Trial Outcomes & Findings for Transplantation for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow (NCT NCT02757885)

NCT ID: NCT02757885

Last Updated: 2023-10-12

Results Overview

Event-free Survival (EFS) is defined as the survival with stable donor erythropoiesis with no new clinical evidence of sickle cell disease (SCD). Primary or late graft rejection with disease recurrence or death will count as events for this endpoint.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 10 participants
• Primary outcome timeframe: Up to One Year
• Results posted on: 2023-10-12

Participant Flow

Participants were recruited from Children's Healthcare of Atlanta (CHOA) in Atlanta, Georgia, USA. Participant enrollment began July 10, 2019, and all follow up was complete by December 14, 2021.

Donors in this trial were not considered research participants. Donors were consented per standard of care; these consents were obtained by non-research physicians. Demographics and/or other outcomes were not collected on the donors. Donor selection criteria are included in the protocol to specify the donor preference to be studied in this particular transplant recipient group. Donors provided consent disclosing that the marrow donation would be used by a recipient who was in a research study.

Participant milestones

Measure	Bone Marrow Recipient Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-mismatched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.
Overall Study STARTED	10
Overall Study COMPLETED	6
Overall Study NOT COMPLETED	4

Reasons for withdrawal

Measure

Bone Marrow Recipient Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-mismatched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Overall Study Screen Failures

4

Baseline Characteristics

Transplantation for Patients With Sickle Cell Disease From Mismatched Family Donors of Bone Marrow

Baseline characteristics by cohort

Measure	Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.
Age, Categorical <=18 years	5 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	6 participants n=5 Participants

PRIMARY outcome

Timeframe: Up to One Year

Event-free Survival (EFS) is defined as the survival with stable donor erythropoiesis with no new clinical evidence of sickle cell disease (SCD). Primary or late graft rejection with disease recurrence or death will count as events for this endpoint.

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Event-free Survival (EFS) Rate

5 Participants

PRIMARY outcome

Timeframe: Day 42

Primary graft rejection is defined as the absence of donor cells assessed by peripheral blood chimerism assays on day 42. Primary graft rejection can be accompanied by pancytopenia and marrow aplasia or by autologous hematopoietic reconstitution without aplasia.

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Primary Graft Rejection Rate

1 Participants

PRIMARY outcome

Timeframe: Day 42 Post transplant up to 1 year

The absence of donor hematopoietic cells in peripheral blood beyond day 42 up to 1 year in a patient who had initial evidence of hematopoietic recovery with > 20% donor cells will be considered a late graft rejection.

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Late Graft Rejection Rate

0 Participants

PRIMARY outcome

Timeframe: Up to One Year

Disease recurrence is defined as the return of sickle erythropoiesis (HbS level > 70%) and the absence of donor cell representation.

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Rate of Disease Recurrence

1 Participants

SECONDARY outcome

Timeframe: Up to One Year

Overall survival is defined as survival with or without sickle cell disease (SCD) after hematopoietic cell transplantation (HCT).

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Overall Survival Rate

6 Participants

SECONDARY outcome

Timeframe: Up to One Year

Cumulative incidence of Neutrophil Engraftment and Platelet Engraftment. Neutrophil engraftment is defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of ≥ 500/µL after conditioning.

Platelet engraftment is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count > 50,000/µL and did not receive a platelet transfusion in the previous 7 days.

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Cumulative Incidence of Neutrophil Engraftment and Platelet Engraftment.

5 Participants

SECONDARY outcome

Timeframe: Up to One Year

Genomic DNA extracted from peripheral blood will be analyzed for variable number of tandem repeats (VNTR) to detect donor engraftment in myeloid and lymphoid fractions.

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Chimerism Rate Following Hematopoietic Cell Transplantation for Sickle Cell Disease

5 Participants

SECONDARY outcome

Timeframe: Up to One Year

IPS is diagnosed by evidence of widespread alveolar injury:

1. Radiographic evidence of bilateral, multi-lobar infiltrates (by chest x-ray or CT scan); AND

2. Evidence of abnormal respiratory physiology based upon oxygen saturation (SpO2) < 93% on room air or the need for supplemental oxygen to maintain oxygen saturation ≥ 93%; AND

3. Absence of active lower respiratory tract infection

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Frequency of Idiopathic Pneumonia Syndrome (IPS)

0 Participants

SECONDARY outcome

Timeframe: Up to One Year

VOD is diagnosed by the presence of ≥ 2 of the following with no other identifiable cause for liver disease:

1. Jaundice (direct bilirubin ≥ 2 mg/dL or > 34 μmol/L)

2. Hepatomegaly with right upper quadrant pain

3. Ascites and/or weight gain (> 5% over baseline)

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Veno-occlusive Disease (VOD) Rate

0 Participants

SECONDARY outcome

Timeframe: Up to One Year

CNS toxicity will be defined as seizures, CNS hemorrhage, or PRES. PRES is defined as an increased diffusion coefficient in areas of T2 hyperintensity on diffusion-weighted imaging in the context of clinical symptoms or physical findings including headache, seizures, visual disturbances, and altered level of consciousness.

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Rate of Central Nervous System (CNS) Toxicity

2 Participants

SECONDARY outcome

Timeframe: Up to One Year

Significant infections will be recorded including but not limited to bacterial or fungal sepsis, CMV reactivation with/without clinical disease, adenovirus infection, EBV PTLD, other significant viral reactivations or community-acquired viral infections and invasive mold infections.

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Infection Rate

5 Participants

SECONDARY outcome

Timeframe: Up to One Year

An overt stroke is defined as a focal neurologic event and neurologic deficit lasting > 24 hours with neuroimaging changes.

Outcome measures

Measure

Bone Marrow Recipient n=6 Participants Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.

Frequency of Stroke

0 Participants

Adverse Events

Bone Marrow Recipient

Serious events: 6 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Measure	Bone Marrow Recipient n=6 participants at risk Patients with SCD will receive a Bone Marrow Transplant (BMT) infusion from an HLA-matched donor through a central venous catheter. Hydroxyurea (HU): HU is part of the BMT preparative regimen. Dose: 30 mg/kg orally once a day for 90 days (days -100 to -10). HU Dose adjusted in patients weighing \>125% IBW. Thiotepa: Thiotepa is part of the BMT preparative regimen. Dosed at 10mg/kg intravenously (IV) over 2 hrs or per institutional guidelines on day -7. Dose adjusted in patients weighing \>125% IBW. Fludarabine (FCR) monophosphate: FCR is part of the BMT preparative regimen. FCR given IV: 30 mg/m2/day over a min. of 30 minutes on days -7 to -3 (150 mg/m2 over 5 consecutive days). Dose adjusted in patients weighing \>125% IBW. Cyclophosphamide (CP): CP is part of the BMT preparative regimen. Given over 1-2 hrs on days -6 and -5 prior to BMT infusion at a dose of 14.5 mg/kg IV. Post BMT infusion CP is infused over 1-2 hrs on days +3 (60- and 72-hrs post BMT infusion) and +4 (approx. 24 hrs after day +3 dose) at a dose of 50 mg/kg IV. Dose adjusted in patients weighing \>125% IBW. Rabbit Anti-thymocyte Globulin (ATG): Rabbit (ATG) is part of the BMT preparative regimen, an infusion of rabbit-derived antibodies against human T cells used for the prevention of acute rejection in organ transplantation. Rabbit ATG is given on days -9 at 0.5 mg/kg and on days -8 and -7 at 2 mg/kg (4.5 mg/kg). Total Body Irradiation: Participants will receive 200 cGy of TBI in a single fraction.
Blood and lymphatic system disorders Non-engraftment	16.7% 1/6 • Number of events 1 • Data collected up to one year post-transplant.
Nervous system disorders Central Nervous System Toxicity	33.3% 2/6 • Number of events 2 • Data collected up to one year post-transplant.
Immune system disorders Graft-versus-host disease (GVHD)	66.7% 4/6 • Number of events 9 • Data collected up to one year post-transplant.
Blood and lymphatic system disorders Thrombotic microangiopathy (TMA)	16.7% 1/6 • Number of events 1 • Data collected up to one year post-transplant.
Infections and infestations Epstein-Barr virus (EBV)	50.0% 3/6 • Number of events 4 • Data collected up to one year post-transplant.
Blood and lymphatic system disorders Deep vein thrombosis (DVT)	16.7% 1/6 • Number of events 1 • Data collected up to one year post-transplant.
Infections and infestations Cytomegalovirus infection (CMV)	16.7% 1/6 • Number of events 1 • Data collected up to one year post-transplant.
Infections and infestations BK virus (BKV)	16.7% 1/6 • Number of events 1 • Data collected up to one year post-transplant.
Infections and infestations Fever	66.7% 4/6 • Number of events 9 • Data collected up to one year post-transplant.
Infections and infestations Bacteriemia	50.0% 3/6 • Number of events 3 • Data collected up to one year post-transplant.

Other adverse events

Adverse event data not reported

Additional Information

Professor of Pediatrics, Dr. Suhag H. Parikh

Emory University

Phone: 4047853240

Email: suhag.parikh@emory.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place