Stem Cell Transplant Using Peripheral and Cord Blood Stem Cells to Treat Severe Aplastic Anemia and Myelopdysplastic Syndrome - Full Text View

Sponsored by:	National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00604201

Purpose

This study will evaluate the safety and effectiveness of treating patients with severe aplastic anemia (SAA) or myelopdysplastic syndrome (MDS) with both peripheral blood stem cells from a family member and umbilical cord blood stem cells from an unrelated donor.

Patients with SAA or MDS for whom other treatments have failed or are not available may be eligible for this study. Candidates may not have a tissue-matched sibling or matched unrelated donor and must have a family member who is a partial tissue type match.

Participants undergo the following tests and procedures:

Insertion of a central intravenous (IV) line (plastic tube) into a large vein. The tube is used for giving the donated stem cells and antibiotics and other medicines, for transfusions of red blood cells and platelets, and for collecting blood samples.
Preparatory chemotherapy (fludarabine, cyclophosphamide and anti-thymocyte globulin) and total body irradiation to suppress immunity and prevent rejection of the donated cells.
Infusion of the donated stem cells and umbilical cord cells.
Immune suppression with the drugs tacrolimus, mycophenolate mofetil and prednisone to prevent rejection of the donated cells and to prevent graft-versus-host disease (GVHD), a complication of stem cell transplants in which the donor's immune cells destroy the patient's healthy tissues.

The average hospital stay after stem cell transplantation is 3 to 4 weeks. Patients return for frequent follow-up visits for the first 2 to 4 months after transplantation. Once the patient returns home, his or her referring physician is asked to send results of any laboratory testing to the NIH researchers at least every 3 months for the first 3 years and annually thereafter. Patient follow-up visits are scheduled at NIH at 1, 2, 3, 4 and 5 years after transplantation to monitor for signs of disease or post-transplantation complications, such as infection or GVHD. After 5 years, participants are offered the opportunity to enroll in NHLBI's long-term evaluation and follow-up care protocol....

Condition	Intervention	Phase
Myelodysplastic Syndrome (MDS) Severe Aplastic Anemia (SAA)	Other: Umbilical Cord Blood Other: Haploidentical Stem Cells Device: Miltenvi CliniMACs CD34 Reagent System	Phase II

MedlinePlus related topics: Anemia

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study
Official Title:	Co-Infusion of Umbilical Cord Blood and Haploidentical CD34+ Cells Following Nonmyeloablative Conditioning as Treatment for Severe Aplastic Anemia and MDS Associated With Severe Neutropenia Refractory to Immunosuppressive Therapy

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

Day 42 cord engraftment [ Time Frame: Day 42 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

200 day treatment related mortality (TRM) and standard transplant outcome variables (non-hematological toxicities, incidence and severity of acute and chronic GVHD, and relapse of disease) [ Time Frame: Day 200 ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	40
Study Start Date:	January 2008

Intervention Details:

N/A

Detailed Description:

Severe aplastic anemia (SAA) and MDS are life-threatening bone marrow disorders. For SAA patients, long term survival can be achieved with immunosuppressive treatment. However, of those patients treated with immunosuppressive therapy, one quarter to one third will not respond, and about 50 percent of responders will relapse.

Allogeneic bone marrow transplantation from either HLA-matched sibling or matched unrelated donor cures about 70 percent of patients with SAA and 30-60 percent of patients with MDS. Unfortunately, most patients with these disorders are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible donor. For such patients, transplantation using unrelated cord blood (UCB) has been shown to be a reasonable alternative transplant strategy. The advantage to UCB transplant is the ease and rapidity of availability, requirement of less than perfect HLA match, and lower rates of graft versus host disease compared to mismatched bone marrow or peripheral blood stem cell transplants. The major disadvantage of UCB transplantation in adults is the limited number of nucleated cells contained within the cord unit resulting in prolonged neutropenia and failure of engraftment which contributes to infection and TRM. In order to harness the advantage of UCB availability and to overcome the disadvantage of delayed neutrophil recovery, we propose to test whether co-administration of unrelated umbilical cord blood and a relatively low number of highly purified haploidentical peripheral blood CD34+ cells from a related donor might promote rapid engraftment and reduce TRM secondary to prolonged neutropenia associated with conventional UCBT.

This research protocol is therefore designed to evaluate the safety and effectiveness of co-infusion of unrelated umbilical cord blood and haploidentical CD34 plus cells from a related donor following nonmyeloablative conditioning for neutropenic patients with SAA or MDS (RA) that has proven to be refractory to immunosuppressive therapy. Subjects will receive a novel non-myeloablative immunosuppressive conditioning regimen of cyclophosphamide, fludarabine, horse ATG and one dose of total body irradiation (200cGy) followed by an infusion of the allografts. The haploidentical stem cell product will be T-cell depleted and enriched for CD34 plus cells using the Miltenyi CliniMacs system. To reduce TRM secondary to prolonged neutropenia associated with conventional UCB transplantation, haploidentical CD34+ stem cells will be co-infused with a single UCB unit (serologically matched at greater than or equal to 4/6 HLA loci).

The primary endpoint will be cord engraftment (persistent cord derived ANC greater than or equal to 500 cells/ul) by day 42. Secondary endpoints will include standard transplant outcome variables such as non-hematological toxicities, incidence and severity of acute and chronic GVHD, and relapse of disease. We will also evaluate ANC recovery (ANC greater than 500 cells/ul) at day 22 and 200 day treatment related mortality (TRM) of this novel transplant approach.

Eligibility

Ages Eligible for Study:	8 Years to 55 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

INCLUSION CRITERIA - RECIPIENT:
Diagnosed with severe aplastic anemia characterized by all of the following:
1. Bone marrow cellularity less than 30% (excluding lymphocytes)
2. Transfusion dependence for platelets and/or RBCs
3. Neutropenia (absolute neutrophil count less than 500 cells/ uL)

OR

Diagnosed with myelodysplastic syndrome characterized by:
1. Refractory Anemia (RA) OR (Refractory anemia with ringed sideroblasts (RARS)
2. Neutropenia (absolute neutrophil count less than 500 cells/ uL)
3. History of 1 or more opportunistic infections related to neutropenia
Intolerance of or failure to respond after at least 6 months standard immunosuppressive therapy.
Availability of at least one HLA-haploidentical related family member donor (2-75 years old)
Availability of at least one 4/6 HLA-matched (HLA-A, B, and DR loci) cord blood unit from the NMDP. The cord blood unit must contain a minimum TNC (prior to thawing) of at least 1.5 x 10(7) cells per kilogram of recipient body weight with the following exception: if the minimum criterion of TNC is not met the cord unit must contain at least 1.7 x 10(5) CD34 plus cells/kg (prior to thawing).
Ages 8-55 years inclusive
Ability to comprehend the investigational nature of the study and provide informed consent. The procedure will be explained to patients aged 8-17 years with formal consent being obtained from parents or legal guardian.

EXCLUSION CRITERIA - RECIPIENT:

Availability of an HLA identical or 5/6 HLA matched-relative to serve as a stem cell donor
The patient is deemed to be a candidate for a 6/6 HLA matched unrelated stem cell transplant (availability of a donor and resources required for such a transplant).
ECOG performance status of 2 or more
Major anticipated illness or organ failure incompatible with survival from transplant
Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance with the transplant treatment unlikely and making informed consent impossible.
Positive pregnancy test for women of childbearing age.
HIV positive
Diagnosis of Fanconi's anemia or dyskeratosis congenita.
Diffusion capacity of carbon monoxide (DLCO) less than 40 percent predicted
Left ventricular ejection fraction less than 40 percent (evaluated by ECHO) or less than 30 percent (evaluated by MUGA)
Transaminases greater than 5x upper limit of normal (when transaminases are elevated, the patient may be excluded at the discretion of the PI)
Serum bilirubin greater than 4 mg/dl
Creatinine clearance less than 50 cc/min by 24 hr urine collection (adjusted for body surface area, i.e.50 ml/min/1.73m(2))
Failure to collect an adequate number of CD34+ cells (i.e. greater than or equal 2 x 10(6) CD34+ cells/kg) for transplantation from the patient's haploidentical relative
Presence of an active infection not adequately responding to appropriate therapy
History of a malignant diseases liable to relapse or progress within 5 years

INCLUSION CRITERIA - RELATED DONOR DONATING PURIFIED CD34 PLUS CELLS:

HLA haploidentical (i.e. greater than 3/6 HLA match) family donor available to donate CD34+ cells
Ages 7-75 inclusive
Weight greater than or equal to 18 kg
For adults: Ability to comprehend the investigational nature of the study and provide informed consent. For minors: Written informed consent from one parent or guardian who is not the recipient of the transplant and informed assent: The process will be explained to the minor on a level of complexity appropriate for their age and ability to comprehend.

EXCLUSION CRITERIA - RELATED DONOR (ANY OF THE FOLLOWING):

Pregnant or lactating
A pediatric haplo-identical donor will be excluded if a suitable adult haplo-identical donor is available.
Unfit to receive filgrastim (G-CSF) and undergo apheresis (history of stroke, MI, unstable angina, uncontrolled hypertension, severe heart disease or palpable spleen)
HIV positive (Donors who are positive for HBV, HCV or HTLV I/II may be used at the discretion of the investigator following counseling and approval from the recipient)
Sickling hemoglobinopathies including HbSS, HbAS, HbSC
Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance with the BMT treatment unlikely and making informed consent impossible.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00604201

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike	Recruiting
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

More Information

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood. 1995 Jun 15;85(12):3367-77. Review. No abstract available.

Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. Review. No abstract available.

Zoumbos NC, Gascon P, Djeu JY, Trost SR, Young NS. Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med. 1985 Jan 31;312(5):257-65.

Responsible Party:	National Institutes of Health ( Richard W. Childs, M.D./National Heart, Lung, and Blood Institute )
Study ID Numbers:	080046, 08-H-0046
Study First Received:	January 8, 2008
Last Updated:	December 6, 2008
ClinicalTrials.gov Identifier:	NCT00604201
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Myelodyplastic Syndrome (MDS)
Severe Aplastic Anemia
Stem Cell Transplant
Haploidentical Stem Cells

Umbilical Cord Blood
Severe Aplastic Anemia
Myelodysplastic Syndrome
MDS

Study placed in the following topic categories:

Myelodysplastic syndromes
Neutropenia
Preleukemia
Precancerous Conditions
Hematologic Diseases
Myelodysplasia

Myelodysplastic Syndromes
Anemia, Aplastic
Anemia
Aplastic anemia
Bone Marrow Diseases

Additional relevant MeSH terms:

Neoplasms
Pathologic Processes
Disease
Syndrome

ClinicalTrials.gov processed this record on January 14, 2009