Haploidentical Transplantation in Patients With Acute Leukemia and Myelodysplasia

Leukemia Clinical Trial

Official title:

Delayed Infusion of Ex Vivo Anergized Peripheral Blood Mononuclear Cells Following CD34 Selected Peripheral Blood Stem Cell Transplant From A Haploidentical Donor For Patients With Acute Leukemia and Myelodysplasia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00475384
• Other study ID #: 2005-0695
• Secondary ID: NCINCI-2010-0092
• Status: Completed
• Phase: Phase 1
• First received: May 16, 2007
• Last updated: November 7, 2014
• Start date: June 2006
• Est. completion date: August 2013

Study information

• Verified date: November 2014
• Source: M.D. Anderson Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Objectives:

Primary:

1. To establish the feasibility of delayed infusion of ex vivo anergized donor peripheral blood mononuclear cells (PBMC) after CD34 selected megadose haploidentical hematopoietic stem cell transplant (HSCT) Determine the feasibility of collecting parental allogeneic stimulator cells to induce anergy to the non-shared donor:recipient haplotype Determine the feasibility of collecting donor PBMC as a source of T cells for ex vivo anergization Determine the number of transplanted individuals who meet the criteria for proceeding to delayed infusion of ex vivo anergized donor PBMC

2. To establish the safety of delayed infusion of ex vivo anergized donor PBMC by establishing the maximal number of donor T cells that can be infused without unacceptable graft-versus-host disease (GVHD)

Secondary:

1. To evaluate in vitro the induction and specificity of alloantigen hyporesponsiveness in donor PBMC after ex vivo anergization

2. To assess in vitro the function of immune cells engrafted in the recipient To assess in vitro whether alloantigen hyporesponsive donor T cells are present in the recipient after HSCT To develop preliminary in vitro data on the extent of pathogen-specific immunity and its rate of recovery To describe the patterns of opportunistic infections in patients so treated

Description:

Patients:

The major risk with using a stem cell donor who is not a perfect match for HLA antigens is severe graft versus host disease (GVHD). GVHD is a condition that happens when the donor's T-cells, immune system cells that are found in the transplanted stem cells, react against cells of the patient receiving the transplant. This can cause serious and possibly life-threatening side effects. Severe GVHD can also continue for a long time. This is called "chronic GVHD." Chronic GVHD can result in skin, liver, and intestinal problems, as well as other health-threatening complications.

In order to lower the risk of GVHD, the number of T-cells in the donated stem cells can be lowered. T-cells are an important part of your immune system that can fight infections and cancer cells. While lowering the number of T-cells has helped in lowering the chance of GVHD from transplanting stem cells that do not match perfectly, it takes a long time to build up the number of T-cells in your body again.

Researchers want to find out if treating the donated stem cells with anti-B7 antibodies, before they are transplanted, can help lower the chance of GVHD and still help speed up the process of building up your T-cells again. Anti-B7 antibodies are proteins that attach to immune system cells and interfere with the immune response. This may help to keep the transplanted T-cells from attacking the cells in your body.

Small groups of people will be enrolled in steps in this trial. The first group (up to 8 participants) will be given a certain number of anti-B7 antibody treated donor immune cells. If they have few or manageable side effects, the next small group of people enrolled will receive a higher number of donor immune cells. This increase in numbers with groups of people will continue until the study doctors find the highest number of anti-B7 antibody treated donor immune cells that can be given without causing severe or unmanageable side effects.

The initial group of patients (3 to 5 patients) that enter this study will receive a very small number of donor immune cells. This phase of the study will help the cell processing laboratory determine if the techniques and procedures are working correctly before proceeding to higher doses of immune cells for the next patients that will participate in the study.

You will have a central venous catheter (CVC) inserted, so that daily blood draws and daily medicine and fluids can be given without extra "needle sticks" or IV lines. The CVC is a needle and tube that is inserted into a vein in your chest or back, that stays in the whole time you are on treatment. You will be given a separate form that will explain this procedure. Your surgeon and anesthesiologist will review this with you.

Your stem cell donor will be asked to sign a consent form, so that the stem cells can be collected through a process called leukapheresis.

Once enough stem cells have been collected from your donor, you will begin treatment with total body irradiation (TBI), followed by chemotherapy. This treatment is generally referred to as either "conditioning" or "preparative" therapy. It is given in order to kill the leukemia cells, as well as your own stem cells, and your immune cells. The TBI will be given 2 times a day for 3 days, and will last 20-40 minutes each time. All of the chemotherapy will be given intravenously (IV--through a needle in your vein), usually through your CVC. You will receive the chemotherapy drug thiotepa once a day for 2 days, fludarabine once a day for 5 days, and anti-thymocyte globulin (ATG) once a day for 4 days. Methylprednisolone, a steroid drug, will be given with the ATG to lower the risk of any side effects.

After the radiation and chemotherapy treatments, you will receive the transplant of your donor's normal and T-cell depleted stem cells by IV or CVC. If some or all of the donor cells are not used during the transplant, the leftover cells will be stored. The leftover stored cells will be thrown away if your doctor decides you do not need them any more. After 10 years, the Cell Processing Laboratory at M. D. Anderson will throw away any remaining stored cells.

The stem cell transplant will have 2 parts: the first infusion of normal donor stem cells, and then an infusion of stem cells treated with the anti-B7 antibodies.

In order to perform the treatment with anti-B7 antibodies, T-cells must be collected from the blood of both the same person who donated the stem cells and either you or a family member who shares some of your genetic tissue typing. If the cells come from your family member, they will be collected 32 days after the transplant. If you are donating your own cells for this purpose, they will be collected before the conditioning treatment starts, and then the cells will be frozen, stored, and then thawed on Day 32 after transplant.

The donor immune cells and the cells from yourself or a family member who shares some of your tissue typing will be taken to the laboratory where they will be mixed with anti-B7 antibodies on Day 32. The mixture will be kept in the laboratory for 3 days. Adding the anti-B7 antibodies to this mixture of stem cells will keep certain interactions between the two cell types from happening. Researchers believe this will "teach" the donor's immune cells what kinds of cells to leave alone when those donor cells are put back into your body. The anti-B7 antibodies will then be rinsed away from the mixture, and the cells will be given to you by IV infusion on Day 35 after transplant. If the infusion needs to be put off based on your medical condition, the cells will be collected on Day 39 and given on Day 42.

Throughout your stay in the hospital, which should be about 4-6 weeks, blood tests (about 4 teaspoons) and physical exams will often be performed. Depending on your clinical condition, other tests, including radiologic scans and/or biopsies, may also be needed. These will be discussed with you as needed.

After you are sent home from the hospital, you will be asked to come back to the clinic several times. The frequency of visits will be determined in part by your clinical condition. You may need to come as often as every day for about 3 months. At these visits, a physical exam, blood tests (about 2 teaspoons), and a check-up for GVHD will be done. Most of these tests will be related to your regular medical care, but some blood tests will be related to the study only. Whenever possible, the study blood tests will be collected at the same time as the blood being drawn for routine tests. Your size and your blood counts will help the study staff decide the correct amount of blood to draw (no more than 6 teaspoons each time). These samples will be frozen and stored until they are used for study tests.

You will be in the study for about 1 year. This time includes the screening visit, treatment before the transplant, and follow-up visits after the transplant. After you are able to return to your own home and own physicians, the study staff will contact you every 3 months until 2 years after the transplant, to see how you are doing. You will be asked to return to the program at about 6 months, 1 year, and 2 years after the transplant.

At these follow up visits, the study staff will collect information about you from doctors' notes and medical records. This information will include any transplant side effects, treatments, and information obtained from procedures, including lab tests, scans, and biopsies. The study staff will collect your health information until the end of the research. They may collect some follow-up information, such as your disease status, and treatments that you receive, from your medical record even after your direct participation in the research study ends.

This is an investigational study. The treatment in this study is authorized for use in research only. Up to 40 patients will take part in this multicenter study. About 20 will be enrolled at M. D. Anderson.

Peripheral Blood Mononuclear Cell (PBMC) Collection from Family Donors:

Your family member will receive a stem cell transplant with a certain type of cells called lymphocytes removed. This is being done to help prevent graft-versus-host disease (GVHD) in the patient, but it may also lower the ability of the donated stem cells to fight infections.

The transplant treatment being used for your family member involves collecting stem cells from the peripheral blood of the person in your family who is acting as the stem cell donor. During the process of collecting these donor peripheral blood stem cells, large numbers of T lymphocytes (or "T-cells") are also collected. Because these donor T-cells can cause GVHD in the person receiving the transplant, the stem cells collected will be purified to lower the number of T-cells. This may lower the risk of GVHD. This procedure is called T-cell depletion.

The stem cells, minus the T-cells, will then be given to the patient. The side effect of removing these T cells, however, is that there may be a higher risk of infection. Researchers want to give the patient another infusion of extra blood cells containing T-cells, about 5 weeks after the transplant. Before giving them these cells, the study staff will add anti-B7 antibodies to them, to try to lower the chances that they will cause GVHD when they are given. To change the cells this way, researchers need blood cells from a family member, to mix with the donor's T-cells. You are being asked to provide these extra cells, to be mixed with the anti-B7 antibodies.

If you decide to take part as a blood donor, you will first have a physical exam and blood tests (less than 3 tablespoons) performed to make sure you are healthy enough to donate. These blood tests include routine tests, tests of kidney and liver function, and other tests, depending upon your health history. Women who are able to have children must have a negative blood pregnancy test before donating blood in this study.

Your blood sample will also be tested for the human immunodeficiency virus (HIV), the virus that causes AIDS. You have the right to know the results of this test, and you will be notified privately if your HIV test is positive. What that test result means to you will be explained by a member of the medical staff. If you are found to be HIV positive, you will not be eligible to be a donor, as it may not be safe for the patient.

You will also be tested for syphilis, hepatitis, and other viral diseases that could be passed on to the patient if you donate blood cells. You have the right to know the results of these tests. Any unusual test results will be discussed with you by a member of the medical staff.

If you are still able to take part in this study, the collection of circulating blood will happen on Day 32 (in some cases, Day 39) after the patient's stem cell transplant. The number of T-cells being given to your family member will be decided as he or she enters the study. If your family member is being given a small or moderate number of T-cells, the process of collecting blood immune cells from you will involve placement of an intravenous (IV) needle into a vein in your arm and drawing blood. The amount of blood may be as little as 2 tablespoons or as much as 7-12 tablespoons.

If your family member is receiving the largest possible number of T-cells, it is possible that researchers will need to use a pheresis machine to collect enough blood immune cells from you. Apheresis is a process used to collect blood cells and uses a technique very similar to a platelet collection. Apheresis requires having an IV needle placed in each arm before the procedure, or a central venous catheter (CVC) placed in a large vein by a surgeon. If a CVC is needed, you will be given a separate informed consent document, which will explain the procedure and its risks. The blood is drawn, processed in a machine that separates out the cells that are needed, and the remaining blood parts are returned to you through the second IV or the other port of the catheter. No medication is required before this collection, and the procedure would be done on a single day.

Your participation will start with your screening tests, before the patient's transplant. The blood cells will be collected on Day 32 (or 39) after the transplant. This will end your participation on the main part of this study. You can stop your participation at any time. Your doctor can also stop your participation in this study at any time, if it is in your best interest to do so.

This is an investigational study. The treatment in this study is authorized for use in research only. About 37 patients will take part in this study. About 20 will be enrolled at M. D. Anderson.

Stem Cell Mobilization and Collection from Family Donors:

This study will look at the use of mismatched, related donors as the source of stem cells and immune cells for transplantation for patients with acute leukemias or myelodysplastic syndrome. You are being asked to donate blood stem cells and immune cells (T-lymphocytes, also called T-cells).

The circulating blood contains stem cells that are the basis for both the blood and immune systems. Drugs can be used to increase the number of these stem cells in the blood to high enough numbers for transplantation. Stem cells will be taken from the circulating blood you donate, and then will be given to your family member. Your healthy stem cells will replace your family member's bone marrow to help fight his/her disease. During the process of blood stem cell collection, large numbers of T-cells are also collected. Sometimes these immune system cells will actually "attack" the person they're being given to. This is called "graft versus host disease" (GVHD). Your blood stem cells will be purified, so that the number of these T-cells are lowered. This will help lower the risk of GVHD. This is called "T-cell depletion."

The second part of this study involves more donated blood cells from you and another donor. Removing T-cells from the donated stem cells may raise the risk of the patient getting an infection. To prevent this, you will be asked to donate more blood for stem cells about a month after the first transplant. These stem cells will be mixed with T-cells from another donor that have been treated with anti-B7 antibodies. Researchers want to find out if this mixture will lower the risk of GVHD by "teaching" your T-cells not to attack the patient's cells.

If you agree to take part in this study, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will have a physical exam and blood tests (less than 3 tablespoons) to make sure you are healthy enough to donate. These blood tests will include routine tests, tests of your liver and kidney function, and possibly other tests, based upon your health history. Women who are able to have children must also have a negative blood pregnancy test before taking part in this study.

Your blood will be tested for the human immunodeficiency virus (HIV), the virus that causes AIDS. You have the right to know the results of this test, and you will be notified privately if your HIV test is positive. What that test result means to you will be explained by a member of the medical staff. If you are found to be HIV positive, you will not be eligible to be a donor as it may not be safe for the patient. You will also be tested for syphilis, hepatitis, and other viral diseases that could be passed on to the patient if you donate blood. You have the right to know the results of these tests. Any abnormal test results will be discussed with you by a member of the medical staff.

If you are still eligible to take part in this study, you will begin drug treatment before the stem cell collection. You will be asked to inject yourself each morning for 4-6 days with a drug called filgrastim (G-CSF, Neupogen). Filgrastim is a protein that causes bone marrow to make more stem cells. A nurse or other trained professional in the clinic will teach you how to inject the Filgrastim under your skin.

The first dose of filgrastim must be given in the clinic, so that the study staff can watch for any side effects. Blood samples (about 4 teaspoons) will be drawn on Day 4 of the filgrastim injections, to check your white blood cell count level. These blood tests will happen every day until the stem cell collections are done. Based on the results of these blood tests, your dose of filgrastim may be changed.

On Day 4 or 5 of your filgrastim treatments, your blood stem cell collection will start. Blood stem cells are collected using a process called apheresis. Apheresis uses a technique very similar to a platelet collection. Apheresis requires having an IV needle placed in each arm before the procedure, or a central venous catheter (CVC) placed in a large vein by a surgeon. If a CVC is needed, you will be given a separate informed consent document, which will explain the procedure and its risks. The blood is drawn, processed in a machine that separates out the cells that are needed, and the remaining blood parts are returned to you through the second IV or the other port of the catheter. The collection may take up to 4 days, though it usually takes 1-2 days to collect enough stem cells. If not enough cells can be collected in this time, the study staff will look for another donor.

Your T-cells will later be collected on Day 32 after the patient's stem cell transplant. Before you can donate T-cells, you will again go through the screening tests, and must not have any infections or medical conditions that would be a health risk to the person receiving your blood. About 2 tablespoons of blood will be drawn for these tests.

The number of T cells being given to your family member will be decided as they enter the study. If your family member is being given a small or moderate number of T-cells, the process of collecting blood immune cells from you will involve placement of an intravenous (IV) needle into a vein in your arm and drawing blood. The amount of blood may be as little as 4 tablespoons or as much as 7-12 tablespoons.

If your family member is receiving the largest possible number of T-cells, it is possible that researchers will need to perform apheresis on you again, to collect enough blood immune cells from you. However, you would not need to take any filgrastim or other drug before this collection, and the apheresis would be limited to a single day.

If the stem cells do not grow well in the patient, the doctors may ask you for more stem cells within the first months after the patient's treatment, in an effort to further improve the growth of the stem cells and better treat the patient's disease.

You can stop your participation at any time. Tell the study doctor if you are thinking about stopping or decide to stop. Your doctor can also stop your participation in this study at any time, if it is in your best interest to do so.

This is an investigational study. Filgrastim is an FDA approved drug. Apheresis is a standard procedure for some blood or platelet donors and stem cell donors. It is important that you tell your study doctor if you have been injured because of taking part in this study. About 37 patients will take part in this study. About 20 will be enrolled at M. D. Anderson.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: August 2013
• Est. primary completion date: August 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 50 Years

Eligibility

Inclusion Criteria:

1. Patients </= 50 years of age meeting standard performance and end-organ function criteria for stem cell transplantation.

2. Cardiac function: left ventricular ejection fraction > 45%

3. Renal function: Serum creatinine < 2x upper limit of normal for age or if serum creatinine elevated beyond normal, must have creatinine clearance or glomerular filtration rate > 50% lower limit of normal for age

4. Hepatic function: AST/ALT < 3x upper limit of normal for age and bilirubin < 2.0 mg/dl. These criteria do not apply if liver is involved with disease.

5. Pulmonary function: Patient must have room air O2 saturation >95% and no clinical evidence of pulmonary insufficiency unless the lungs are involved with disease.

6. Patients with acute myelogenous leukemia (AML): induction failure with < 3 induction courses, >/= second or greater complete remission (CR) (defined as <5% blasts in bone marrow and no active extramedullary disease) , CR1 with high risk features defined as history of induction failure, 5q- or monosomy 7 cytogenetic findings;

7. Patients wih acute lymphocytic leukemia (ALL): >/= second or greater CR (defined as <5% blasts in bone marrow and no active extramedullary disease), CR1 with high risk features defined as history of induction failure or Ph+ or t(4;11) on cytogenetic analysis or any infant with MLL rearrangements on cytogenetic analysis;

8. Patients with myelodysplastic syndrome (MDS): refractory anemia (RA) with excess blasts (EB) with intermediate (INT)-1, INT-2 or high International Prognosis Score System (IPSS) score, refractory anemia with excess blasts (RAEB) in transformation (iT) with INT-1, INT-2 or high IPSS score and patients with RA and INT-2 IPSS score

9. Patients lacking a suitably matched family donor defined by genotypic or phenotypic identity for >/= 5/6 A, B, DR loci

10. Patients lacking an immediately available genotypically matched (6/6) unrelated marrow donor or umbilical cord blood donor with suitable cell dose after a search of greater than or equal to 2 months OR patients whose medical condition is at high risk of deteriorating or whose disease is at high risk of progression during a donor search

11. Patients must have a healthy family member donor who must be at least genotypically HLA-A, B, C, DR haploidentical to the patient.

12. Donors must sign voluntary, written informed consent OR in the case of minor donors such consent must be signed by the parent or guardian and assent will be requested as age appropriate.

13. Donors must be capable of undergoing leukapheresis, have adequate venous access and be willing to undergo placement of a central venous catheter should leukapheresis via peripheral access be inadequate.

14. Note that satisfactory mobilization of donor peripheral blood stem cells (PBSC) to meet protocol criteria must take place prior to initiation of conditioning of the patient.

15. Donors must be informed that they would be requested to undergo a second donation of PBSC or a BM harvest should the patient fail to demonstrate sustained engraftment after HSCT

16. Donors must meet all the medical criteria for blood product donation, including negative test for HIV, freedom from other active infection, absence of medical condition posing a health risk to donation of PBSC or function of the graft.

17. To provide a source of peripheral blood mononuclear cells to serve as allosensitizers patients must EITHER: (a) have a parent disparate with the donor for the haplotype shared by the patient and parent but not shared by the patient and donor; OR (b) be able to donate sufficient autologous cells by peripheral blood draw or unstimulated leukapheresis

18. Female patients of child-bearing age must have a negative pregnancy test and be using an form of contraception considered effective and medically acceptable by the investigator.

19. Voluntary written informed consent. Children will be asked for assent wherever age appropriate.

Exclusion Criteria:

1. Active infection. Freedom from active infection is defined as: absence of an infectious diagnosis or (in patients who have had a recent positive infectious diagnosis) the resolution of fever, documentation of negative cultures or antigen testing, continuation or completion of a course of appropriate therapy, and presence of stable to resolving clinical symptoms.

2. Evidence of HIV infection or known HIV positive serology

3. Presence of active central nervous system (CNS) disease

4. ALL patients who relapse with isolated extramedullary disease after completion of treatment

5. Any prior stem cell transplant

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lymphocytic Leukemia
• Acute Myelogenous Leukemia
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia

Intervention

Drug:
• Fludarabine
40 mg/m^2 By Vein Over 30 Minutes x 5 Days
• Thiotepa
5 mg/kg By Vein Daily x 2 Days

Radiation:
• Total Body Irradiation
200 centigray (cGy) (BID) Twice Daily Over 20-40 Minutes x 3 Days

Drug:
• Melphalan
140 mg/m^2 by vein x 1 Day

Biological:
• Stem Cell Transplant (SCT)
Infusion of normal donor stem cells on Day 0

Procedure:
• Anergized Cell Infusion
Infusion of stem cells treated with the anti-B7 antibodies on Day 35+ or 42+.

Locations

Country	Name	City	State
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	University of Florida Shands Hospital	Gainesville	Florida
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Childrens Hospital Los Angeles	Los Angeles	California

Sponsors (2)

Lead Sponsor	Collaborator
M.D. Anderson Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility of delayed infusion of ex vivo anergized donor PBMC after CD34 selected megadose HSCT		Day 0 and Day +35 or 42+ (day of infusion of anergized cells)	Yes

External Links

•   University of Texas MD Anderson Cancer Center Website