Bone Marrow Transplant With Abatacept for Non-Malignant Diseases

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Brief Title

Bone Marrow Transplant With Abatacept for Non-Malignant Diseases

Official Title

Abatacept for Post-Transplant Immune Suppression in Children and Adolescents Receiving Allogeneic Hematopoietic Stem Cell Transplants for Non-Malignant Diseases

Brief Summary

      This is a single arm, phase I study to assess the tolerability of abatacept when combined
      with cyclosporine and mycophenolate mofetil as graft versus host disease prophylaxis in
      children undergoing unrelated hematopoietic stem cell transplant for serious non-malignant
      diseases as well as to assess the immunological effects of abatacept. Participants will be
      followed for 2 years.

Detailed Description

      Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only viable cure for
      children who suffer from a wide variety of rare, serious non-malignant diseases, such as
      Fanconi Anemia, Hurler syndrome, and hemophagocytic lymphohistiocytosis. A major obstacle to
      the success of HSCT is morbidity and mortality from graft versus host disease (GVHD), driven
      by donor T cells recognizing and reacting against disparate host antigens. This trial is
      being conducted as a step toward testing the long-term hypothesis that the costimulation
      blockade agent abatacept can be added to a standard post-transplant GVHD prophylaxis regimen,
      cyclosporine and mycophenolate mofetil, to improve disease-free survival after unrelated
      hematopoietic stem cell transplantation (HSCT) using reduced intensity conditioning for
      children with non-malignant diseases (NMD). This study will have the following Specific Aims:

      Specific Aim #1: To conduct a multicenter pilot assessing the tolerability of abatacept
      (n=10). Patients will receive four doses (10 mg/kg IV on days -1, +5, +14 and +28), a
      schedule well tolerated by adolescents and adults with hematologic malignancies in a previous
      pilot. Abatacept will be combined with cyclosporine and mycophenolate mofetil.

      Specific Aim #2: To examine the immunological effects of abatacept in this setting.

      Three reduced intensity conditioning regimens that have been shown to be effective in
      achieving sustained engraftment in patients with non-malignant diseases are available for
      use, depending on the patient's disease:

        -  Patients with Fanconi anemia will receive fludarabine, low dose cyclophosphamide, and
           anti-thymocyte globulin.

        -  Patients with severe aplastic anemia will receive low dose total body irradiation,
           fludarabine, cyclophosphamide, and anti-thymocyte globulin.

        -  Patients with other NMD will receive either the low dose total body irradiation regimen
           or an alemtuzumab, fludarabine, thiotepa, and melphalan regimen.

Study Phase

Phase 1

Study Type


Primary Outcome

Tolerability of Abatacept

Secondary Outcome

 Proportion of Participants Experiencing Regimen-related Toxicity (RRT)


Hurler Syndrome



Study Arms / Comparison Groups

Description:  4 doses of abatacept 10 mg/kg/dose will be given on days -1, +5, +14, and +28.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

January 2014

Completion Date

September 19, 2019

Primary Completion Date

September 19, 2019

Eligibility Criteria

        Inclusion Criteria:

          -  Must be between the ages of 0-21 years at the time of admission for transplant.

          -  Must have one of the following diseases:

               1. Glanzmann thrombasthenia

               2. Wiskott-Aldrich syndrome or other combined immune deficiency

               3. Chronic-granulomatous disease

               4. Severe congenital neutropenia (with resistance to granulocyte-colony stimulating
                  factor (GCSF) or chronic requirement of GCSF doses ≥10 mcg/kg)

               5. Leukocyte adhesion deficiency

               6. Shwachman-Diamond syndrome

               7. Diamond-Blackfan anemia ((transfusion dependent, including steroid failure or
                  inability to wean steroids)

               8. Thalassemia major

               9. Fanconi anemia

              10. Hemophagocytic lymphohistiocytosis (inherited or acquired refractory to therapy
                  or with recurrent episodes of hyperinflammation)

              11. Dyskeratosis-congenita

              12. Hurler Syndrome

              13. Chediak-Higashi syndrome

              14. Acquired (immune; non-inherited, non-congenital) severe aplastic anemia

              15. Sickle cell disease (SCD) (Hgb SS or S-Beta 0 thalassemia) will be eligible
                  between ages 3 and 9.99 and with severe disease.

              16. Other inherited or congenital marrow failure syndromes complicated by severe
                  aplastic anemia

              17. Other inherited or congenital red blood cell disorders requiring monthly chronic
                  transfusion therapy.

              18. Congenital platelet disorders requiring frequent platelet transfusions (patient
                  must have received at least 10 transfusions in the last 3 years).

              19. Other inherited or congenital granulocyte disorders resulting in at least three
                  inpatient hospitalizations in the past three years for infection.

          -  Must have an unrelated adult donor (marrow or PBSC) who is at least a 7/8 match (A, B,
             C, DRB1; the mismatch can be at an allele or antigen level) or an unrelated cord blood
             unit that is matched at least seven of eight loci (A, B and C antigen level-DRB1
             allele level) and provides a minimum pre-cryopreservation total nucleated cell (TNC)
             dose of 7.5 x 107 TNC/kg recipient weight. Mismatches at the DRB1 locus may be at an
             antigen or allele level.

        Exclusion Criteria:

          -  Human leukocyte antigen (HLA) matched related donor.

          -  Severe combined immune deficiency.

          -  Bridging (portal to portal) fibrosis or cirrhosis of the liver.

          -  Pulmonary: diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for
             hemoglobin), forced expiratory volume (FEV1) or forced vital capacity (FVC) < 40% of
             predicted. In child unable to perform pulmonary function testing, a chronic need for
             supplemental oxygen will serve as the exclusionary criterion.

          -  Severe renal dysfunction defined as estimated glomerular filtration rate (GFR) of <60

          -  Severe cardiac dysfunction defined as shortening fraction < 25%.

          -  Neurologic impairment other than hemiplegia, defined as full-scale intelligence
             quotient (IQ) less than or equal to 70, quadriplegia or paraplegia, inability to
             ambulate, or any impairment resulting in decline of Lansky performance score to < 70%.

          -  Clinical stroke within 6 months of anticipated transplant.

          -  Karnofsky or Lansky functional performance score < 50%

          -  HIV infection.

          -  Uncontrolled viral, bacterial, fungal or protozoal infection at the time of study

          -  Patient with unspecified chronic toxicity serious enough to detrimentally affect the
             patient's capacity to tolerate bone marrow transplantation.

          -  Patient or patient's guardian(s) unable to understand the nature and risks inherent in
             the blood and marrow transplant process.

          -  History of non-compliance severe enough in the estimation of the treating team to
             preclude the patient from undergoing unrelated donor transplantation.

          -  Patient is pregnant or lactating

          -  Patients HLA antibody testing demonstrates an antibody directed against a disparate
             HLA molecule.




N/A - 21 Years

Accepts Healthy Volunteers



John T Horan, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Responsible Party

Principal Investigator

Study Sponsor

Emory University

Study Sponsor

John T Horan, MD, Principal Investigator, Children's Healthcare of Atlanta/Emory University

Verification Date

December 2019