacterial, viral, fungal or parasitic infections

          -  Uncontrolled CNS metastases

          -  Known amyloid deposition in heart

          -  Organ dysfunction

               -  LVEF <40% or cardiac failure not responsive to therapy

               -  FVC, FEV1, or DLCO <50% of predicted and/or receiving supplementary continuous
                  oxygen

               -  Evidence of hepatic synthetic dysfunction, or total bilirubin >2x or AST >3x ULN

               -  Measured creatinine clearance <20 ml/min

               -  Karnofsky score <70%

          -  Life expectancy limited by another co-morbid illness

          -  Diagnosed or treated for another malignancy within 3 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

          -  Female subject is pregnant or breast-feeding (women) or unwilling to use acceptable
             birth control methods (men or women) for twelve months after treatment. Confirmation
             that the subject is not pregnant must be established by a negative serum β-human
             chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening.
             Pregnancy testing is not required for post-menopausal or surgically sterilized women.

          -  Documented hypersensitivity to fludarabine or melphalan or to bortezomib, boron or
             mannitol or any components of the formulation

          -  Patients unable or unwilling to provide consent

          -  Myocardial infarction within 6 months prior to enrollment or has New York Heart
             Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled
             angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
             of acute ischemia or active conduction system abnormalities. Prior to study entry, any
             ECG abnormality at screening has to be documented by the investigator as not medically
             relevant

          -  Patient has received other investigational drugs with 14 days before enrollment

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study

        Donor Inclusion and Exclusion Criteria

        Donor Inclusion Criteria:

        HLA 6/6 (HLA-A, B, DrB1) related donor or 7/8 (HLA-A, B, C, DrB1) unrelated donor Related
        donors will be evaluated in accordance with HUMC standard practice guidelines for the
        evaluation and management of allogeneic donors Unrelated donors will be identified,
        evaluated, and managed in accordance with National Marrow Donor Program standards Age ≥18
        and <70 yrs KPS of ≥70% Willing to donate bone marrow using standard techniques or
        peripheral blood HSC by leukapheresis Have adequate veins for apheresis or agree to
        placement of a central venous catheter (femoral, subclavian) if donating peripheral blood
        HSC

        Donor Exclusion Criteria Identical twin Female donors who are pregnant or breastfeeding
        Infection with HIV or viral hepatitis (B or C) Known allergy to filgrastim Current serious
        systemic illness Uncontrolled bacterial, viral, or fungal infection Receiving experimental
        therapy or investigational agents History of cancer other than treated basal cell cancer of
        the skin or carcinoma in situ of the cervix. Cancer treated with curative intent >5 yrs
        before donation will be reviewed on a case-by-case basis by the principal investigator