Chemotherapy, Total-Body Irradiation, Donor Natural Killer Cell Infusion, Aldesleukin, and UCB Transplant in Treating Patients With Relapsed or Refractory AML
Condition: Leukemia
MeSH terms: Leukemia
Intervention: aldesleukin; cyclophosphamide; fludarabine phosphate; umbilical cord blood transplantation; total-body irradiation
Intervention description: IL-2 will be administered (9 million units; 5 million units if weight is less than 45 kg) every other day beginning on day +3 for a total of 6 doses and again on day +60 every other day for 6 doses.; 60 mg/kg over 1 hour intravenously (IV) on days -7 and -6.; 25 mg/m^2 intravenously (IV) over 1 hour on days -7 through -5.; On day 0, transplantation will occur with double T-cell depleted (TCD) umbilical cord blood (UCB) units; administered on days -5 through -2; 330 cGy daily
Intervention MeSH terms: Aldesleukin; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Interleukin-2
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Maximum age: 45 Years
Healthy volunteers: No
Keywords: recurrent adult acute myeloid leukemia; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); recurrent childhood acute myeloid leukemia; secondary acute myeloid leukemia; childhood acute myeloid leukemia with 11q23 (MLL) abnormalities; childhood acute myeloid leukemia with inv(16)(p13;q22); childhood acute myeloid leukemia with t(15;17)(q22;q12); childhood acute myeloid leukemia with t(16;16)(p13;q22); childhood acute myeloid leukemia with t(8;21)(q22;q22)

Summary:

      RATIONALE: Giving chemotherapy and total-body irradiation before a donor umbilical cord blood
      stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's
      immune system from rejecting the donor's stem cells. When the healthy stem cells and natural
      killer cells from a 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. Giving
      interleukin-2 (IL-2, aldesleukin) after transplant may stimulate the natural killer cells to
      kill any remaining cancer cells.

      PURPOSE: This phase II trial is studying the side effects of giving combination chemotherapy
      together with total-body irradiation followed by interleukin-2 (IL-2, aldesleukin), and
      umbilical cord blood transplant and to see how well it works in treating patients with
      relapsed or refractory acute myeloid leukemia.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Aged 0 to 45 years 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 acute myeloid leukemia (AML) with low disease burden

                    -  For patients 19 through 45 years of age: must have less than 10% marrow
                       blasts at time of enrollment for patients who did not receive re-induction
                       or measured at least 28 days from the start of re-induction therapy.
                       Patients who have relapsed more than 12 months following a prior
                       hematopoietic cell transplant (HCT) and did not reach CR following one
                       re-induction cycle but have less than 10% marrow blasts are eligible.

                    -  For patients 0 through 18 years of age: must have less than 50% marrow
                       blasts after no more than 3 induction attempts

               -  CR3 or greater. This will include CRp defined as CR without platelet recovery to
                  100,000/mcL.

               -  CR1 or CR2 with high risk features (therapy induced, prior myelodysplastic
                  syndrome (MDS) or myeloproliferative disease (MPD), high risk cytogenetic or
                  molecular phenotype) with no available alternate (sibling, URD or UCB) donors.

          -  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 enrollment defined as:

               -  Renal: creatinine ≤ 2.0 mg/dL (adult patients) or calculated creatinine clearance
                  > 40 ml/min (pediatric patients)

               -  Hepatic: bilirubin, AST/ALT, ALP ≤ 5 x upper limit of normal

               -  Pulmonary function: DLCOcorr > 50% of normal, (oxygen saturation [>92%] can be
                  used in child where PFT's cannot be obtained)

               -  Cardiac: left ventricular ejection fraction ≥ 45%

          -  Karnofsky score (adults) > 70% or Lansky score > 50% (pediatrics)

          -  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 anti-mouse antibody
             (HAMA). For patients with no prior antibody therapy exposure, no further action will
             be taken.

          -  Not receiving prednisone or other immunosuppressive medications

          -  Voluntary written consent

        Exclusion Criteria:

          -  Active infection at time of enrollment or documented fungal infection within 3 months

          -  Evidence of HIV infection or known HIV positive serology

          -  Pregnant or breast feeding. The agents used in this study may be teratogenic to a
             fetus and there is no information on the excretion of agents into breast milk. All
             females of childbearing potential must have a blood test or urine study within 2 weeks
             prior to registration to rule out pregnancy.

          -  If ≤ 18 years old, prior myeloablative transplant within the last 6 months. If > 18
             years old prior myeloablative allotransplant or autologous transplant

          -  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 total body
             irradiation (TBI).

        Criteria for Second Course of IL-2 (begin day +60):

          -  No Graft-Versus-Host Disease (GVHD), active infection or any other severe medical
             co-morbidity

          -  Absolute neutrophil count (ANC) > 1000 without growth factor support

          -  No grade 4 toxicity (except fevers) attributed to IL-2 during course #1