Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation

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Brief Title

Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation

Official Title

Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation for Children With Non-Malignant Diseases Who Have Been Multiply Transfused: a Pilot Study

Brief Summary

      Allogeneic blood and marrow transplantation remains the only viable cure for children who
      suffer from many serious non-malignant hematological diseases. Transplantation, however,
      carries a high risk of fatal complications. Much of the risk stems from the use of high dose
      radiation and chemotherapy for conditioning, the treatment administered just prior to
      transplant that eliminates the patients' marrow and immune system, effectively preventing
      rejection of the donors' cells. Attempts to make blood and marrow transplantation safer for
      children with non-malignant diseases by using lower doses of radiation and chemotherapy have
      largely failed because of a high rate of graft rejection.

      In many such cases, it is likely that the graft is rejected because the recipient is
      sensitized to proteins on donor cells, including bone marrow cells, by blood transfusions.
      The formation of memory immune cells is a hallmark of sensitization, and these memory cells
      are relatively insensitive to chemotherapy and radiation. Alefacept, a drug used to treat
      psoriasis, on the other hand, selectively depletes these cells. The investigators are
      conducting a pilot study to begin to determine whether incorporating alefacept into a low
      dose conditioning regimen can effectively mitigate sensitization and, thereby, prevent
      rejection of allogeneic blood and marrow transplants for multiply transfused children with
      non-malignant hematological diseases.

Detailed Description

      There are a large number of serious non-malignant diseases of childhood, most of them
      congenital and rare, which can be corrected by HSCT. These diseases are all characterized by
      deficiencies, either in number or in function, of marrow derived cells. These diseases
      usually affect immune or blood cells and frequently involve transfusion therapy with
      erythrocytes, platelets or granulocytes. Examples of such diseases include sickle cell
      disease, thalassemia major, Glanzmann thrombasthenia, Wiskott-Aldrich syndrome,
      chronic-granulomatous disease, severe congenital neutropenia, leukocyte adhesion deficiency,
      Shwachman-Diamond syndrome, Diamond-Blackfan anemia, Fanconi anemia, dyskeratosis-congenita,
      Chediak-Higashi syndrome, and severe aplastic anemia.

      Allogeneic blood HSCT, whether performed for a malignant or a non-malignant condition, relies
      on the use of a pre-transplant conditioning regimen. Traditionally, very high doses of
      chemotherapy or total body irradiation have been utilized as conditioning. The use of
      intensive conditioning, which, practically speaking eliminates the host marrow and immune
      system, however, can produce serious and sometimes fatal infections and injuries to vital
      organs, such as the liver and lung. In children, the use of intensive conditioning can also
      produce serious late effects, including hypogonadism, stunted growth, impaired cognitive
      development and secondary malignancies.

      Over the past decade, there has been a move to minimize the risk for such complications by
      reducing the intensity of conditioning regimens. Added impetus for reducing conditioning
      intensity arose from the observation in transplantation for thalassemia and sickle cell
      disease that sustained mixed chimerism, that is partial donor engraftment, is usually
      sufficient to cure non-malignant diseases. This observation suggested that sustained
      engraftment could be achieved without "ablation" or elimination of the host marrow.
      Pre-clinical studies demonstrated in small and large animals that sustained mixed chimerism
      can be achieved with preparative regimens consisting of TBI doses as low as 100-300 cGy (by
      comparison, standard intensity regimens typically employ 1000 cGy or more in combination with

      This approach was first translated in a clinical trial involving 45 adults with hematological
      malignancies who were not candidates for standard conditioning because of older age or
      serious co-morbidities. Using a single 200 cGy dose of TBI, sustained engraftment was
      achieved in 80% of cases and, remarkably, transplant related mortality was only 6.7% in this
      frail group of patients at 14 months. It is also notable that these transplants were
      performed primarily in the outpatient setting-the median length of hospitalization was 1 day.
      Low-dose TBI based conditioning has also been safely and effectively utilized for infants and
      children with severe combine immune deficiency and other severe immune deficiencies,
      undergoing related and unrelated donor transplantation. This clinical experience strongly
      suggests that if an effective low-dose TBI conditioning regimen can be developed for children
      with non-malignant diseases it could transform BMT from a costly, highly morbid, and
      sometimes life-taking procedure to a relatively inexpensive, safe and well-tolerated one.

      Thousands and thousands of children around the world suffer from sickle cell disease and
      thalassemia major. There is a myriad of other less common serious non-malignant hematological
      diseases, which have even more devastating effects, for which HSCT remains the only viable
      cure. Low-dose TBI based conditioning represents a minimally toxic approach to
      transplantation for these children-a way to overcome alloimmunization, however, is needed to
      make this approach more effective. Alefacept, the only currently FDA approved agent that
      specifically targets memory T cells, the investigators believe, holds the key to making
      low-dose TBI based conditioning more effective and could, thereby, dramatically alter the
      field of transplantation for non-malignant diseases. sustained donor engraftment needs to be

Study Type


Primary Outcome

Feasibility of Alefacept Pre-conditioning, Measured by Number of Subjects With Full Donor Engraftment

Secondary Outcome

 Number of Participants That Expressed Grade 2 or 3 Regimen-Related Toxicity





Study Arms / Comparison Groups

Description:  Pediatric subjects with non-malignant diseases (NMD) will receive pre-conditioning with alefacept 0.5 mg/kg/dose i.v. with the first dose split on days -40 and -39 and the remaining doses given on days -33, -26, -19, and -12 (e.g. weekly for 5 doses).


* 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

September 2010

Completion Date

September 2013

Primary Completion Date

September 2013

Eligibility Criteria

        Inclusion Criteria:

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

          2. Must have been transfused with at least five platelet, erythrocyte or granulocyte
             units (partial or full)

          3. Must have one of the following diseases:

             (a) hemoglobin SS or hemoglobin SB Sβ0 thalassemia and meet one of the criteria below
             for having severe sickle cell disease (i) Previous central nervous system event
             lasting longer than 24 hours, plus objective imaging evidence of CNS vasculopathy,
             with or without residual neurologic findings (ii) Frequent (≥ 3 per year for 2 years)
             painful vaso-occlusive episodes (defined as episode lasting ≥ 4 hours and requiring
             hospitalization or outpatient treatment with parenteral opioids/opiates). Must have
             also (iii) Recurrent (≥ 3 in lifetime) acute chest syndrome events which have
             necessitated exchange transfusion or chronic transfusion therapy. (iv) Any combination
             of ≥ 3 acute chest syndrome episodes and vasoocclusive pain episodes (defined as
             above) yearly for 3 years. (v) Stage I or II sickle lung disease (see appendix 1) (vi)
             Pulmonary hypertension, measured by tricuspid regurgitant jet velocity (TRV) of
             greater than 2.5m/s (vii) Osteonecrosis involving multiple joints. (viii) Sickle Cell
             nephropathy with moderately severe renal insufficiency estimated GFR ≥30 ml/min, but
             ≤60 ml/min/1.73 m2 (Requires evaluation by a nephrologist). (b) Thalassemia major (c)
             Glanzmann thrombasthenia (d) Wiskott-Aldrich syndrome (e) Chronic-granulomatous
             disease (f) Severe congenital neutropenia (g) Leukocyte adhesion deficiency (h)
             Shwachman-Diamond syndrome (i) Diamond-Blackfan anemia (j) Fanconi anemia (k)
             Dyskeratosis-congenita (l) Chediak-Higashi syndrome (m) Acquired (immune;
             non-inherited, non-congenital) severe aplastic anemia (only patients whose best graft
             source is a mismatched related donor, unrelated marrow donor or cord blood unit) (n)
             Other inherited or congenital marrow failure syndromes complicated by severe aplastic
             anemia (o) Other inherited or congenital red blood cell disorders requiring monthly
             chronic transfusion therapy. (p) Other inherited or congenital platelet disorders
             resulting in at least three inpatient hospitalizations in the past two years for
             bleeding. (q) Other inherited or congenital granulocyte disorders resulting in at
             least three inpatient hospitalizations in the past two years for infection.

          4. Must have an available HLA identical sibling (HLA matched related), a non-HLA
             identical parent or sibling who is matched at least seven of eight loci (mismatch can
             be at an allele or antigen level), an unrelated adult donor who is matched at least
             seven of eight loci (mismatch can be at an allele or antigen level) or an unrelated
             cord blood unit that is matched at five of six loci (A (antigen level), B (antigen
             level), DRB1 (allele level)) and provides a minimum pre-cryopreservation TNC dose of
             5.0 x 107 TNC/kg recipient weight.

        Exclusion Criteria:

          1. Hemophagocytic lymphohistiocytosis or other disorder characterized by NK cell
             dysfunction, since alefacept's effect is mediated by NK cells.

          2. Biopsy proven cirrhosis (score IV).

          3. SCD chronic lung disease ≥ stage III (see appendix 1)

          4. Severe renal dysfunction defined as estimated GFR of <30 ml/min.

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

          6. Severe neurologic impairment other than hemiplegia alone, defined as full scale IQ ≤
             70, quadriplegia or paraplegia, inability to ambulate, inability to communicate
             without assistive device, or any impairment resulting in decline of Lansky performance
             score to <50%.

          7. Karnofsky or Lansky functional performance score < 50%

          8. Confirmed HIV seropositivity.

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

         10. Patient or patient's guardian(s) unable to understand the nature and risks inherent in
             the BMT process.

         11. History of lack of compliance with medical care that would jeopardize transplant

         12. Patient is pregnant or lactating

         13. Donor who for psychological, physiologic, or medical reasons is unable to tolerate a
             bone marrow harvest or receive general anesthesia.

         14. Donor is HIV infected.

         15. Donor is pregnant

         16. Hemoglobin SS, or hemoglobin Sβ0 thalassemia patient who is eligible for one of the
             two trials of myeloablative conditioning currently being conducted by the Aflac Center
             (SALT: Alternate-Donor Bone Marrow and Cord Blood Transplantation for Children with
             High-Risk Sickle Cell Disease Busulfan, fludarabine, ATG and Reduced-Dose
             Cyclophosphamide Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation
             in Patients with Severe Sickle Cell Disease: a pilot study

         17. Patients with thalassemia major who are eligible for any multicenter study we are
             participating in.

         18. Patients whose best graft source is a related or unrelated donor/cord blood unit that
             is mismatched and the patient's HLA antibody testing (see below) demonstrates an
             antibody directed against the disparate HLA molecule.




N/A - 21 Years

Accepts Healthy Volunteers



John Horan, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs

BMT Alefacept

Responsible Party

Principal Investigator

Study Sponsor

Emory University


 Children's Healthcare of Atlanta

Study Sponsor

John Horan, MD, Principal Investigator, Emory University/Children's Healthcare of Atlanta

Verification Date

July 2017