T-Cell Depleted Double UCB for Refractory AML
Condition: Acute Myelogenous Leukemia; Refractory Acute Myelogenous Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Allopurinol; Fludarabine; Total body irradiation; Cyclophosphamide; Levetiracetam; Busulfan; Umbilical Cord Blood Transplantation; Interleukin-2
Intervention description: On Day 8 pre-transplant, start hydration with allopurinol per standard of care.; On Days 7, 6 and 5 pre-transplant, 25 mg/m^2 intravenously over 1 hour.; On Days 5, 4, 3, and 2 pre-transplant, 165 cGy times 2 (330 cGy daily, 1320 total dose) according to the University Of Minnesota Blood and Marrow Transplant Program total body irradiation (TBI) guidelines.; On Days 7 and 6 pre-transplant, 60 mg/kg intravenously (IV) over 2 hours with a high volume fluid flush and mesna per institutional guidelines.
Alternate Preparative Therapy For Patients Not Able To Receive TBI: Days 5, 4, 3 and 2 pre-transplant; 50 mg/kg/day IV over 2 hours.; Alternate Preparative Therapy for Patients Not Able to Receive Total Body Irradiation (TBI): Hydration therapy on Day 10 pre-transplant.; Alternate Preparative Therapy For Patients Not Able To Receive TBI: Days 9, 8, 7 and 6 pre-transplant; 0.8 mg/kg (1.1 mg/kg if <12 kg) intravenously every 6 hours; Day 0: Two UCB units will compose the graft. The infusion of the first UCB unit should begin within 15 minutes, and no later than 30 minutes after arrival on the Unit. The UCB unit without IL-2 activation will be infused first, followed by the IL-2 activated unit. Both cords will be infused within 30-60 minutes of each other as deemed clinically safe by the BMT attending.; First Course of IL-2 (begin day +3) post-transplant: For patients ≥ 45 kg, IL-2 will be given at 9 million units every other day for a total of 6 doses subcutaneously. Patients weighing less than 45 kilograms, the IL-2 will be dosed at 5 million units/m^2 every other day for a total of 6 doses.
Second Course of IL-2 (day +60):
Patients will receive a second course of IL-2 beginning on Day +60 post transplant to expand and educate the NK cells derived from the UCB graft source.
Intervention MeSH terms: Cyclophosphamide; Busulfan; Fludarabine; Interleukin-2; Allopurinol; Levetiracetam
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 2 Years
Maximum age: 45 Years
Healthy volunteers: No
Keywords: umbilical cord blood transplant

Summary:

      This trial is proposes to build on our experience and is designed to maximize early (day
      3-14) and late (day 60-71) donor-derived natural killer (NK) cell expansion and function in
      vivo. The proposed platform will allow us the unique opportunity to compare in vivo function
      from a transplanted umbilical cord blood (UCB) source (presumed to contain NK progenitors
      requiring "education" in the recipient).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Aged 2 to 45 years with acute myeloid leukemia (AML) who meet one of the following
             criteria:

               -  Primary induction failure defined as no complete remission (CR) after two or
                  three induction cycles (no blast limit).

               -  Relapsed AML with low disease burden: For patients >21 through 45 years of age:
                  must have <30% marrow blasts within 14 days of enrollment and be at least 28 days
                  from the start of last therapy. For patients 2 through ≤ 21 years of age: must
                  have >5% marrow blasts after no more than 3 induction attempts.

        Patients with prior central nervous system (CNS) involvement are eligible provided that it
        has been treated and is in remission. CNS therapy (chemotherapy or radiation) should
        continue as medically indicated during the protocol.

          -  Have acceptable organ function within 14 days of study registration defined as:

               -  Renal: creatinine ≤ 2.0 mg/dL (adult patients) or calculated creatinine clearance
                  > 40 ml/min (pediatric patients)

               -  Hepatic: bilirubin, aspartate aminotransferase (AST), alanine aminotransferase
                  (ALT), alkaline phosphatase (ALP) ≤ 5 times upper limit of normal

               -  Pulmonary function: diffusing lung capacity for carbon monoxide corrected for
                  hemoglobin (DLCOcorr) > 50% of normal, (oxygen saturation [>92%] can be used in
                  child where pulmonary function tests (PFT's) cannot be obtained)

               -  Cardiac: left ventricular ejection fraction ≥ 45%

          -  Karnofsky Performance Status ≥ 70% (≥ 16 years) or Lansky Play Score ≥ 50 (pediatrics
             < 16 years)

          -  Women of childbearing potential must agree to use adequate contraception (diaphragm,
             birth control pills, injections, intrauterine device [IUD], surgical sterilization,
             subcutaneous implants, or abstinence, etc.) for the duration of treatment.

          -  All patients will be questioned about prior exposure to antibody therapy (including
             OKT3, rituximab, trastuzumab, and gemtuzumab) without affect to eligibility. Patients
             with prior exposure will have a blood sample collected for human antimouse antibody
             (HAMA). For patients with no prior antibody therapy exposure, no further action will
             be taken.

          -  Voluntary written consent

        Exclusion Criteria:

          -  Active infection at time of enrollment or documented fungal infection within 3 months
             unless clearance from Infectious Disease

          -  Evidence of HIV infection or known HIV positive serology

          -  Pregnant or breast feeding.

          -  If < or = 21 years old, prior myeloablative transplant within the last 6 months. If >
             21 years old prior myeloablative allotransplant or autologous transplant - if prior
             conditioning regimen included total body irradiation (TBI), then
             busulfan/cyclophosphamide(BU/CY) prep should be used

          -  If > 21 years old - extensive prior therapy including > 12 months of any alkylator
             chemotherapy (etoposide >100 mg/m^2 x 5 days, cyclophosphamide >1 gm/m^2 or
             mitoxantrone >8 gm/m^2) delivered at 3-4 week intervals or > 6 months alkylator
             therapy (as above) with extensive radiation (determined by Radiation Oncology, e.g.
             mantle irradiation for Hodgkin's) and/or prior radiation therapy that makes a patient
             ineligible for TBI.

          -  Known hypersensitivity to any of the study agents