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Antimetabolites

Two Unmanipulated Cord Blood units. Rituxan 375 mg/m2 by vein for patients with CD20 + malignancies. Melphalan 140 mg/m2 by vein on Day -8. Thiotepa 5 mg/Kg by vein on Day -7. Fludarabine 40 mg/m2 by vein on Days -6 to -3.

One Unmanipulated and One Expanded Cord Blood Unit. Fludarabine 40 mg/m2 by vein on Days -6 to -3. Cyclophosphamide 50 mg/kg by vein on Day -6. Mesna 10 mg/kg by vein before the 1st dose of Cyclophosphamide, then 10 mg/kg every 4 hours for four more doses (total of 50 mg/Kg). Total body irradiation (TBI) given on Day -1 at 2 Gy.

Transplantation of Two Unmanipulated Cord Blood Units.

Expanded allogeneic cord blood (CB)

Transplantation of One Unmanipulated and One Expanded Cord Blood Unit.

One Unmanipulated and One Expanded Cord Blood Unit

375 mg/m2 by vein on Day - 9 for patients with CD20 + malignancies.

Rituxan

10 mg/kg by vein before the 1st dose of Cyclophosphamide, then 10 mg/kg every 4 hours for four more doses (total of 50 mg/Kg).

Total body irradiation (TBI) given on Day -1 at 2 Gy.

Total body irradiation (TBI)

Simrit Parmar, MD

The goal of this clinical research study is to learn if combining cord blood units to make the cells "take" faster in recipients will help to improve the results of cord blood transplants.

Cord blood is a source of blood forming cells that can be used for transplantation. The major problem with this type of transplant is the small number of blood forming cells available in each cord unit, which may delay the "take" of the graft in the recipient. Two strategies may be used to try to overcome this problem. One method is the combination of 2 units of cord blood and the other is the growing of the cord blood cells in the laboratory before they are transplanted in order to increase their number.

Participants will be randomly assigned (as in the toss of a coin) to one of two groups. If you are assigned to Study Arm 1, you will receive two cord blood units combined without growing the cells in the laboratory. If you are assigned to Study Arm 2, you will receive one cord blood unit combined with one cord blood unit which will be grown in the laboratory for two weeks before you receive it. Neither you nor your doctors will know in advance to which arm you will be assigned.

Placement of central venous catheter for collection of "back-up" stem cells:

Before you have back-up stem cell collected or you receive chemotherapy, you will require placement of a hollow plastic tube (catheter) into a large vein inside your body. This catheter will be used to draw blood and to give medications and fluids. The catheter is inserted through the skin in the upper chest and extends into the right side of your heart. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for it.

Collection of back up stem cells:

Because collecting additional cells from the donor of the cord blood will not be possible if the transplant with cord blood fails, a back up blood or bone marrow sample will be collected from you and frozen before the high dose chemotherapy begins.

Peripheral blood progenitor cell collection (Leukapheresis):

Before collection of the blood stem cells, you will be treated with a drug called granulocyte colony stimulating factor (G-CSF), which will cause the important stem cells in the marrow to move the peripheral blood where they will be collected. This medication is given as a shot under the skin once a day for 3 - 7 days, at which time your blood stem cells will be collected from your central catheter during a 3-4 hour out-patient procedure. In some cases where a "good vein" cannot be accessed, a silicone venous catheter may be needed to collect your blood.

Bone Marrow Collection:

If the leukapheresis cannot be performed successfully, you will receive general anesthesia in the operating room and will have multiple needle sticks of the hip bones in order to collect bone marrow. Only a small part of your bone marrow (\<5%) will be taken.

Selection of another donor as the alternate source of stem cells:

If your bone marrow or back-up blood stem cells cannot be collected, a family member whose bone marrow is the closest match will be chosen as the back up donor. The potential donor would have testing performed to assure that he/she is eligible to donate.

High-dose therapy:

Your bone marrow transplant doctors will give you one of four chemotherapy treatments, which are discussed below. If you have acute lymphoblastic leukemia, lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, acute myelogenous leukemia, myelodysplastic syndrome, chronic eosinophilic leukemia or chronic myelogenous leukemia, are less than 61 years old, and can receive high-dose chemotherapy, you may be assigned to Treatment Regimen #1 - fludarabine-thiotepa-melphalan. Patients with ALL may be assigned to Treatment Regimen #1 or #3, depending on your doctor's evaluation, age and physical fitness.

You will receive melphalan as a single dose on Day -8, thiotepa as a single dose on Day -7, followed by fludarabine given once a day for 4 days in a row (Days -6 through -3. Rituximab may be given on Day -9 if appropriate for your disease. Day 0 is the day of transplantation, so the negative day numbers are used to label the treatment days before transplant.

If you have any of the diseases listed above, have had a bone marrow transplant in the past, or have a physical that makes you less likely to tolerate high-dose therapy well, you will be in the less aggressive Treatment Regimen #2, Fludarabine, Cyclophosphamide and low dose total body irradiation. The fludarabine will be given on Days -6, -5, -4, and -3. The cyclophosphamide will be given on Day -6. Irradiation will be given on day -1. Rituxan may be given on Day -7 if appropriate for your disease.

If you have acute lymphoblastic leukemia, are 50 years old or younger, and your doctors have decided that full-dose Total body irradiation is the best treatment for you, you will be assigned to Treatment Regimen #3 - total body irradiation-VP16. You will receive total body irradiation on Days -7,-6, -5 and -4, followed by VP16 (also known as etoposide) as a single dose on Day -3. Rituximab may be given on Day -8 if appropriate for your disease.

All chemotherapy, fluids and other medications that must be given by vein will be infused through your catheter. Once the backup stem cells are collected, all patients will be admitted to the hospital on Day -9 to begin receiving fluids. Chemotherapy may be stopped if intolerable side effects occur.

Expansion of expanded cord blood:

On Day -14, if you are in Treatment Group 2, one of your two cord blood units will be thawed and treated in the MD Anderson Stem Cell Laboratory with vitamin-like growth factors for 2 weeks before they are given back to you on day zero as described below. A small amount of cord blood cells (less than 3%) will be used for laboratory procedures that measure the quality of the product.

The CliniMACS System is a medical device that is used to separate types of blood cells from blood that is removed from the body during leukapheresis. These separated cells are processed for use in treatments such as stem cell transplants.

Transplantation of cord blood:

If you are in Treatment Group 1, two days following completion of high-dose therapy (Day 0), both units of cord blood will be thawed and infused (one at a time) through your catheter. Each unit will take about 30 minutes to infuse. Patients in Treatment Group 2 will receive one unit of cord blood that did not go through expansion of cells, followed by infusion of the unit that was grown in the laboratory for 14 days.

Graft versus host disease (GVHD) preventive therapy:

GVHD results from a reaction of the transplanted cord blood cells against certain tissues in your body. In an attempt to prevent or decrease the severity of GVHD, you will receive two drugs.

Mycophenolate mophetyl (MMF) pills will be given starting three days before your transplant, and will be continued until day 30 after the cord blood transplant. If you cannot take pills, the drug can be given through your catheter. If you develop GVHD, the use of MMF may be prolonged.

Tacrolimus will be given as a 24 hour continuous infusion over 3-6 weeks. Around Day 30 or 40 (after engraftment), the tacrolimus will be changed to pills given daily for 6-9 months. The number of tacrolimus pills may vary according to the blood levels of the drug, but usually are between 1 - 5. This medicine is used for 6-9 months (longer if chronic GVHD occurs).

You will remain on study as long as your disease does not return. If your disease returns, you will be taken off study and you may be offered participation in another study or be treated outside of this study.

Follow-up after transplant:

After you leave the hospital, you will be seen regularly in the Department of Blood and Marrow Transplantation at MD Anderson. The frequency of the visits may vary, but may be as often as daily. Blood (1-2 tablespoons) and urine tests will be performed. The frequency of blood tests may also vary, but may be performed daily. Patients will need a bone marrow sample collected before transplant and at 1 month, 3-4 months, and 5-7 months after transplant. After that, bone marrow samples will be collected once a year, indefinitely. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anaesthetic and a small amount of bone marrow is withdrawn through a large needle. Patients with lymphomas and Hodgkin's disease will need CT scan of the thorax, abdomen, and pelvis performed before transplant and then at 1 month, 3-4 months, and 5-7 months after the transplant. After that it will be done yearly.

This is an investigational study. All treatment drugs are FDA approved and commercially available.

A total of 110 patients may take part in this study. All will be enrolled at MD Anderson.

Randomized Double Cord Blood Transplant Study

Randomized Trial of Unmanipulated Versus Expanded Cord Blood

Engraftment is defined as a sustained ANC \> 0.5 x 10\^9/L for at least 3 consecutive days. Engraftment date is the first of the 3 days with sustained absolute neutrophil count (ANC) \>/= 0.5 x 10\^9/L.

Engraftment defined as a sustained absolute neutrophil count (ANC) \> 0.5 x 10\^9/L for at least 3 consecutive days. Engraftment Failure defined as ANC \<500/ul by day +42 and participant has no evidence of donor chimerism on bone marrow examination.

Number of participants who display features of acute GVHD within 100 days of transplant.

Number of participants who present GVHD post-transplant and display features of chronic GVHD. Diagnostic and distinctive features of chronic GVHD are present. There are no features of acute GVHD.

The severity of acute GVHD is determined by an assessment of the degree of involvement of the skin, liver, and gastrointestinal tract. The stages of individual organ involvement is assessed using Glucksberg grade (I-IV) where Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.

National Cancer Institute (NCI)

Cellgenix

M.D. Anderson Cancer Center

Transplantation of Two Unmanipulated CB units. Rituxan 375 mg/m2 IV Day -9 for participants with CD20 + malignancies. Melphalan 140 mg/m2 IV on Day -8. Thiotepa 5 mg/Kg IV on Day -7. Fludarabine 40 mg/m2 IV on Days -6 to -3.

Un-Manipulated CB Arm

Transplantation One Unmanipulated and One Expanded CB Unit. Rituxan: 375 mg/m2 IV on Day - 9 for CD20 + malignancies. Fludarabine 40 mg/m2 IV on Days -6 to -3. Cyclophosphamide 50 mg/kg IV on Day -6. Mesna 10 mg/kg IV before the 1st dose of Cyclophosphamide, then 10 mg/kg every 4 hours for four more doses (total of 50 mg/Kg). TBI Day -1 at 2 Gy.

Expanded CB Arm

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Simrit Parmar, MD/Associate Professor, Stem Cell Transplantation

Time To Neutrophil Engraftment

Number of Participants With Engraftment

Acute GVHD percentage calculated using engrafted participants only (n=89; expanded 44; un-manipulated 45)

Rate of Acute Graft Versus Host Disease (GVHD)

Overall Chronic GVHD

Limited

Extensive

Chronic GVHD percentage calculated using engrafted patients and alive after 100 days (n=77; expanded 40; unmanipulated 37)

Rate of Chronic GVHD

Grade ≤ 2

Grade ≥ 3

No GVHD

For the Acute GVHD the analysis was performed on patients with GVHD in the first 100 days.

Number of Participants Severity of Acute GVHD by Treatment Arm

Transplantation of Two Unmanipulated Cord Blood (CB) units. Rituxan 375 mg/m2 by vein (IV) Day -9 for participants with CD20 + malignancies. Melphalan 140 mg/m2 IV on Day -8. Thiotepa 5 mg/Kg IV on Day -7. Fludarabine 40 mg/m2 IV on Days -6 to -3.

Expanded allogeneic cord blood (CB): Transplantation of Two Unmanipulated Cord Blood Units.

Double Cord Blood Transplant Group (Un-Manipulated)

One Unmanipulated and One Expanded Cord Blood Unit. Rituxan: 375 mg/m2 by vein on Day - 9 for patients with CD20 + malignancies. Fludarabine 40 mg/m2 by vein on Days -6 to -3. Cyclophosphamide 50 mg/kg by vein on Day -6. Mesna 10 mg/kg by vein before the 1st dose of Cyclophosphamide, then 10 mg/kg every 4 hours for four more doses (total of 50 mg/Kg). Total body irradiation (TBI) given on Day -1 at 2 Gy.

Spots Global Cancer Trial Database for one unmanipulated and one expanded cord blood unit