| City: |
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Bethesda |
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State:
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MD |
| Zip Code: |
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20892 |
| Conditions: |
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Severe Aplastic Anemia - Myelodysplastic Syndromes |
| Purpose: |
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Background:
- Stem cell transplants from related donors (allogenic stem cell transplants) can be used
to treat individuals with certain kinds of severe blood diseases or cancers, such as
severe anemia. Allogenic stem cell transplants encourage the growth of new bone marrow
to replace that of the recipient. Because stem cell transplants can have serious
complications, researchers are interested in developing new approaches to stem cell
transplants that will reduce the likelihood of these complications.
- By reducing the number of white blood cells included in the blood taken during the stem
cell collection process, and replacing them with a smaller amount of white blood cells
collected prior to stem cell donation, the stem cell transplant may be less likely to
cause severe complications for the recipient. Researchers are investigating whether
altering the stem cell transplant donation procedure in this manner will improve the
likelihood of a successful stem cell transplant with fewer complications.
Objectives:
- To evaluate a new method of stem cell transplantation that may reduce the possibly of
severe side effects or transplant rejection in the recipient.
Eligibility:
- Recipient: Individuals between 8 and 80 years of age who have been diagnosed with a
blood disease that can be treated with allogenic stem cell transplants, and who have a
related donor to provide the stem cells.
- Donor: Individuals between 2 and 80 years of age who are related to the recipient and
are eligible to donate blood.
Design:
- All participants will be screened with a physical examination and medical history.
- DONORS:
- Donors will undergo an initial apheresis procedure to donate white blood cells.
- After the initial donation, donors will receive injections of filgrastim to release
bone marrow cells into the blood.
- After 5 days of filgrastim injections, donors will have apheresis again to donate stem
cells that are present in the blood.
- RECIPIENTS:
- Recipients will provide an initial donation of white blood cells to be used for
research purposes only.
- From 7 days before the stem cell transplant, participants will be admitted to the
inpatient unit of the National Institutes of Health Clinical Center and will receive
regular doses of cyclophosphamide, fludarabine, and anti-thymocyte globulin to suppress
their immune system and prepare for the transplant.
- After the initial chemotherapy, participants will receive t...
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| Study summary: |
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Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with a variety
of bone marrow failure syndromes (BMFS) including severe aplastic anemia (SAA), paroxysmal
nocturnal hematuria (PNH), and RA MDS associated with cytopenias. Patients with BMFS have
traditionally been transplanted with bone marrow (BM) as a stem cell source. Although
chronic graft versus host disease (cGVHD) occurs less commonly with BM compared to G-CSF
mobilized peripheral blood stem cell (PBSC) transplants, BM allografts have lower CD34+
progenitor cell numbers which increases the risk of graft rejection in heavily transfused
BMFS patients to 15-20 percent. To overcome this risk, our group developed a novel
transplant approach for patients at high risk for graft rejection that utilized
cyclophosphamide, fludarabine and ATG conditioning followed by infusion of a CD34+ cell
rich, T-cell replete G-CSF mobilized PBSC allograft. Remarkably, in 56 consecutive BMFS
patients who had multiple risk factors for graft rejection who underwent this transplant
approach graft rejection did not occur, with all patients achieving complete donor
lyphohematopoietic chimerism. Unfortunately, recipients of G-CSF mobilized PBSC had a higher
incidence of chronic GVHD than has historically been observed with BM transplantation (72
percent vs. 50 percent cumulative incidence of cGVHD at 1 respectively). G-CSF mobilized
PBSC transplants contained approximately a 20 fold higher dose of T-cells that had undergone
a TH- 2 type cytokine polarization, factors which likely contributed to this high incidence
of cGVHD.
In this protocol, we attempt to prevent graft failure and to reduce the incidence of cGVHD
by transplanting high numbers of CD34+ selected PBSC co-infused with a reduced dose of
non-mobilized donor T-cells that have not undergone a TH-2 cytokine polarization.
Patients with BMFS at high risk for graft rejection will undergo allogeneic stem cell
transplantation from an HLA identical sibling using the identical conditioning regimen
utilized in protocol 99-H-050. Using the Miltenyi ClinicMACs system, patients will receive
an allograft on day 0 containing donor CD34+ cells that have been positively selected and
T-cell depleted following G-CSF mobilization (goal CD34+ cell dose of 5 times 10(6) CD34+
cells /kg recipient) combined with 2 times 10(7) cells/kg of non-mobilized CD3+ T-cells
previously collected and cryopreserved from the same donor by apheresis prior to G-CSF
mobilization.
Primary objective: To evaluate whether administering a CD34+ selected, T-cell depleted
peripheral blood stem cell graft with a concomitant infusion of non-mobilized donor T-cells
at a dose that matches the T-cell dose that is infused in historical bone marrow transplant
cohorts will reduce the incidence of cGVHD at 1 year to that observed with a conventional
bone marrow transplant (50 percent) without increasing the risk of graft failure. This trial
design will allow the trial to stop early if it is unlikely that we have reduced the
proportion of one year cGVHD to 50 percent or if the combined event rate for failed donor
engraftment or TRM at day 100 exceeds 20 percent.
The primary endpoint of this study will be cGVHD at day 365.
Secondary end points include transplant related mortality, engraftment, degree of donor-host
chimerism, incidence of acute and chronic graft versus host disease (GVHD), transplant
related morbidity and overall survival. |
| Criteria: |
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- INCLUSION CRITERIA:
Recipient
Patients diagnosed with one of the following hematologic diseases which are associated
with reasonable longevity, shown to be curable by allogeneic BMT but where concern for a
high procedural mortality with conventional BMT may delay or prevent such treatment:
1. Paroxysmal nocturnal hemoglobinuria (PNH) associated with life-threatening
thrombosis, and/or cytopenia, and/or transfusion dependence and/or recurrent and
debilitating hemolytic crisis.
2. Aplastic anemia or pure red cell aplasia (acquired or congenital) associated with
transfusion dependence and/or neutropenia in patients who are not candidates for or
who have failed immunosuppressive therapy
3. Refractory anemia (RA) or RARS MDS patients who have associated transfusion
dependence and/or neutropenia.
Ages 8 to 80
Availability of HLA identical or single HLA locus mismatched family donor
Donor
HLA identical or single HLA mismatched family donor
Age greater than 2 up to 80 years old
Weight 19 kg or more
EXCLUSION CRITERIA:
Recipient: any of the following
Major anticipated illness or organ failure incompatible with survival from PBSC
transplant
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)
Serum creatinine greater than 2.5mg/dl or creatinine clearance less than 50 ml/min by
24 hr urine collection
Serum bilirubin greater than 4 mg/dl, transaminases greater than 5 times the upper
limit of normal
Pregnant or lactating
Fanconi's anemia
ECOG performance status of 3 or more
Other malignant diseases liable to relapse or progress within 5 years, with the
exception of a separate hematologic malignancy where allogeneic stem cell transplant
has been shown to be potentially curative.
Inability to comprehend the investigational nature of the study and provide informed
consent. The procedure will be explained to patients age 8 -17 years with formal
consent being obtained from parents or legal guardian.
Donor: any of the following
Pregnant or lactating
Unfit to receive filgrastim (G-CSF) or 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, T.cruzi (Chagas) may
be used at the discretion of the investigator following counseling and approval from
the recipient)
Sickling hemoglobinopathies including HbSS or HbSC. Donors with HbAS are acceptable.
Ability of donor or guardian of donor to comprehend the investigational nature of the
study and provide informed consent. |
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| Study is available at: |
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National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, MD 20892
United States
Primary Contact:
Patient Recruitment and Public Liaison Office
Email: prpl@mail.cc.nih.gov
Phone: (800) 411-1222 |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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March 23, 2011 |
Modifications to
this listing: |
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Only selected fields are shown, please use the link
above to view all information about this clinical trial. |
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