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Trial record 6 of 19 for:    aplastic anemia | Open Studies | NIH, U.S. Fed

Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes Using G-CSF Mobilized CD34+ Selected Hematopoietic Precursor Cells Co-Infused With a Reduced Dose of Non-Mobilized Donor T-cells

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 3, 2017 by National Institutes of Health Clinical Center (CC)
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ) Identifier:
First received: July 31, 2010
Last updated: April 20, 2017
Last verified: April 3, 2017


  • 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.


- To evaluate a new method of stem cell transplantation that may reduce the possibly of severe side effects or transplant rejection in the recipient.


  • Recipient: Individuals between 4 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 4 and 80 years of age who are related to the recipient and are eligible to donate blood.


  • All participants will be screened with a physical examination and medical history.
  • 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 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 the donated white blood cells and stem cells as a single infusion.
  • After the stem cell and white blood cell transplant, participants will have regular doses of cyclosporine and methotrexate to prevent rejection of the donor cells. Participants will have three doses of methotrexate within the week after the transplant, but will continue to take cyclosporine for up to 4 months after the transplant.
  • Participants will remain in inpatient care for up to 1 month after the transplant, and will be followed with regular visits for up to 3 years with periodic visits thereafter to evaluate the success of the transplant and any side effects.

Condition Intervention Phase
Severe Aplastic Anemia
MDS (Myelodysplastic Syndrome)
Device: Miltenyi CD34 Reagent System
Other: Donor derived G-CSF mobilized PBC
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes Using G-CSF Mobilized CD34+ Selected Hematopoietic Precursor Cells Co-Infused With a Reduced Dose of Non-Mobilized Donor T-Cells

Resource links provided by NLM:

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

Primary Outcome Measures:
  • Primary endpoint of this study is chronic GVHD by one year. [ Time Frame: 1 year ]

Secondary Outcome Measures:
  • 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. [ Time Frame: Cumulative ]

Estimated Enrollment: 95
Study Start Date: July 26, 2010
Estimated Study Completion Date: June 30, 2017
Estimated Primary Completion Date: June 30, 2017 (Final data collection date for primary outcome measure)
Detailed Description:

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 hemoglobinuria (PNH) or myelodysplastic syndrome (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 filgrastim (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 anti-thymocyte globulin (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 lymphohematopoietic 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 year 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, a factor 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.

Subjects with BMFS at high risk for graft rejection will undergo allogeneic stem cell transplantation from an HLA identical sibling or match unrelated donor using the identical conditioning regimen utilized in protocol 99-H-0050. Using the Miltenyi CliniMACs system, recipients 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 treatment related mortality (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. Health related quality of life will also be assessed as a secondary outcome measure pre-transplant, 30 and 100 days post transplant and every 6 months until 5 years post transplant.


Ages Eligible for Study:   4 Years to 80 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • 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) Severe aplastic anemia (SAA) or pure red cell aplasia (PRCA [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 4 to 80 (both inclusive), and weight >18kg
    • Availability of HLA identical or single HLA locus mismatched family donor or 10/10 matched unrelated donor at the allelic level (HLA alleles A, B, C, DR, and DQ).
    • Telomere Length Testing
    • In patients where a suspicion for a familial bone marrow failure syndrome (BMFS) exists, TERC and TERT mutations testing will be performed on protocol 04-H-0012 or performed elsewhere prior to enrolling on 04-H-0012.


-Recipient: any of the following

  • Major anticipated illness or organ failure incompatible with survival from PBSC transplant
  • Diffusion capacity of carbon monoxide (DLCO) <40% predicted (patients under the age of 10 may be excluded from this criterion if they have difficulty performing the test correctly and thus are unable to have their DLCO assessed) using DL Adj and DL/VA/Adj.
  • Left ventricular ejection fraction <40% (evaluated by ECHO) or <30% (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 (See Bone & Marrow Transplant Consortium Supportive Care Guidelines for HSCT Recipients)
  • 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 subjects age 8 -17 years with formal consent being obtained from parents or legal guardian.


-Related Donor:

  • HLA identical or single HLA mismatched family donor
  • Age greater than or equal to 4 and less than or equal to 80 years old
  • Weight > 18 kg
  • If there is a suspicion of familial BMFS in the recipient, then the donor must have underong genetic testing for genes associated with BMFS -performed at a CLIA-certified laboratory, prior to enrolling in this protocol.


-Related 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
  • Inability of donor or guardian of donor to comprehend the investigational nature of the study and provide informed consent.


-The NMDP unrelated donor inclusion criteria will be used as outlined in document (link). Donor eligibility will be completed per NMDP standards and in accordance with most recent and stringent FDA guidelines.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01174108

Contact: Tatyana Worthy, R.N. (301) 594-8013

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010   
University of Maryland at Baltimore/MPRC Recruiting
Catonsville, Maryland, United States, 21228
Contact: Nancy Hardy, M.D.    410-328-1230   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Richard W Childs, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI) Identifier: NCT01174108     History of Changes
Other Study ID Numbers: 100154
Study First Received: July 31, 2010
Last Updated: April 20, 2017

Keywords provided by National Institutes of Health Clinical Center (CC):
Myelodysplastic Syndrome (MDS)
Severe Aplastic Anemia
Pure Red Cell Aplasia
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Miltenyi CD34 Reagent System
Allogeneic Stem Cell Transplant

Additional relevant MeSH terms:
Anemia, Aplastic
Anemia, Hemolytic
Myelodysplastic Syndromes
Hemoglobinuria, Paroxysmal
Pathologic Processes
Hematologic Diseases
Bone Marrow Diseases
Precancerous Conditions
Neoplasms processed this record on April 21, 2017