Allogeneic Stem Cell Transplant for Patients With Severe Aplastic Anemia

Phase 2

Terminated

• Conditions: Aplastic Anemia
• Interventions: Drug: Cytoxan; Drug: Campath; Radiation: Total Body Irradiation (TBI); Drug: FK-506; Drug: Methotrexate; Procedure: Stem cell infusion

• Registration Number: NCT00578903
• Lead Sponsor: Baylor College of Medicine

Brief Summary

Patients have been diagnosed with severe Aplastic Anemia that have not responded to treatment with immunosuppressive therapy (drugs that suppress the immune system, for example Steroids). The immune system is the system in the body that helps protect the body and fights bacterial, viral and fungal infections.

Research studies have shown that patients with Aplastic Anemia have improved survival (may live longer) after receiving a HLA (Human Leukocyte Antigen) identical sibling (brother and sister) stem cell transplants. Patients who do not have matched siblings can undergo immunosuppressive therapy, which has also shown to improve outcome. Unfortunately patients who do not respond to immunosuppressive therapy usually die. The best chance of survival for these patients is an HLA matched unrelated or mismatched related stem cell transplant as described below.

Stem cells are created in the bone marrow. They mature into different types of blood cells that people need including red blood cells which carry oxygen around the body, white blood cells which help fight infections, and platelets which help the blood to clot and prevent bleeding. For a matched unrelated stem cell transplant, stem cells are collected from a person (donor) who is not related to the patient but who has the same type of stem cells. For a mismatched related stem cell transplant, stem cells are collected from a donor who is related to the patient and whose stem cells are almost the same as those of the patient but not exactly. The patient then receives high dose chemotherapy. This chemotherapy kills the stem cells in the patient's bone marrow. Stem cells that have been collected from the donor are then given to the patient to replace the stem cells that have been killed.

The major problems associated with these types of stem cell transplants are graft rejection (where the patient's immune system rejects the donor stem cells) and severe graft versus host disease (GVHD), where the donors stem cell reacts against the patient's tissues in the body.

Detailed Description

Before patients receive any treatments, they will have the following:

* Complete history and physical exam

* Dental consultation

* Bone marrow aspirate

* Blood tests

* Urinanalysis

* Tests to look at your lungs (Chest X-ray and PFT's and DLCO)

* Tests to look at your heart (EKG, MUGA, or echocardiogram)

* Pregnancy test for females of childbearing age.

Once the decision has been made by the patients to have a mismatched related or matched unrelated stem cell transplant, the patient will receive treatment called a "conditioning regimen" to prepare their body for the transplant. The purpose of this conditioning regimen is to kill the stem cells in the bone marrow, so that the patients immune system is suppressed (lowered or stopped from working), so their body will not reject the donors stem cells (transplant).

The medicines which will be given as part of the conditioning regimen include Cyclophosphamide (Cytoxan) and Campath 1H. Both of these medications are approved by the Food and Drug Administration. Cyclophosphamide will be given for four days in a row. Cyclophosphamide is broken down into different chemicals and removed from the body in the urine. These different chemicals can cause bleeding in the bladder. Mesna is a drug that will be given with Cytoxan to prevent the build up of these chemicals that cause bleeding from the bladder. Campath 1H will also be given for four days. After the medicines, the patient will receive total body irradiation (TBI). Total body irradiation is strong doses of radiation (like x-rays) given to almost the whole body. One dose of TBI will be given to patients receiving a matched stem cell infusion while two doses of TBI will be given to patients receiving a mismatch stem cell infusion. After the conditioning regimen, the patient will then receive the stem cells (transplant). These stem cells will be given as an infusion (drip) into a vein.

Patients will receive the drugs Tacrolimus (FK506) and Methotrexate to help prevent the complication of graft versus host disease. Methotrexate will be given on days 1, 3, 6 and 11 after they receive the stem cells. During this time, the patient will be on the stem cell transplant unit in protective isolation to help protect from developing infections.

The following evaluations will be done as part of the stem cell transplant.

EVALUATION DURING THE FIRST 100 DAYS:

* Physical examination daily until discharged, then weekly.

* Peripheral Blood for chimerism studies (looks at the presence of cells from the donor and from the patient existing together after the transplant)

* Complete blood count (CBC) and platelets daily until discharge, then at least weekly

* Blood chemistry (Electrolytes, BUN, creatinine, glucose, calcium, uric acid, total protein, albumin, ALT, AST, LDH, total bilirubin, LDH, magnesium) checked daily until discharge, then at least weekly

* FK506 blood levels twice a week until discharge, then at least weekly

* Blood tests for CMV (a type of virus) weekly

DAY 100-365:

* Physical examination at least monthly through Day 365

* Peripheral blood for chimerism studies

* Follow-up for patients with chronic GVHD as needed

* Chest X-ray

* CBC and Blood chemistry tests as above checked monthly

YEARLY EVALUATION:

* Biopsies as needed (taking tissue samples for testing)

* Chest x-ray

* CBC and Blood chemistry evaluations as listed above

* Peripheral blood for chimerism studies

IMMUNOLOGIC TESTING:

We will also be looking at the patients immune function. To do this, we will take 30 ml (2 tablespoonfuls) of blood every two weeks for two months, then monthly for 6 months, and then every 3 months for 2 years. When possible, the blood that is taken will be taken through an existing IV line. However, at times drawing the blood will require another stick with a needle. These blood tests will be done for research purposes as part of this study. All other blood tests listed above are done as part of good clinical care for patients receiving a stem cell transplant.

Study Timeline

• Study Start: 2002-02
• Study First Submitted: 2007-12-19
• Study First Submitted QC: 2007-12-20
• Study First Posted: 2007-12-21
• Primary Completion: 2012-07
• Study Completion: 2012-07
• Results First Submitted: 2013-08-04
• Results First Submitted QC: 2013-08-04
• Results First Posted: 2013-10-11
• Status Verified: 2016-03
• Last Update Submitted: 2016-03-24
• Last Update Posted: 2016-04-22

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 22

Inclusion Criteria

1. Diagnosis of Severe Aplastic Anemia (SAA) based on bone marrow aspirate and biopsy results.
2. Failure to respond to immunosuppressive therapy.
3. Lack of an Human Leukocyte Antigen (HLA) identical family member.
4. A 6/6 or 5/6 HLA matched unrelated donor or a 5/6 matched related donor available after high resolution HLA typing.
5. Age from birth to 60 years.

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Exclusion Criteria

1. Severe disease other than aplastic anemia that would limit the probability of survival during the graft procedure. Patients who present with active infection must be treated to maximally resolve this problem before beginning the conditioning regimen.
2. Human immunodeficiency virus (HIV) seropositive patients
3. Patients who have clonal cytogenetic abnormalities or a myelodysplastic syndrome.
4. Patient greater than 60 years of age.
5. Women who are pregnant or nursing.
6. Patients with active hepatitis
7. Patients with severe cardiac dysfunction defined as shortening fraction < 25%.
8. Patients with severe renal dysfunction defined as creatinine clearance < 40 ml/mim/1.73m2.
9. Patient with severe pulmonary dysfunction with forced expiratory volume in the first second (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) 40% of predicted or 3 standard deviations (SD) below normal.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Patients	Stem cell infusion	Patients with a diagnosis of severe aplastic anemia who require an allogeneic stem cell transplant but lack an Human Leukocyte Antigen (HLA) identical family member. Cytoxan, Campath, TBI-Total Body Irradiation, FK-506, Methotrexate, Stem Cell Infusion
Patients	Total Body Irradiation (TBI)	Patients with a diagnosis of severe aplastic anemia who require an allogeneic stem cell transplant but lack an Human Leukocyte Antigen (HLA) identical family member. Cytoxan, Campath, TBI-Total Body Irradiation, FK-506, Methotrexate, Stem Cell Infusion
Patients	Cytoxan	Patients with a diagnosis of severe aplastic anemia who require an allogeneic stem cell transplant but lack an Human Leukocyte Antigen (HLA) identical family member. Cytoxan, Campath, TBI-Total Body Irradiation, FK-506, Methotrexate, Stem Cell Infusion
Patients	Campath	Patients with a diagnosis of severe aplastic anemia who require an allogeneic stem cell transplant but lack an Human Leukocyte Antigen (HLA) identical family member. Cytoxan, Campath, TBI-Total Body Irradiation, FK-506, Methotrexate, Stem Cell Infusion
Patients	FK-506	Patients with a diagnosis of severe aplastic anemia who require an allogeneic stem cell transplant but lack an Human Leukocyte Antigen (HLA) identical family member. Cytoxan, Campath, TBI-Total Body Irradiation, FK-506, Methotrexate, Stem Cell Infusion
Patients	Methotrexate	Patients with a diagnosis of severe aplastic anemia who require an allogeneic stem cell transplant but lack an Human Leukocyte Antigen (HLA) identical family member. Cytoxan, Campath, TBI-Total Body Irradiation, FK-506, Methotrexate, Stem Cell Infusion

Primary Outcome Measures

Name	Time	Method
Number of Subjects Alive at 100 Days Post Transplant	100 days

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Engraftment Rate at 100 Days Post Transplant	100 days post transplant	Absolute neutrophil count greater than 0.5 X 10\^9/ml for at least 3 days
Number of Patients With Acute GVHD at 100 Days Post Transplant	100 days
Number of Patients With Chronic GVHD at 2 Years Post Transplant	2 years
Number of Subjects Alive at 1 Year Post Transplant	1 year
Number of Subjects Alive at 2 Years Post Transplant	2 years

Trial Locations

Locations (2)

The Methodist Hospital; 🇺🇸 Houston, Texas, United States

Texas Children's Hospital; 🇺🇸 Houston, Texas, United States