Reduced Intensity, Sequential Double Umbilical Cord Blood Transplantation Using Prostaglandin E2 (PGE2)

• Time to engraftment of umbilical cord blood units [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Fractional chimerism of transplanted cord blood units [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Rates of acute and chronic GVHD [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• 30- and 100-day treatment related mortality [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Measures of immune reconstitution and relapse-free and overall survival at 1 and 2 years after transplantation [ Time Frame: 2 years ] [ Designated as safety issue: No ]

• Time to engraftment of umbilical cord blood units [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Fractional chimerism of transplanted cord blood units [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Rates of acute and chronic GVHD [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• 30- and 100-dat treatment related mortality [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
• Measures of immune reconstitution and relapse-free and overall survival at 1 and 2 years after transplantation [ Time Frame: 2 years ] [ Designated as safety issue: No ]

The purpose of this research study is to determine the effects of 16, 16 Dimethyl-Prostaglandin E2 (dmPGE2) treatment on umbilical cord blood units to be used in transplantation. dmPGE2 treatment is being tested to see if it can improve the ability of umbilical cord blood stem cells to grow after transplantation. The growth of stem cells after transplantation is sometimes referred to as "engraftment". One of the major problems after umbilical cord transplantation is the time required for engraftment. After transplantation of two umbilical cord blood units, the average time to achieve engraftment is 21 days. In addition, up to 10% of patients who undergo umbilical cord blood transplantation never engraft, a potentially life-threatening condition. In laboratory studies, treatment of umbilical cord blood stem cells with dmPGE2 was shown to enhance engraftment.

• On the day of admission to the hospital, two intravenous catheters will be placed in the large veins in the participant's upper chest underneath the collarbone. The catheters will remain in place throughout the transplant.
• The chemotherapy portion of the treatment is called "Conditioning Therapy". The chemotherapy is used to prepare the bone marrow space to receive the transplanted umbilical cord blood units. It consists of three intravenous medications; fludarabine, melphalan and antithymocyte globulin or thymoglobulin.
• Starting three days before transplant and every day for 6-9 months after the transplant, participants will receive the immune suppressive drugs tacrolimus and sirolimus. These drugs are used to prevent Graft-Vs.-Host-Disease (GVHD), which might develop as the transplant engrafts.
• After the participant completes the "Conditioning Therapy", they will have their transplant. The day of the transplant is referred to as Day 0. On the day of the transplant, each cord blood unit will be thawed and washed in the laboratory and be given through the central venous catheter. All participants receive 2 cord blood units 2-5 hours apart.
• As part of this research study some cord units will be treated in the laboratory with dmPGE2 before it is given to the participant. 3 different dmPGE2 treatment groups will be tested. Group 1: will have the second cord blood unit treated; Group 2: will have their first cord blood unit treated and; Group 3 will expand the experience of treating the first cord blood unit. The three groups will be treated sequentially. If the treatment strategy in Group 1 is deemed to be safe, Group 2 will be treated. If there is evidence that the treated umbilical cord blood units from Groups 1 and 2 are engrafting, and that the treatment is safe, Group 3 will be tested.
• Participants will also be treated with antibiotics to prevent and treat infection. They may also receive transfusions of red blood cells and platelets. To help with engraftment, they will be given the drug G-CSF (Neupogen) starting five days after the transplant and until their white blood cells recover.
• After participants leave the hospital, they will be required to come back for monitoring and routine care very frequently. This is standard after umbilical cord blood transplantation.

• Hematologic Malignancies
• Allogeneic Stem Cell Transplantation

• Drug: Fludarabine
  30mg/m2/day IV x 6 days
• Drug: Melphalan
  100 mg/m2/day IV x 1 day
• Drug: Antithymocyte Globulin
  1mg/kg/day x 4 days
• Drug: Sirolimus
  GVHD Prophylaxis: Target range 3-12 ng/ml
• Drug: Tacrolimus
  GVHD Prophylaxis: Target range 5-10 ng/ml
• Other: Ex-vivo 16, 16 dimethyl-prostaglandin E2 expansion
  Thawed cord blood is washed with and resuspended in Dextran/albumin. 16, 16 dimethyl-prostaglandin E2 is added and the mix is incubated for 2 hours.

• Active Comparator: Group 1
  2 umbilical cord units: Second cord blood unit treated with dmPGE2
  Interventions:

  • Drug: Fludarabine
  • Drug: Melphalan
  • Drug: Antithymocyte Globulin
  • Drug: Sirolimus
  • Drug: Tacrolimus
  • Other: Ex-vivo 16, 16 dimethyl-prostaglandin E2 expansion
• Active Comparator: Group 2
  2 umbilical cord units: First cord blood unit treated with dmPGE2
  Interventions:

  • Drug: Fludarabine
  • Drug: Melphalan
  • Drug: Antithymocyte Globulin
  • Drug: Sirolimus
  • Drug: Tacrolimus
  • Other: Ex-vivo 16, 16 dimethyl-prostaglandin E2 expansion
• Active Comparator: Group 3
  2 umbilical cord units: First cord blood unit treated with dmPGE2
  Interventions:

  • Drug: Fludarabine
  • Drug: Melphalan
  • Drug: Antithymocyte Globulin
  • Drug: Sirolimus
  • Drug: Tacrolimus
  • Other: Ex-vivo 16, 16 dimethyl-prostaglandin E2 expansion

Inclusion Criteria:

• Patients with hematologic malignancies for whom allogeneic stem cell transplantation is deemed clinically appropriate
• Patient must be ineligible for traditional myeloablative transplantation according to treating physician
• Lack of 6/6 or 5/6 HLA-matched related, 8/8 HLA-matched unrelated donor, or unrelated donor not available within a time frame necessary to perform a potentially curative stem cell transplant
• 18-65 years of age
• ECOG Performance Status 0-2

Exclusion Criteria:

• The following hematologic malignancies are excluded:

  • Myelofibrosis unless there has been exposure to cytotoxic chemotherapy for the treatment of progression to acute myeloid leukemia
  • Chronic Myelogenous Leukemia, unless there has been exposure to cytotoxic chemotherapy for the treatment of blast phase, 3) Aplastic anemia, in the absence of transformation to Myelodysplastic disorder
• Cardiac disease: symptomatic congestive heart failure or evidence of left ventricular dysfunction as measured by gated radionucleotide ventriculogram or echocardiogram; active angina pectoris, or uncontrolled hypertension
• Pulmonary disease: symptomatic chronic obstructive lung disease, symptomatic restrictive lung disease, or corrected DLCO of < 50% of predicted, corrected hemoglobin
• Renal disease: serum creatinine > 2.0mg/dl
• Hepatic disease: serum bilirubin > 2.0mg/dl (expect in the case of Gilbert's syndrome or ongoing hemolytic anemia), SGOT or SGPT > 3 x upper limit of normal
• Neurologic disease: symptomatic leukoencephalopathy, active CNS malignancy or other neuropsychiatric abnormalities believed to preclude transplantation
• HIV antibody
• Uncontrolled infection
• Pregnancy or breast feeding mother
• Inability to comply with the requirements for care after allogeneic stem cell transplantation

• Brigham and Women's Hospital
• Massachusetts General Hospital
• Harvard University
• Dana-Farber Cancer Institute
• National Heart, Lung, and Blood Institute (NHLBI)