Donor Umbilical Cord Blood Natural Killer Cells, Aldesleukin and Umbilical Cord Blood Transplant in Patients With Refractory Hematologic Cancers.

Phase 2

Terminated

Conditions: Leukemia
Myelodysplastic Syndromes

Interventions: Biological: aldesleukin
Biological: filgrastim
Biological: natural killer cell (NK) therapy
Drug: cyclophosphamide
Drug: cyclosporine
Drug: fludarabine phosphate
Drug: methylprednisolone
Drug: mycophenolate mofetil
Procedure: Umbilical Cord Blood Transplantation (UCBT)
Radiation: Total body irradiation (TBI)

Registration Number: NCT00354172

Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief Summary: RATIONALE: Giving chemotherapy, natural killer cells, aldesleukin, and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of abnormal cells and cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine, mycophenolate mofetil, and methylprednisolone before and after transplant may stop this from happening.

PURPOSE: This clinical trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by donor umbilical cord blood natural killer cells, aldesleukin, and umbilical cord blood transplant works in treating patients with refractory hematologic cancer or other diseases.

Detailed Description: OBJECTIVES:

Primary

* Determine the incidence of 6-month disease free survival. The primary laboratory objective is the measure of in vivo expansion of umbilical cord blood (UCB) derived natural killer cells (NK) after a fully ablative preparative regimen.

Secondary

* Determine the incidence of transplant-related mortality at 6 months after NK UCB + double UCBT

* Evaluate the pattern of chimerism after NK UCB + double UCBT

* Determine the incidence of neutrophil engraftment at day 42 after NK UCB + double umbilical cord blood transplantation (UCBT)

* Determine the incidence of platelet engraftment at 6 months after NK UCB + double UCBT

* Determine the incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV at day 100 after NK UCB + double UCBT

* Determine the incidence of chronic GVHD at 1 year after NK UCB + double UCBT

* Determine the disease-free survival at 1 after NK UCB + double UCBT

* Determine the incidence of relapse at 1 after NK UCB + double UCBT

OUTLINE: This is a single arm, nonrandomized, open-label study.

* Myeloablative conditioning regimen: Patients receive fludarabine intravenously (IV) over 1 hour on days -18 to -16 and cyclophosphamide intravenously (IV) on days -18 and -17. Patients undergo total-body irradiation twice daily on days -16 to -13.

* Haploidentical umbilical cord blood (UCB) natural killer (NK) cell therapy and aldesleukin: Patients undergo haploidentical UCB-enriched NK cell (CD3- depleted) infusion on day -13. Patients then receive aldesleukin subcutaneously on days -13, -11, -9, -7, -5, and -3. Some patients may also receive methylprednisolone IV on days -1 and 0.

* UCB transplantation (UCBT): Patients undergo a single or double UCBT on day 0. Beginning on day 1, patients receive filgrastim (G-CSF) IV once daily until blood counts recover.

* Graft-vs-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours 2-3 times daily beginning on day -1 and continuing until day 100, followed by a taper until day 180. Patients also receive mycophenolate mofetil IV or orally 2-3 times daily beginning on day -1 and continuing until day 30 (or 7 days after engraftment) in the absence of acute GVHD.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 16

Inclusion Criteria

Diagnosis of 1 of the following:
- Acute myeloid leukemia with active leukemia (i.e., not in complete remission [CR]), defined by light microscopy (bone marrow) and having failed ≥ 1 round of standard chemotherapy
- Chronic myelogenous leukemia with myeloid blast crisis not in second chronic phase after ≥ 1 course of standard chemotherapy and imatinib mesylate
- Myelodysplastic syndromes (MDS) or other myeloproliferative disorders more than 10% blasts after ≥ 1 course of standard chemotherapy
Unrelated umbilical cord blood (UCB) donor(s) available - Each unit must be 4-6/6 HLA-A, -B, and -DRB1 matched with the recipient (and to each other if 2 units are utilized) (for UCB graft) AND 3/6 HLA-A, -B, and -DRB1 matched with the recipient (for UCB natural killer [NK] cells)
Karnofsky performance status (PS) 80-100% (adult patients) or Lansky PS 50-100% (pediatric patients)
Creatinine ≤ 2.0 mg/dL (adult patients) OR creatinine clearance > 40 mL/min (pediatric patients)
Bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase ≤ 5 times upper limit of normal (ULN)
Corrected Carbon Monoxide Diffusing Capacity (DLCO) > 50% normal OR oxygen saturation > 92% (in pediatric patients who cannot undergo pulmonary function tests)
Left ventricular ejection fraction ≥ 45%

Exclusion Criteria

Pregnant or nursing
Positive pregnancy test (Fertile patients must use effective contraception)
History of HIV infection
Active infection at time of transplantation
- Active infection with Aspergillus or other mold within the past 120 days
Less than 6 months since prior myeloablative transplant (≤ 18 years old)
Prior myeloablative allotransplant or autologous transplant (> 18 years old)
No prior extensive therapy including > 12 months of any alkylator chemotherapy or > 6 months of alkylator therapy with extensive radiation (e.g., mantle irradiation for Hodgkin's lymphoma)
Prior radiation therapy that would make the patient ineligible for total-body irradiation

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treated Patients	aldesleukin	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.
Treated Patients	filgrastim	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.
Treated Patients	natural killer cell (NK) therapy	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.
Treated Patients	cyclophosphamide	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.
Treated Patients	Umbilical Cord Blood Transplantation (UCBT)	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.
Treated Patients	Total body irradiation (TBI)	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.
Treated Patients	cyclosporine	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.
Treated Patients	fludarabine phosphate	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.
Treated Patients	mycophenolate mofetil	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.
Treated Patients	methylprednisolone	All patients receiving treatment with chemotherapy and radiation, along with natural killer cells, aldesleukin and umbilical cord blood transplant.

Primary Outcome Measures

Name	Time	Method
Number of Participants (Patients) Who Were Disease-free and Alive at 6 Months	6 Months Post Transplant	Number of patients who were alive and free of disease (malignancy) at 6 months after transplant.

Secondary Outcome Measures

Name	Time	Method
Number of Participants (Patients) Who Were Disease-free and Alive at 12 Months	12 Months Post transplant	Number of patients who were alive and free of disease (malignancy) at 12 months after transplant.
Number of Patients Who Were Disease-free and Alive at 24 Months	24 Months Post transplant	Number of patients who were alive and free of disease (malignancy) at 24 months after transplant.
Number of Participants (Patients) Who Died Due to Transplant.	6 Months Post Transplant	Patients who had transplant-related mortality (TRM). TRM = adverse event(s) that occur(s) after the patient has received a transplant, the principal investigator decides it is related to the procedure and the patient dies within 6 months.
Number of Participants (Patients) Who Attained Neutrophil Engraftment	Day 42 Post Transplant	Defined as absolute neutrophils (ANC) \> 5 x 10\^8/Liter for 3 consecutive days. ANC is the real number of white blood cells (WBCs) that are neutrophils. The absolute neutrophil count is commonly called the ANC. The ANC is not measured directly. It is derived by multiplying the WBC count times the percent of neutrophils in the differential WBC count. The percent of neutrophils consists of the segmented (fully mature) neutrophils) + the bands (almost mature neutrophils). The normal range for the ANC = 1.5 to 8.0 (1,500 to 8,000/mm3).
Number of Participants (Patients) Who Attained Platelet Engraftment	1 Year Post Transplant	Platelet engraftment is defined as platelet counts \> 50 x 10\^9/Liter for 3 consecutive days.
Number of Participants (Patients) With Acute Graft-versus-host Disease (GVHD) Grade II-IV	Day 100 Post Transplant	Graft-versus-host disease (GVHD) is a common complication of transplantation in which functional immune cells in the transplanted marrow recognize the recipient as foreign and mount an immunologic attack. The acute or fulminant form of the disease (aGVHD) is normally observed within the first 100 days post-transplant, and is a major challenge to transplants owing to associated morbidity and mortality. Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of I to a high of IV. Patients with grade IV GVHD usually have a poor prognosis.
Number of Participants (Patients) With Acute Graft-versus-Host Disease at Grade III-IV	Day 100 post transplant	Graft-versus-host disease (GVHD) is a common complication of transplantation in which functional immune cells in the transplanted marrow recognize the recipient as foreign and mount an immunologic attack. The acute or fulminant form of the disease (aGVHD) is normally observed within the first 100 days post-transplant, and is a major challenge to transplants owing to associated morbidity and mortality. Acute GVHD is staged as follows: overall grade (skin-liver-gut) with each organ staged individually from a low of I to a high of IV. Patients with grade IV GVHD usually have a poor prognosis.
Number of Participants (Patients) With Chronic Graft-Versus-Host Disease	Day 100 through 1 Year Post Transplant	The chronic form of graft-versus-host-disease (cGVHD) normally occurs after 100 days. The appearance of moderate to severe cases of cGVHD adversely influences long-term survival.
Number of Participants (Patients) Who Died by 12 Months	1 year Post Transplant	Number of patients who died after receiving treatment within 12 months post transplant.
Number of Participants (Patients) Who Died by 24 Months	2 years post-transplant	Number of patients who died after receiving treatment within 24 months post transplant.
Number of Participants (Patients) Who Experienced Relapse by 12 Months	1 Year Post Transplant	Number of patients who experienced recurrence or progression of disease from the time of transplant.
Number of Participants (Patients) Who Experienced Relapse by 24 Months	2 Years Post transplant	Number of patients who experienced recurrence or progression of disease from the time of transplant.
Number of Participants (Patients) With Successful Natural Killer Cell Expansion	10-13 Days Post Infusion	Defined by an absolute circulating donor-derived natural killer cell count of \>100 cells/microliter 10-13 days after infusion with \<5% donor T and B cells in the mononuclear population
Chimerism After Double Umbilical Cord Blood Transplant (UCBT)	Day 21, Day 100, 6 Months	Calculation of Median (range) of percentage of donor cells engrafted (present) in the recipient (patient).