Non-myeloablative Haploidentical HCT Study for Patients With Sickle Cell Disease, Including Compromised Organ Function

Non-myeloablative Phase I/II Haploidentical HCT Study for Patients With Sickle Cell Disease, Including Compromised Organ Function

Background:

Sickle cell disease (SCD) is a genetic disorder where red blood cells, that carry oxygen, are stiff and become stuck in small blood vessels. As a result, affected patients can experience severe pain and serious organ damage. SCD can be cured with a hematopoietic cell transplant (HCT), that is, when they receive blood stem cells from a family donor. But HCT can also have serious side effects, especially in people with organ damage. Researchers want to find ways to make HCT safer for everyone.

Objective:

To test a new combination of drugs (briquilimab, abatacept, and alemtuzumab), used along with radiation, in people undergoing HCT for SCD.

Eligibility:

People aged 16 and older with SCD. They must be eligible for HCT and have a family member who is a good donor match. Donors must be aged 4 and older.

Design:

Participants with SCD will be screened. They will have blood tests and tests of organs including their heart and lung function. Donors will have blood drawn.

Participants with SCD will have a tube inserted into a blood vessel in their chest (intravenously). This line will remain in place up to 2 months; it will be used to draw blood and administer the donor cells and other medications.

Briquilimab will be administered intravenously 1 time, along with other drugs used to prepare for HCT. Participants will receive abatacept 6 times, from just before they receive their donor cells until 6 months after. Participants will undergo radiation therapy and take other drugs that are standard for HCT. Most HCT recipients remain in the hospital for about 30 days after HCT.

Follow-up visits will continue for 5 years....

Study Overview

• Status: Active, not recruiting
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Filgrastim; Biological: Briquilimab; Drug: Abatacept; Drug: Sirolimus; Drug: Cyclophosphamide

Detailed Description

Study Description:

Haploidentical hematopoietic cell transplantation offers a widely available curative option for individuals with sickle cell disease. The goal is to reverse SCD while avoiding unacceptable graft rejection, graft-versus-host disease, infectious complications, and hyperinflammatory responses. We hypothesize that a moderate amount of immunosuppression will maximize efficacy while avoiding unacceptable toxicity.

Objectives:

Primary Objective:

-Evaluate the regimen success rate where success is defined as successful engraftment (persistent donor chimerism and free of acute SCD complications) and absence of acute grade 3 or higher GVHD or moderate to severe chronic GVHD evaluated at 1 year posttransplant.

Secondary Objectives:

• Event-free survival and overall survival.
• Incidence of recipient-type hemoglobin defined as HbS >10% when donors have HbAA and HbS >50% when donors have sickle cell trait (HbAS).
• The proportion of patients with myeloid chimerism >= 95% at 1 and 2 years post-HCT.
• Incidence of acute and chronic GVHD.
• Prevalence of donor type hemoglobin at 1-year post-transplant in SCD patients who have not been transfused in the previous 3 months.
• Incidence of viral reactivation and disease.
• Incidence of autoimmune and hyperinflammatory complications.
• Incidence of hematologic malignancies.
• Transplant-related mortality.

Exploratory Objective:

• Perform gene therapy research involving cell culture or genetic manipulation to produce normal or therapeutic hemoglobin on excess autologous CD34+ cells collected from recipients.
• Evaluate the impact of this non-myeloablative conditioning regimen on organs including the heart, lung, kidneys, liver, brain, neurocognitive function, and endocrine organs
• Evaluate the impact of this non-myeloablative conditioning regimen on quality of life.

Endpoints:

Primary Endpoint:

-The percentage of SCD patients at 1 year (+/- 3 months) posttransplant who have not experienced graft failure and who are without severe graft-versus-host disease (defined as grade 3 and higher acute GVHD and moderate to severe chronic GVHD).

Secondary Endpoints:

• Total hemoglobin and percent HbS levels
• Percent donor myeloid chimerism and donor CD3 chimerism
• Day of neutrophil engraftment
• Day of platelet engraftment
• RBC transfusion requirement
• Rates of acute and chronic GVHD
• Rates of viral reactivation and disease
• Rates of autoimmune and hyperinflammatory complications
• Transplant-related mortality
• Non-transplant-related mortality
• Rates of graft failure
• Rates of leukemia and related disorders

Exploratory Endpoint:

Completion of gene therapy research involving cell culture or genetic manipulation to produce normal or therapeutic hemoglobin on excess autologous CD34+ cells collected from recipients.

Organ function and quality of life

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

Recipient:

Participants must fulfill one disease category, either at least one organ damage or no other access to curative therapy.

1. Adult patients with sickle cell disease at high risk for disease-related morbidity or mortality, according to A, B, C, D, or E or complication(s) not ameliorated by SICKLE CELL-SPECIFC THERAPIES (F):

   A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination (>=200 m/s); OR

   B. Silent cerebral infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2- weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s); OR

   C. Sickle cell-related renal insufficiency defined by a creatinine level >=1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome; OR

   D. Tricuspid regurgitant jet velocity (TRV) of >=2.5 m/s at least 3 weeks after a vaso-occlusive crisis and/or right heart catheterization-documented pulmonary hypertension; OR

   E. Sickle hepatopathy defined as EITHER ferritin >1000 mcg/L OR direct bilirubin >0.4 mg/dL at baseline AND a platelet count <250 K/microliter (without vaso-occlusive crisis); OR

   F. Any one of the below complications:

   Complication: Vaso-occlusive crises; Eligible for HCT: >1 hospital admission per year while on a therapeutic dose of a SCD treatment/medication

   Complication: Acute chest syndrome (ACS); Eligible for HCT: Any ACS while on SCD treatment/medication

   Pediatric patients with sickle cell disease at high risk for disease-related morbidity or mortality, defined as A, B, C, D, E, or F

   A. A neurological event resulting in focal neurologic deficits that lasted >= 24 hours (classical clinical definition of stroke, not requiring imaging studies of the brain) OR a focal neurological event resulting in abnormalities on T2-weighted or FLAIR images using a MRI scan, indicative of an acute infarct, with no other reasonable medical explanation (definition of a stroke supported with MRI imaging scans of the brain), OR both; OR

   B. Abnormal transcranial Doppler (TCD) measurement with a timed average maximum mean velocity of at least 200 cm/sec in the terminal portion of the internal carotid or proximal portion of middle cerebral artery or if the imaging TCD method is used > 185 cm/sec plus evidence of intracranial vasculopathy; OR

   C. Silent Cerebral Infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2-weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s); OR

   D. Three acute severe vaso-occlusive pain episodes requiring hospitalization and recalcitrant to maximum medical therapy; OR

   E. At least one acute chest syndrome episode resulting in intensive care admission requiring nonmechanical ventilatory support: simple nasal cannula, face mask that requires oxygen content (venti mask, non-rebreather), simple nasal cannula, face mask oxygen (e.g. ventimask, nonrebreather), continuous positive airway pressure, synchronized inspiratory positive airway pressure, bilevel positive airway pressure, high flow nasal cannula or invasive mechanical ventilatory support (delivered by endotracheal tube or tracheostomy); OR

   F. Right heart catheterization confirmed pulmonary hypertension defined as pulmonary artery pressure >25 mmHg

2. AND evidence of severe organ damage with at least one of the following who are typically excluded from other HCT protocols:

   A. Kidney damage: CrCl <60 mL/min/1.73m^2 cystatin C-based or iothalamate/iohexol-based or other equivalent GFR testing including patients on hemodialysis or peritoneal dialysis

   B. Heart damage: Ejection fraction 35-40%

   C. Liver damage: Bridging fibrosis, cirrhosis, direct bilirubin >= 2x the upper limit of normal and/or ALT >= 5x the upper limit of normal

   D. Lung damage: Adjusted diffusion capacity of carbon monoxide (DLCO) 35-40% OR who have no other option for curative therapy (including allogeneic HCT, gene therapy, or gene editing studies) on a different SCD HCT protocol.

3. Non disease-specific:

   • Male or female, age >=18 years (pediatric subjects >=16 years may be enrolled after 6 successful adult transplants)
   • Haploidentical relative donor available
   • Ability to comprehend and willing to sign an informed consent before the initiation of any study procedures
   • Negative serum or urine b-HCG, when applicable

   • Agree to use birth control for 12 months after drug product infusion.

     • Female subjects must agree to use a medically acceptable method of birth control such as an oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection from start of screening through 12 months after drug product infusion.
     • Male subjects must agree to use effective contraception (including condoms) from start of screening through 12 months after drug product infusion.
   • Stated willingness to comply with all study procedures and availability for the duration of the study

Donor:

Haploidentical relative donor deemed suitable and willing to donate, per clinical evaluations. Donors age 4 or older and >=20 kg, eligible to donate hematopoietic stem cells, and who are additionally willing to donate blood for research. Related donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all related donors, but is not required for a donor to make a stem cell donation, so it is possible that not all related donors will enroll onto this study.

EXCLUSION CRITERIA:

Recipient:

An individual who meets any of the following criteria will be excluded from participation in this study:

• Available HLA-matched sibling donor
• ECOG performance status of 3 or more.
• DLCO <35% predicted (corrected for hemoglobin).
• Baseline oxygen saturation of <85% or PaO2 <70 mmHg
• Left ventricular ejection fraction: <35% estimated by ECHO
• Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen. HCT candidates with pre-transplant respiratory viral infections will undergo careful clinical assessment with the help of our transplant infectious disease team for lower respiratory tract disease, which may include thorough physical examination, imaging, and/or bronchoalveolar lavage. In case of lower respiratory tract disease or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity, the transplant will be delayed until resolution.
• Major anticipated illness or organ failure incompatible with survival from PBSC transplant.
• Pregnant or breastfeeding
• Donor specific anti-HLA antibodies (DSAs) >=2000 Mean Fluorescence Intensity (MFI)
• Patients seronegative for EBV who have EBV seropositive donors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Human Leukocyte Antigens (HLA) Haploidentical Related Stem Cell Donor; A haploidentical relative donor will receive filgrastim (G-CSF) 10 to 16 µg/kg/d subcutaneously or intravenously for up to 6 days with apheresis collections of peripheral blood hematopoietic progenitor cells (PBPC) after the 5th day (and after the 6th day if required).	Drug: Filgrastim; A haploidentical relative donor will receive filgrastim (G-CSF) 10 to 16 µg/kg/d subcutaneously or intravenously for up to 6 days with apheresis collections of peripheral blood hematopoietic progenitor cells (PBPC) after the 5th day (and after the 6th day if required).; Other Names: Granulocyte colony-stimulating factor (G-CSF)
Experimental: PBSC Transplant With 50 mg/kg Post-transplant Cyclophosphamide (PT- Cy); Stem cell recipients with Sickle Cell Disease will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors. This group will receive a single dose of PT-Cy; 50 mg/kg, on day +3 post-HCT	Biological: Briquilimab; All stem cell recipient participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors.; Drug: Abatacept; All stem cell recipient participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors.; Drug: Sirolimus; All stem cell recipient participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors.; Drug: Cyclophosphamide; For cohort 1, stem cell recipient participants will receive a single dose of PT-Cy; 50 mg/kg, on day +3 post-HCT. For cohort 2, stem cell participants will receive two doses of PT-Cy; 50mg/kg, on days +3 and +4 (total 100 mg/kg) post-HCT.; Other Names: Cy
Experimental: PBSC Transplant With 100 mg/kg Post-transplant Cyclophosphamide (PT- Cy); Stem cell recipients with Sickle Cell Disease will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors. This group will receive a total of two doses of PT-Cy; 50mg/kg, on days +3 and +4 (total 100 mg/kg) post-HCT	Biological: Briquilimab; All stem cell recipient participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors.; Drug: Abatacept; All stem cell recipient participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors.; Drug: Sirolimus; All stem cell recipient participants will receive the same dose of the investigational briquilimab antibody and abatacept added to the NIH-established regimen of alemtuzumab-TBI-sirolimus and infusion of filgrastim-mobilized peripheral blood hematopoietic cells from haploidentical related donors.; Drug: Cyclophosphamide; For cohort 1, stem cell recipient participants will receive a single dose of PT-Cy; 50 mg/kg, on day +3 post-HCT. For cohort 2, stem cell participants will receive two doses of PT-Cy; 50mg/kg, on days +3 and +4 (total 100 mg/kg) post-HCT.; Other Names: Cy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Successful Engraftment and Absence of Acute Grade 3 or Higher GVHD	Number of participants at 1 year post stem cell transplant who have not experienced graft failure and who are without severe graft-versus-host disease (defined as grade 3 and higher acute GVHD). Graft failure is defined as the absence of or insufficient donor chimerism associated with the return of acute complications of sickle cell disease. As defined by CIMBTR criteria for Organ Stages of Acute GVHD: Grade III: Skin = Rash on >50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea > 1500 mL/day. Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin >15 mg/dL; Lower GI = Severe abdominal pain with or without ileus. Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.	Up to 1 year
Number of Participants With Successful Engraftment and Absence of Moderate to Severe Chronic Graft-versus-host Disease	Number of participants at 1 year post stem cell transplant who have not experienced graft failure and who are without moderate to severe chronic graft-versus-host disease (GVHD) Graft failure is defined as the absence of or insufficient donor chimerism associated with the return of acute complications of sickle cell disease. CIMBTR criteria definition for Chronic GVHD: Moderate chronic GVHD involves EITHER 3 organs/sites with no clinically significant functional impairment OR a less than or equal to 1 organ/site with clinically significant functional impairment, but no major disability. Severe GVHD is associated with a major disability caused by chronic GVHD.	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Event-free Survival and Overall Survival	length of study
Viral Reactivation and Disease	length of study
Autoimmune and Hyperinflammatory Complications	length of study

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Courtney F Joseph, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2023
• Primary Completion (Actual): October 27, 2025
• Study Completion (Estimated): November 26, 2027

Study Registration Dates

• First Submitted: November 22, 2023
• First Submitted That Met QC Criteria: November 22, 2023
• First Posted (Actual): November 24, 2023

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Sickle Cell Disease; Haploidentical; Hematopoietic Cell Transplant; Organ Damage
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Immunoconjugates; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Hydrocarbons; Biological Factors; Carbohydrates; Antibodies; Immunoglobulins; Blood Proteins; Serum Globulins; Globulins; Macrolides; Lactones; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Intercellular Signaling Peptides and Proteins; Glycoproteins; Glycoconjugates; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Abatacept; Sirolimus; Cyclophosphamide; Granulocyte Colony-Stimulating Factor; Filgrastim
• Other Study ID Numbers: 10001635; 001635-H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No