Brief Summary
This multisite prospective study seeks to determine if HLA-identical sibling donor transplantation using alemtuzumab, low dose total-body irradiation, and sirolimus (Sickle transplant Using a Nonmyeloablative approach, "SUN") can decrease the toxicity of transplant while achieving a high cure rate for children with sickle cell disease (SCD).
Brief Title
Minimizing Toxicity in HLA-identical Sibling Donor Transplantation for Children With Sickle Cell Disease
Detailed Description
This is a prospective, multicenter phase II study of HLA-identical sibling donor HSCT in 30 pediatric patients with SCD using nonmyeloablative conditioning with alemtuzumab, total-body irradiation, and sirolimus. The primary Objective of this study is to determine if the SUN regimen can decrease the incidence of grade II-IV acute graft-versus host disease (GVHD) by day +100 while maintaining similar disease-free survival compared to establish HLA-identical donor hematopoietic stem cell transplant (HSCT) regimens in children with SCD. The secondary Objective is to determine if health-related quality of life (HRQoL) for children undergoing SUN HSCT is preserved during the early post-transplant time period. To determine if the SUN regimen can decrease the number of platelet transfusions compared to established HLA-identical HSCT regimens in children with SCD. The tertiary/Exploratory Objectives: To describe other markers of toxicity (duration of neutropenia, mucositis, length of hospitalization) and indicators of a successful HSCT (HRQoL at 1 year, proportion needing additional immunosuppression during the first year, proportion able to wean sirolimus at 1 year).
With protocol version 5.0, added new secondary objective to determine if the change from intravenous to subcutaneous alemtuzumab and the addition of post-HSCT G-CSF can decrease the incidence of poor donor engraftment.
With protocol version 5.0, added new secondary objective to determine if the change from intravenous to subcutaneous alemtuzumab and the addition of post-HSCT G-CSF can decrease the incidence of poor donor engraftment.
Categories
Central Contacts
Central Contact Role
Contact
Central Contact Phone
202-476-5000
Central Contact Email
RNickel@childrensnational.org
Central Contact Role
Contact
Central Contact Phone
202-476-5000
Central Contact Email
FHoq@childrensnational.org
Completion Date
Completion Date Type
Estimated
Conditions
Sickle Cell Disease
Eligibility Criteria
Inclusion criteria:
Patients with genotypes hemoglobin SS and Sβ0 thalassemia must have at least one of the following:
* History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥200 cm/sec by the non-imaging technique (or ≥185 cm/sec by the imaging technique) measured at a minimum of two separate occasions.
* History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm in one dimension, visible in two planes on fluid-attenuated inversion recovery T2-weighted images).
* History of two or more episodes of acute chest syndrome (ACS) in lifetime.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in lifetime.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Patients with all other sickle genotypes (hemoglobin SC, Sβ+ thalassemia) must have at least one of the following:
* Clinically significant neurologic event (overt stroke).
* History of two or more episodes of ACS in the 2-years period preceding enrollment.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the 1-year period preceding enrollment.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Exclusion Criteria:
* General: Life expectancy less than 6 months. Pregnant or breastfeeding patients.
* Infection Disease: Uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning. Patients with confirmed seropositivity for HIV and patients with active Hepatitis B or C determined by serology and/or NAAT are excluded.
* Liver: Direct (conjugated) bilirubin \> 1.5 mg/dL, transaminases \>5x upper limit of normal for age.
* Cardiac: Left ventricular shortening fraction \<25% or ejection fraction \<50% by ECHO.
* Kidney: Estimated creatinine clearance less than 60 mL/min/1.73m2.
* Pulmonary function: Diffusion capacity of carbon monoxide (DLCO) \<35% (adjusted for hemoglobin). Baseline oxygen saturation \<85% or PaO2 \<70.
* Heme: History of RBC alloantibodies against donor RBC antigens (even if current antibody screen is negative). Major ABO incompatibility with donor.
Patients with genotypes hemoglobin SS and Sβ0 thalassemia must have at least one of the following:
* History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥200 cm/sec by the non-imaging technique (or ≥185 cm/sec by the imaging technique) measured at a minimum of two separate occasions.
* History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm in one dimension, visible in two planes on fluid-attenuated inversion recovery T2-weighted images).
* History of two or more episodes of acute chest syndrome (ACS) in lifetime.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in lifetime.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Patients with all other sickle genotypes (hemoglobin SC, Sβ+ thalassemia) must have at least one of the following:
* Clinically significant neurologic event (overt stroke).
* History of two or more episodes of ACS in the 2-years period preceding enrollment.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the 1-year period preceding enrollment.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Exclusion Criteria:
* General: Life expectancy less than 6 months. Pregnant or breastfeeding patients.
* Infection Disease: Uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning. Patients with confirmed seropositivity for HIV and patients with active Hepatitis B or C determined by serology and/or NAAT are excluded.
* Liver: Direct (conjugated) bilirubin \> 1.5 mg/dL, transaminases \>5x upper limit of normal for age.
* Cardiac: Left ventricular shortening fraction \<25% or ejection fraction \<50% by ECHO.
* Kidney: Estimated creatinine clearance less than 60 mL/min/1.73m2.
* Pulmonary function: Diffusion capacity of carbon monoxide (DLCO) \<35% (adjusted for hemoglobin). Baseline oxygen saturation \<85% or PaO2 \<70.
* Heme: History of RBC alloantibodies against donor RBC antigens (even if current antibody screen is negative). Major ABO incompatibility with donor.
Inclusion Criteria
Inclusion criteria:
Patients with genotypes hemoglobin SS and Sβ0 thalassemia must have at least one of the following:
* History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥200 cm/sec by the non-imaging technique (or ≥185 cm/sec by the imaging technique) measured at a minimum of two separate occasions.
* History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm in one dimension, visible in two planes on fluid-attenuated inversion recovery T2-weighted images).
* History of two or more episodes of acute chest syndrome (ACS) in lifetime.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in lifetime.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Patients with all other sickle genotypes (hemoglobin SC, Sβ+ thalassemia) must have at least one of the following:
* Clinically significant neurologic event (overt stroke).
* History of two or more episodes of ACS in the 2-years period preceding enrollment.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the 1-year period preceding enrollment.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Patients with genotypes hemoglobin SS and Sβ0 thalassemia must have at least one of the following:
* History of an abnormal transcranial Doppler measurement defined as TCD velocity ≥200 cm/sec by the non-imaging technique (or ≥185 cm/sec by the imaging technique) measured at a minimum of two separate occasions.
* History of cerebral infarction on brain MRI (overt stroke, or silent stroke if ≥3 mm in one dimension, visible in two planes on fluid-attenuated inversion recovery T2-weighted images).
* History of two or more episodes of acute chest syndrome (ACS) in lifetime.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in lifetime.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Patients with all other sickle genotypes (hemoglobin SC, Sβ+ thalassemia) must have at least one of the following:
* Clinically significant neurologic event (overt stroke).
* History of two or more episodes of ACS in the 2-years period preceding enrollment.
* History of three or more SCD pain events requiring treatment with an opiate or IV pain medication (inpatient or outpatient) in the 1-year period preceding enrollment.
* History of any hospitalization for SCD pain or ACS while receiving hydroxyurea treatment.
* History of two or more episodes of priapism (erection lasting ≥4 hours or requiring emergent medical care).
* Administration of regular RBC transfusions (≥8 transfusions in the previous 12 months).
* At least two episodes of splenic sequestration requiring red blood cell transfusion or splenectomy after at least one episode of splenic sequestration.
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
25 Years
Minimum Age
2 Years
NCT Id
NCT03587272
Org Class
Other
Org Full Name
Children's National Research Institute
Org Study Id
IRB 10322
Overall Status
Recruiting
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
Minimizing Toxicity in HLA-identical Sibling Donor Transplantation for Children With Sickle Cell Disease
Primary Outcomes
Outcome Description
Acute grade II-IV GVHD
Outcome Measure
Acute GVHD
Outcome Time Frame
100 days post transplant
Secondary Outcomes
Outcome Description
PedsQL 4.0 assessments of health related quality of life before/after transplant
Outcome Time Frame
Day +30, and day +100 post transplant
Outcome Measure
PedsQL 4.0 Measurement model for the Pediatric Quality of Life Inventory
Outcome Description
graft rejection, stem cell boost, or 1-year donor myeloid chimerism \<50%
Outcome Time Frame
day +365
Outcome Measure
Poor donor engraftment
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Locked Fields
Render the field
Maximum Age Number (converted to Years and rounded down)
25
Minimum Age Number (converted to Years and rounded down)
2
Investigators
Investigator Type
Principal Investigator
Investigator Name
Mahvish Rahim
Investigator Email
mrahim@montefiore.org