| Study summary: |
|
Umbilical 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. A strategy to overcome this problem is to give 2 cord blood units, increasing
the number of cord blood cells in one of them in the laboratory before they are
transplanted. This is done in order to increase their number. The expansion of 1, but not
both, of the cord blood units will allow the research team to decide more effectively
whether the laboratory expansion is responsible for the speed and content of the "take." At
this time, no proof exists that this expansion technique will improve the performance of the
cord blood specimens.
In order to collect a larger expansion of the numbers of cord blood cells, recent research
suggests that growing the cord blood cells on a layer of bone marrow stromal cells increases
the number of expanded cells which can be collected. In the body, these stromal cells form
a matrix or "spider web" in the bone marrow. Blood-forming bone marrow cells (looking like
dewdrops) grow on this stromal cell matrix (spider web) and are nurtured by the stromal
cells. In this research study, researchers will collect marrow stromal cells from a family
member through a bone marrow aspiration. These stromal cells will hopefully improve the
performance of the cord blood cells after they are given to you.
Before you can start treatment on this study, you will have "screening tests." These tests
will help the doctor decide if you are eligible to take part in this study. Women who are
able to have children must have a negative blood (about 1 teaspoon) pregnancy test.
Placement of central venous catheter for collection of "back-up" peripheral blood progenitor
cells (PBPC):
Before you have back-up PBPC 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 to a point above 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 this procedure.
Collection of back-up stem cells:
Because collecting additional cells from the donor of the cord blood is not possible if the
transplant with cord blood fails, a back-up PBPC or bone marrow sample to ensure recovery of
your marrow function will be collected from you and frozen before the high dose chemotherapy
begins. This specimen will only be used if doctors think it is necessary.
Peripheral blood progenitor cell collection (Leukapheresis):
Before collection of the PBPC, 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 PBPC will be collected from your
central catheter during a 3-4 hour outpatient procedure. This procedure is standard, and is
called leukapheresis. You will be required to sign a separate consent form for this
procedure.
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. Less than 5 percent of your bone marrow will be taken. This
procedure, if done, will also require you to sign a separate consent form.
Selection of alternate back-up donor:
If your own back-up bone marrow or back-up PBPC cannot be collected, the family member whose
bone marrow is collected for the marrow stromal cells will be asked to serve as a back-up
donor or an identified third cord blood unit may be used should both the cord blood units
fail to function. A back-up donor or product will be required for you to participate in this
research
Selection of family member as a stromal cell donor for cord cultures:
In this study, researchers will also collect about 7 tablespoons of bone marrow from one of
your family members whose tissue type (HLA antigens) does not exactly match yours. That bone
marrow will be taken to the laboratory where over 3-4 weeks, marrow stromal cells will be
grown. These marrow stromal cells produce vitamin-like growth factors that may help your
cord blood cells expand to greater numbers. If a family member is not appropriately HLA
matched, does not meet eligibility, is not a candidate due to health reasons, or if the
participant's disease is getting worse so that there is not enough time to grow the family
member's marrow cells into marrow stromal cells, then "off-the-shelf" marrow stromal cells
that have been collected from a healthy donor will be used for the procedure. These
"off-the-shelf" marrow stromal cells were grown and frozen by Angioblast Systems. These
cells have been safely given to patients with peripheral vascular disease, but their use in
this study is considered investigational.
Your bone marrow transplant doctors will assign you to one of two chemotherapy treatments,
which are discussed below (Treatment Groups 1 and 2).
High-dose chemotherapy treatment (Myeloablative)
Treatment Group 1:
If you are older than 1 and 55 years of age or less and can receive high-dose chemotherapy,
or you are between 55 and 65 years old and your doctor agrees, you will be in Treatment
Group 1: fludarabine-thiotepa-melphalan. 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, a protein which can kill lymphoid cells, 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.
Lower-dose chemotherapy treatment (Non-myeloablative)
Treatment Group 2:
If you are older than 55 and 80 years of age or less, or are of any age with a pre-existing
medical condition that prevents you from receiving Regimen 1. You will be in Treatment
Group 2: fludarabine- cyclophosphamide-total body irradiation. You will receive
cyclophosphamide as a single dose on Day -6. Fludarabine will be given once a day for 4
days in a row (Days -6 through -3). You will also receive a single treatment of low-dose
total body irradiation on Day -1. Rituximab may be given on Day -9 if appropriate for your
disease.
For each of the treatment groups, all chemotherapy drugs, fluids, and other medications that
must be given by vein will be infused through the catheter. Once the back-up cells are
collected, all participants will be admitted to the hospital as indicated by their assigned
treatment plan schedule. Chemotherapy may be stopped if intolerable side effects occur.
All participants will receive antithymocyte globulin (ATG) on the last 2 days of
chemotherapy (Days -4 and -3), to decrease the chances of the cord blood graft being
rejected (not working).
Expansion of cord blood:
On Day -14, one of your two cord blood units will be thawed in the M. D. Anderson Stem Cell
Laboratory and expanded over a layer of marrow stromal cells from your family member or from
"off-the-shelf" marrow stromal cells. The expansion will continue for about 2 weeks and when
complete, the cells will be given to you on Day 0 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:
Two (2) days after completion of high or lower-dose therapy (Day 0), both units of cord
blood (the expanded and the unexpanded cord) will be infused into you (one at a time)
through your catheter. The unexpanded cord will be thawed and infused first, followed by the
infusion of the cells that were expanded in the lab. Each unit will take about 30 minutes to
infuse. You will then be hospitalized until your marrow function is restored enough. This
usually takes between 3-6 weeks. During this time, you will receive a variety of
medications, transfusions, and other standard procedures aimed at decreasing the risks of
this procedure, such as graft vs. host disease (GVHD).
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 2
drugs. Mycophenolate will be given through your catheter 2 times per day (morning and
evening) on Days -3 through Day 100. 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 once a day for 180 days (6 months). If GVHD is present, tacrolimus
may then be continued longer. The number of tacrolimus pills may vary according to the blood
levels of the drug, but usually are between 1-5 pills. Your dose of tacrolimus can be
gradually lowered around Day 180 if no GVHD is present. 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 other
standard treatments.
Follow-up after transplant:
After you leave the hospital, you will be seen regularly in the Department of Blood and
Marrow Transplantation at M. D. Anderson. The frequency of the visits may vary, but may be
as often as daily. Routine blood (1-2 tablespoons) and urine tests will be performed. The
frequency of blood tests may also vary, but may be performed daily. You will have bone
marrow samples collected before transplant and then as needed during the first 100 days
after transplant, every 3 months during the first year after transplant, and then once a
year while you are on study. After that, bone marrow samples will be collected once a year,
indefinitely. These samples are being collected to look for tumor (as a staging test) and to
look for chimerism (the percent of tumor cells detectable that can predict graft failure
and/or relapse). To collect a bone marrow sample, an area of the hip or chest bone is
numbed with anesthetic and a small amount of bone marrow is withdrawn through a large
needle.
Participants with lymphomas and Hodgkin's disease will need a computed tomography (CT) scan
of the chest, abdomen, and pelvis performed before transplant, then as needed during the
first 100 days after transplant, and then every 3 months for the first year after
transplant. After that, these scans will be done yearly. You will be on study for 1 year
but then will be followed yearly as is standard of care.
This is an investigational study. All treatment drugs given to you are FDA approved and
commercially available. The CliniMACS device is not FDA approved. At this time, it is being
used in research only. A total of 100 patients may take part in this study. All will be
enrolled at M. D. Anderson. |
| Criteria: |
|
Inclusion Criteria:
1. Acute Myelogenous Leukemia (AML), Myelodysplastic Syndrome (MDS): induction failure,
high-risk for relapse first remission (with high-risk cytogenetics, flt3 mutation
positive and/or evidence of minimal residual disease by flow cytometry), secondary
leukemia from prior chemotherapy and/or arising from MDS, Langerhan's cell
histiocytosis, second or third complete remission, or second relapse.
2. Acute Lymphoblastic Leukemia (ALL): induction failure, first complete remission with
Philadelphia chromosome or translocation (4;11), hypodiploidy, and/or evidence of
minimal residual disease by flow cytometry;second third complete remission, or second
relapse.
3. CML second chronic phase or accelerated phase.
4. Non-Hodgkin's Lymphoma (NHL): Induction failures, second or third complete remission,
or relapse (including relapse post autologous)
5. Hodgkin's Disease (HD): Induction failures, second or third complete remission,or
relapse (including relapse post autologous hematopoietic stem cell transplant).
6. Chronic Lymphocytic Leukemia (CLL): Progressive disease following standard therapy
7. Multiple Myeloma: stage II or III , symptomatic , secretory Multiple Myeloma
requiring treatment.
8. Age greater than or equal to 1 year but less than or equal to 55 years (Myeloablative
Regimen 1). Eligibility for pediatric patients will be determined in conjunction with
an MDACC pediatrician. Patients >55 but < 65 years who have a Performance Status of 0
or 1 and no comorbidities may receive the myeloablative regimen 1 at the discretion
of the investigator(s).
9. Age greater than 55 years and less than or equal to 80 years (Nonmyeloablative
Regimen 2)
10. Age greater than or equal to 1 but less than or equal to 80 years old that in the
opinion of the investigator(s) would preclude myeloablative therapy and who cannot
receive Total Body Irradiation (TBI) may receive reduced intensity regimen 3.
11. Performance score of at least 60% by Karnofsky or PS less than 3 (ECOG) (age greater
than or equal to 12 years), or Lansky Play-Performance Scale of at least 60% or
greater (age <12 years)
12. Left ventricular ejection fraction of at least 40% (Myeloablative Regimen 1, Reduced
Intensity Regimen 3) or 30% (Nonmyeloablative Regimen 2)
13. Pulmonary function test demonstrating a diffusion capacity of least 50% predicted
(Myeloablative Regimen 1, Reduced Intensity Regimen 3) or at least 40% predicted
(Nonmyeloablative Regimen 2). For children < 7 years of age who are unable to perform
PFT, oxygen saturation > 92% on room air by pulse oximetry.
14. Creatinine < 1.6 mg/dL (Myeloablative Regimen 1, Reduced Intensity Regimen 3) or <
3.0 mg/dL (Nonmyeloablative Regimen 2).
15. SGPT/bilirubin < / = to 2.0 x normal (Myeloablative Regimen 1, Reduced Intensity
Regimen 3) or < / = 4.0 x normal (Nonmyeloablative Regimen 2)
16. Negative Beta HCG test in a woman with child bearing potential defined as not
post-menopausal for 12 months or no previous surgical sterilization and willing to
use an effective contraceptive measure while on study.
17. Unrelated Cord Blood will be used as a source of hematopoietic support if a 5 or 6/6
related or 6/6 unrelated bone marrow donor is not available, or if the tempo of a
patient's disease dictates it is not in the patient's best interest to wait for an
unrelated marrow donor to be procured.
18. Patients must have two Cord Blood units available which are matched with the patient
at 4, 5, or 6/6 HLA class I (serological) and II (molecular) antigens. Each cord must
contain at least 10 million total nucleated cells/Kg recipient body weight (pre-thaw)
19. Patients must have a family member who is matched at 2, 3, or 4 HLA antigens typed as
described above and willing to donate 80-100 ml or bone marrow for MSC generation or
the Angioblast Mesenchymal Precursor Cells will be used for the cord blood
co-cultures. Patients that are high risk for relapse are eligible to use the
Angioblast "off-the-shelf" Mesenchymal Precursor Cells.
20. Patient must be willing to undergo bone marrow harvest or peripheral blood progenitor
cells collection for use in case of engraftment failure.
21. If the patient is unable / fails to successfully undergo autologous bone marrow
harvest or peripheral blood progenitor cells collection a family member must be
identified who agrees to donate bone marrow or peripheral blood progenitor cells for
T-depleted transplant. A third cord blood unit could be used in case of engraftment
failure. This cord blood unit must be identified prior to enrollment in this study.
22. If the family member is to be used as the donor, he/she must freely document his /
her willingness to comply with this donation by signing a donor informed consent form
prior to preparative regimen for transplantation. This donor could be the same person
who donates the bone marrow aspirate for mesenchymal stem cell generation
Exclusion Criteria:
1. HIV positive
2. Positive Pregnancy Test
3. Uncontrolled serious medical condition such as persistent septicemia despite adequate
antibiotic therapy, decompensated congestive heart failure despite cardiac
medications or pulmonary insufficiency requiring intubation. (excluding primary
disease for which CB transplantation is proposed), or psychiatric condition that
would limit informed consent.
4. Patients with active (untreated) CNS disease
5. Availability of appropriate, willing, HLA-matched related marrow donor. |