Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation

NCT01319851 | Terminated Results DMC

• 2 other identifiers: IRB00039680BMT Alefacept
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

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.

Conditions

Thalassemia; Sickle Cell Disease; Glanzmann Thrombasthenia; Wiskott-Aldrich Syndrome; Chronic-granulomatous Disease; Severe Congenital Neutropenia; Leukocyte Adhesion Deficiency; Schwachman-Diamond Syndrome; Diamond-Blackfan Anemia; Fanconi Anemia; Dyskeratosis-congenita; Chediak-Higashi Syndrome; Severe Aplastic Anemia

Keywords

bone marrow transplant; sickle cell disease; thalassemia; Glanzmann thrombasthenia; Wiskott-Aldrich syndrome; chronic-granulomatous disease; severe congenital neutropenia; leukocyte adhesion deficiency; Schwachman-Diamond syndrome; Diamond-Blackfan anemia; Fanconi anemia; dyskeratosis-congenita; Chediak-Higashi syndrome; severe aplastic anemia

Outcome Measures

Primary Outcomes (1)

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

  All subjects received alefacept prior to hematopoietic stem cell transplantation and were followed up to at least two years after transplantation to ensure successful engraftment.

  Two years post-transplant

Secondary Outcomes (6)

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

  Day 42 post-transplant

• Number of Participants That Expressed Successful Neutrophil Engraftment

  Day 100 post-transplant

• Incidence of Greater Than or Equal to 85% CD3 Donor Chimerism

  Day 30 post-transplant

• Incidence of 100% CD33 Donor Chimerism

  Day 30 post-transplant

• Number of Participants Who Experienced Acute Graft-versus-host Disease (aGVHD), Measured by NIH Consensus Criteria (NCC) Score: Grade II-IV

  Day 30 post-transplant

Study Arms (1)

Alefacept

EXPERIMENTAL

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).

Drug: Alefacept

Interventions

Alefacept DRUG

0.25 mg/kg IV on day -40 and day -39 0.5 mg/kg IV on days -33, -26, -19 and -12 Alefacept was diluted in sterile water (2 ml total volume) and administered via i.v. push followed by a normal saline flush per package insert.

Also known as: Amevive

Alefacept

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Must be between the ages of 0-21 years at the time of admission for transplant
• Must have been transfused with at least five platelet, erythrocyte or granulocyte units (partial or full)
• 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.
• 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.

You may not qualify if:

• Hemophagocytic lymphohistiocytosis or other disorder characterized by NK cell dysfunction, since alefacept's effect is mediated by NK cells.
• Biopsy proven cirrhosis (score IV).
• SCD chronic lung disease ≥ stage III (see appendix 1)
• Severe renal dysfunction defined as estimated GFR of \<30 ml/min.
• Severe cardiac dysfunction defined as shortening fraction \< 25%.
• 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%.
• Karnofsky or Lansky functional performance score \< 50%
• Confirmed HIV seropositivity.
• 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 BMT process.
• History of lack of compliance with medical care that would jeopardize transplant course.
• Patient is pregnant or lactating
• Donor who for psychological, physiologic, or medical reasons is unable to tolerate a bone marrow harvest or receive general anesthesia.
• Donor is HIV infected.
• Donor is pregnant

Sponsors & Collaborators

• Emory University: lead
• Children's Healthcare of Atlanta: collaborator

Study Sites (1)

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Related Publications (1)

• Stenger EO, Chiang KY, Haight A, Qayed M, Kean L, Horan J. Use of Alefacept for Preconditioning in Multiply Transfused Pediatric Patients with Nonmalignant Diseases. Biol Blood Marrow Transplant. 2015 Oct;21(10):1845-52. doi: 10.1016/j.bbmt.2015.06.005. Epub 2015 Jun 19.

  PMID: 26095669 DERIVED

MeSH Terms

Conditions

Thalassemia; Anemia, Sickle Cell; Thrombasthenia; Wiskott-Aldrich Syndrome; Granulomatous Disease, Chronic; Neutropenia, Severe Congenital, Autosomal Recessive 3; Leukocyte adhesion deficiency type 1; Shwachman-Diamond Syndrome; Anemia, Diamond-Blackfan; Fanconi Anemia; Dyskeratosis Congenita; Chediak-Higashi Syndrome; Anemia, Aplastic

Interventions

Alefacept

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Blood Platelet Disorders; Hemorrhagic Disorders; Lymphopenia; Leukopenia; Cytopenia; Leukocyte Disorders; Genetic Diseases, X-Linked; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Phagocyte Bactericidal Dysfunction; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Exocrine Pancreatic Insufficiency; Pancreatic Diseases; Digestive System Diseases; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipomatosis; Anemia, Hypoplastic, Congenital; Red-Cell Aplasia, Pure; DNA Repair-Deficiency Disorders; Skin Abnormalities; Congenital Abnormalities; Skin Diseases, Genetic; Skin Diseases; Skin and Connective Tissue Diseases; Albinism; Eye Diseases, Hereditary; Eye Diseases

Intervention Hierarchy (Ancestors)

CD58 Antigens; Membrane Glycoproteins; Glycoproteins; Glycoconjugates; Carbohydrates; Immunoglobulin G; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Membrane Proteins; Recombinant Fusion Proteins; Recombinant Proteins

Limitations and Caveats

Production of alefacept was halted in 2011.

Results Point of Contact

• Title: Dr. John Horan
• Organization: Emory University

jthoran@emory.edu

404-785-1272

Study Officials

• John Horan, MD

  Emory University/Children's Healthcare of Atlanta

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: September 15, 2010
• First Posted: March 22, 2011
• Study Start: September 1, 2010
• Primary Completion: September 1, 2013
• Study Completion: September 1, 2013
• Last Updated: July 27, 2017
• Results First Posted: March 9, 2015

Record last verified: 2017-07

Locations

US (1)