Abatacept for GVHD Prophylaxis After Hematopoietic Stem Cell Transplantation for Pediatric Sickle Cell Disease
- Conditions
- Interventions
- Registration Number
- NCT02867800
- Lead Sponsor
- Monica Bhatia
- Brief Summary
To assess the tolerability of the costimulation blocking agent abatacept (CTLA4-Ig) when added to the standard graft versus host disease (GVHD) prophylaxis regimen of a calcineurin inhibitor and methotrexate in patients receiving early alemtuzumab followed by fludarabine, thiotepa, melphalan, and alemtuzumab for conditioning.
- Detailed Description
Outcomes of hematopoietic stem cell transplantation (HSCT) for children and adolescents with sickle cell disease (SCD) have improved. Graft versus host disease (GVHD), however, remains a barrier to success. GVHD accounts for most of the transplant related mortality and much of the morbidity in this setting-in part through the injury it directly causes and in...
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 24
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Patients with hemoglobin (Hgb) SS or SB0 thalassemia between the ages of 3 and 20.99 years who are at least 10 kg getting an human leukocyte antigen (HLA) matched bone marrow transplant, will be eligible if they are at increased risk for graft versus host disease (GVHD) and have severe SCD.
(a) Patients falling into one of the following three groups will be considered to be at increased risk for GVHD:
(i) Are between 10 and 20.99 years and receiving their transplant from an HLA matched related donor.
(ii) Are between 3 and 9.99 years and receiving their transplant from an HLA matched related donor who is at least 10 years.
(iii) Are between 3 and 20.99 years and receiving their transplant from an HLA matched unrelated donor. Donors must be matched at the A, B, C and DRB1 loci at the allele level.
(b) Patients who meet one of the following criteria will qualify as having severe SCD:
(i) Previous clinical stroke, as evidenced by a neurological deficit lasting longer than 24 hours, which is accompanied by radiographic evidence of ischemic brain injury and cerebral vasculopathy.
(ii) Asymptomatic cerebrovascular disease, as evidenced by one the following:
- Progressive silent cerebral infarction, as evidenced by serial MRI scans that demonstrate the development of a succession of lesions (at least two temporally discreet lesions, each measuring at least 3 mm in greatest dimension on the most recent scan) or the enlargement of a single lesion, initially measuring at least 3 mm). Lesions must be visible on T2-weighted MRI sequences.
- Cerebral arteriopathy, as evidenced by abnormal transcranial doppler (TCD) testing (confirmed elevated velocities in any single vessel of time-averaged maximum mean velocities (TAMMV) > 200 cm/sec for non-imaging TCD) or by significant vasculopathy on magnetic resonance angiogram (MRA) (greater than 50% stenosis of > 2 arterial segments or complete occlusion of any single arterial segment).
(iii) Frequent ( ≥ 3 per year for preceding 2 years) painful vaso-occlusive episodes (defined as episode lasting ≥ 4 hours and requiring hospitalization or outpatient treatment with parenteral opioids). If patient is on hydroxurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 2 years prior to the start of this drug.
(iv) Recurrent ( ≥ 3 in lifetime) acute chest syndrome events which have necessitated erythrocyte transfusion therapy.
(v) Any combination of ≥ 3 acute chest syndrome episodes and vaso-occlusive pain episodes (defined as above) yearly for 3 years. If patient is on hydroxurea and its use has been associated with a decrease in the frequency of episodes, the frequency should be gauged from the 3 years prior to the start of this drug.
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All patients and/or their parents or legal guardians must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
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Must have been evaluated and adequately counseled regarding treatment options for severe SCD by a pediatric hematologist.
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Because of the elective and non-urgent nature of hematopoietic stem cell transplantation (HSCT) for SCD, it is important that all patients and families be counseled regarding fertility preservation measures available to them. All patients and/or their parents or legal guardians must indicate on the consent and assent forms that they have received this counseling.
- Bridging (portal to portal) fibrosis or cirrhosis of the liver.
- Parenchymal lung disease stemming from SCD or other process defined as a diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin) or forced vital capacity of less than 45% of predicted. Children unable to perform pulmonary function testing will be excluded if they require daytime oxygen supplementation.
- Renal dysfunction with an estimated glomerular filtration rate (GFR) < 50% of predicted normal for age.
- Cardiac dysfunction with shortening fraction < 25%.
- Neurologic impairment other than hemiplegia, defined as full-scale IQ ≤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 < 70%.
- Patient is human immunodeficiency virus (HIV) infected.
- Donor is HIV infected.
- Donor has Hgb SS, SC or SB0 thalassemia.
- 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 bone marrow transplant (BMT) process.
- History of lack of compliance with medical care that would jeopardize transplant course.
- Donor who for psychological, physiologic, or medical reasons is unable to tolerate a bone marrow harvest or receive general anesthesia.
- Active viral, bacterial, fungal or protozoal infection.
- Donor is pregnant.
- Patient is pregnant.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Standard GVHD Prophylaxis + Abatacept Cyclosporine Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Tacrolimus Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Fludarabine Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Marrow infusion Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Diphenhydramine Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Acetaminophen Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Thymoglobulin Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Methylprednisolone Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Meperidine Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Alemtuzumab Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Melphalan Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Thiotepa Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Methotrexate Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Abatacept Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Mycophenolate Mofetil Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0. Standard GVHD Prophylaxis + Abatacept Sirolimus Subjects will receive * premedication (Diphenhydramine, Acetaminophen, Methylprednisolone; and Meperidine as needed) * immunosuppression (Alemtuzumab, or Thymoglobulin) * conditioning regimen (Fludarabine, Thiotepa, and Melphalan) * GVHD prophylaxis: calcineurin inhibitor (Cyclosporine,Tacrolimus, Sirolimus or Mycophenolate Mofetil with permission of the sponsor) and Methotrexate plus Abatacept on days -1, +5, +14 and +28, and a marrow infusion on day 0.
- Primary Outcome Measures
Name Time Method Number of patients who tolerate abatacept Within 100 days of receiving the last prescribed dose of abatacept Patients will be deemed to be evaluable for tolerability if they received all prescribed doses of abatacept.
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- Secondary Outcome Measures
Name Time Method Bearman Scale Score of Regimen-Related Toxicity (RRT) Day 42 post-transplant RRT will be assessed according to Bearman Scale.
Number of infections Up to 180 days post transplant Infections will include viremia, posttransplant lymphoproliferative disease and immune reconstitution.
Trial Locations
- Locations (7)
North Carolina Cancer Hospital
🇺🇸Chapel Hill, North Carolina, United States
Columbia University Irving Medical Center
🇺🇸New York, New York, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States
Floating Hospital for Children at Tufts Medical Center
🇺🇸Boston, Massachusetts, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States