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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

Primary Purpose

Severe Aplastic Anemia, MDS (Myelodysplastic Syndrome)

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Miltenyi CD34 Reagent System
Donor derived G-CSF mobilized PBC
Sponsored by
National Heart, Lung, and Blood Institute (NHLBI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Severe Aplastic Anemia focused on measuring Myelodysplastic Syndrome (MDS), Severe Aplastic Anemia, Pure Red Cell Aplasia, Paroxysmal Nocturnal Hemoglobinuria (PNH), Miltenyi CD34 Reagent System

Eligibility Criteria

4 Years - 80 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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) 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).
    • 9/10 donors where all the HLA sequences have the same antigen/peptide binding domains in key exons to the patient. This can result in identical protein sequences between patient and donor. Allele mismatches in p and g groups can be considered acceptable due to the exact matching which exists in the binding domains.
    • Telomere Length Testing
    • Germline/Inherited gene panel in patients where a suspicion for a familial bone marrow failure syndrome (BMFS) exists, hTERC and hTERT, GATA2 mutation testing will be performed on protocol 04-H-0012 or performed elsewhere prior to enrolling on 04-H-0012.

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) <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)
  • 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.
  • Presence of an active infection not adequately responding to appropriate therapy.
  • 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.

INCLUSION CRITERIA:

-Related Donor:

  • Related donor deemed suitable and eligible, and willing to donate, per clinical evaluations who are additionally willing to donate blood samples for research. Related donors will be evaluated in accordance with existing Standard Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all related donors, but study participation is not required for a donor to make a stem cell donation, so it is possible that not all related donors will enroll onto this study
  • Age greater than or equal to 4 and less than or equal to 80 years old

EXCLUSION CRITERIA:

-Related Donor: None

INCLUSION CRITERIA & EXCLUSION CRITERIA: Unrelated Donor

- Donor eligibility will be completed per NMDP standards and in accordance with most recent and stringent FDA guidelines.

Sites / Locations

  • University of Maryland, Baltimore (UMB)Recruiting
  • National Institutes of Health Clinical CenterRecruiting
  • National Marrow Donor Program (NMDP)Recruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

1

2

Arm Description

Target doses: CD34+ cells 8 x 106/kg; CD3+ cells 2 x 107/kg

Donor

Outcomes

Primary Outcome Measures

Primary endpoint of this study is chronic GVHD by one year.
chronic GVHD

Secondary Outcome Measures

Full Information

First Posted
July 31, 2010
Last Updated
October 6, 2023
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT01174108
Brief 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
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 4, 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 10, 2010 (Actual)
Primary Completion Date
December 30, 2025 (Anticipated)
Study Completion Date
June 30, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes

5. Study Description

Brief Summary
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 4 and 80 years of age who have been diagnosed with a blood disease that can be treated with allogenic stem cell transplants. Donor: Individuals between 4 and 80 years of age who are related to the recipient and are eligible to donate blood. OR unrelated donors found through the National Marrow Donor Program. 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 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.
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%. 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 cGVHD than has historically been observed with BM transplantation (72% vs. 50% 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 x 106 CD34+ cells /kg recipient) combined with 2 x 107 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%) 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% or if the combined event rate for failed donor engraftment or treatment related mortality (TRM) at day 100 exceeds 20%. 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 (cGVHD), 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. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Aplastic Anemia, MDS (Myelodysplastic Syndrome)
Keywords
Myelodysplastic Syndrome (MDS), Severe Aplastic Anemia, Pure Red Cell Aplasia, Paroxysmal Nocturnal Hemoglobinuria (PNH), Miltenyi CD34 Reagent System

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Target doses: CD34+ cells 8 x 106/kg; CD3+ cells 2 x 107/kg
Arm Title
2
Arm Type
No Intervention
Arm Description
Donor
Intervention Type
Device
Intervention Name(s)
Miltenyi CD34 Reagent System
Intervention Description
The CliniMACS CD34 Reagent System is a medical device that is used in vitro to select and enrich specific cell populations.
Intervention Type
Other
Intervention Name(s)
Donor derived G-CSF mobilized PBC
Intervention Description
Cell Therapy
Primary Outcome Measure Information:
Title
Primary endpoint of this study is chronic GVHD by one year.
Description
chronic GVHD
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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) 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). 9/10 donors where all the HLA sequences have the same antigen/peptide binding domains in key exons to the patient. This can result in identical protein sequences between patient and donor. Allele mismatches in p and g groups can be considered acceptable due to the exact matching which exists in the binding domains. Telomere Length Testing Germline/Inherited gene panel in patients where a suspicion for a familial bone marrow failure syndrome (BMFS) exists, hTERC and hTERT, GATA2 mutation testing will be performed on protocol 04-H-0012 or performed elsewhere prior to enrolling on 04-H-0012. 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) <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) 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. Presence of an active infection not adequately responding to appropriate therapy. 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. INCLUSION CRITERIA: -Related Donor: Related donor deemed suitable and eligible, and willing to donate, per clinical evaluations who are additionally willing to donate blood samples for research. Related donors will be evaluated in accordance with existing Standard Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all related donors, but study participation is not required for a donor to make a stem cell donation, so it is possible that not all related donors will enroll onto this study Age greater than or equal to 4 and less than or equal to 80 years old EXCLUSION CRITERIA: -Related Donor: None INCLUSION CRITERIA & EXCLUSION CRITERIA: Unrelated Donor - Donor eligibility will be completed per NMDP standards and in accordance with most recent and stringent FDA guidelines.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Melissa M Spencer, R.N.
Phone
(301) 402-5609
Email
melissa.spencer@nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard W Childs, M.D.
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Maryland, Baltimore (UMB)
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Individual Site Status
Recruiting
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY dial 711
Email
ccopr@nih.gov
Facility Name
National Marrow Donor Program (NMDP)
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55401
Country
United States
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
.Currently the protocol does not specify whether the IPD will be shared. The prospect of IPD sharing is currently under consideration by the PI.
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2010-H-0154.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

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

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