A Blood Stem Cell Transplant for Sickle Cell Disease

Pilot Study to Evaluate the Safety and Feasibility of Induction of Mixed Chimerism in Sickle Cell Disease Patients With COH-MC-17: a Non-Myeloablative, Conditioning Regimen and CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant

Blood stem cells can produce red blood cells (which carry oxygen), white blood cells of the immune system (which fight infections) and platelets (which help the blood clot).

Patients with sickle cell disease produce abnormal red blood cells. A blood stem cell transplant from a donor is a treatment option for patients with severe sickle cell disease. The donor can be healthy or have the sickle cell trait. The blood stem cell transplant will be given to the patient as an intravenous infusion (IV). The donor blood stem cells will then make normal red blood cells - as well as other types of blood cells - in the patient. When blood cells from two people co-exist in the patient, this is called mixed chimerism.

Most children are successfully treated with blood stem cells from a sibling (brother/sister) who completely shares their tissue type (full-matched donor). However, transplant is not an option for patients who (1) have serious medical problems, and/or (2) do not have a full-matched donor. Most patients will have a relative who shares half of their tissue type (e.g. parent, child, and brother/sister) and can be a donor (half-matched or haploidentical donor).

Adult patients with severe sickle cell disease were successfully treated with a half-matched transplant in a clinical study. Researchers would like to make half-matched transplant an option for more patients by (1) improving transplant success and (2) reducing transplanted-related complications.

This research transplant is being tested in this Pilot study for the first time. It is different from a standard transplant because:

1. Half-matched related donors will be used, and
2. A new combination of drugs (chemotherapy) that does not completely wipe out the bone marrow cells (non-myeloablative treatment) will be used to prepare the patient for transplant, and
3. Most of the donor CD4+ T cells (a type of immune cells) will be removed (depleted) before giving the blood stem cell transplant to the patient to improve transplant outcomes.

It is hoped that the research transplant:

1. Will reverse sickle cell disease and improve patient quality of life,
2. Will reduce side effects and help the patient recover faster from the transplant,
3. Help the patient keep the transplant longer and
4. Reduce serious transplant-related complications.

Study Overview

• Status: Active, not recruiting
• Conditions: Sickle Cell Disease; Anemia, Sickle Cell; Hemoglobinopathies; Thalassemia; Sickle Cell Disorder
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Pentostatin; Drug: Rabbit anti-thymocyte globulin; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Biological: CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant

Detailed Description

This is a pilot study to determine the safety and feasibility of the COH-MC-17 regimen and ability of the regimen to induce a mixed chimeric status in severe sickle cell disease patients (hemoglobin SS or S-βº Thalassemia). The COH-MC-17 regimen consists of a non-myeloablative regimen (cyclophosphamide, pentostatin and rabbit-anti-thymocyte globulin (ATG)) followed by a CD4+ T-cell-depleted haploidentical hematopoietic cell transplant (HaploHCT).

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion:

1. Confirmed diagnosis of hemoglobin SS or S-βº Thalassemia sickle cell disease

2. Severe disease status as defined by presence of one or more of the following:

   1. Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours; or increased transcranial Doppler velocity (>200 m/s). A stroke is defined as a sudden neurologic change lasting more than 24 hours that is accompanied by cerebral magnetic resonance imaging (MRI) changes.
   2. History of ≥ 1 episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea).
   3. History of ≥ 2 severe vaso-occlusive pain crises (VOC) per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea). A severe VOC is defined as an episode of pain lasting more than 2 hours severe enough to require care at a medical facility. Note that priapism that lasts more than 2 hours and requires care at a medical facility is also considered a VOC.
   4. Osteonecrosis of ≥ 2 joints despite the institution of supportive care measures.
   5. Prior treatment with regular RBC transfusion therapy, defined as receiving ≥ 8 transfusions per year for > 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome)
3. No HLA matched sibling or 10/10 matched unrelated donor

4. Related donor who:

   1. Is genotypically haploidentical on HLA-A, B, C and DRB1 loci AND
   2. Meets institutional criteria
5. Failed prior hydroxyurea therapy or have intolerance to hydroxyurea
6. Meets protocol specified organ function criteria
7. Women of childbearing potential or sexually active male: Agreement to use adequate contraception prior to study entry and 6 months post-transplant.

Exclusion Criteria

1. Prior stem cell transplant
2. Prior bone marrow transplant
3. Concurrent other investigational agents, chemotherapy, biological therapy or radiation therapy
4. Planned use of moderate and strong CYP3A4 inhibitors
5. Active infection
6. Major surgery within the last 30 days
7. Clinically significant liver fibrosis or cirrhosis if on chronic transfusion therapy > 6 months
8. Active malignancy (other than non-melanoma skin cancers)
9. History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the pre- or post-transplant regimen.
10. Women of childbearing potential: pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: COH-MC-17 and immunosuppressants; Participants receive COH-MC-17: a 21-day nonmyeloablative conditioning regimen (cyclophosphamide, pentostatin and rabbit anti-thymocyte globulin), followed by CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant on Day 0. Immunosuppressants (tacrolimus and mycophenolate mofetil) given on Day -1 onwards until discontinuation post-transplant. The minimally manipulated transplant product is manufactured using the CliniMACS device.

Drug: Cyclophosphamide; Orally daily; Other Names: Cytoxan; Drug: Pentostatin; Intravenous; Other Names: NIPENT; Drug: Rabbit anti-thymocyte globulin; Intravenous; Other Names: Thymoglobulin; Rabbit ATG; Drug: Tacrolimus; Initially IV. If patient tolerates, convert to oral.; Other Names: PROGRAF®; Drug: Mycophenolate mofetil; IV or oral; Other Names: Myfortic; MMF; CellCept®; Biological: CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant; Infusion; Other Names: CD4+ T-cell depleted HaploHCT; CD4+ T-cell depleted hematopoietic progenitor cell (HPC) product

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Toxicity per NCI-Common Terminology Criteria for Adverse Events version 4.0	Day -22 to 2 years post-transplant
Unacceptable Toxicity at least possibly related to COH-MC-17	Day -22 to Day +60 post-transplant
Mixed Chimerism defined as 30-90% donor cells	Day +60 post-transplant
Feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product	From apheresis to Day 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events of Grade 3 or higher		Up to 2 years post-transplant
Neutrophil count ≥ 500/mm3, time to recovery		Up to 2 years post-transplant
Platelet count ≥ 20,000/mm3, time to recovery		Up to 2 years post-transplant
Marrow failure		Up to 2 years post-transplant
Sickle cell disease related complications		Up to 2 years post-transplant
Non-relapse mortality		Up to 2 years post-transplant
Acute Graft versus Host Disease per 1994 Keystone Consensus Criteria		Day + 100 post-transplant
Chronic Graft versus Host Disease per 2014 National Institutes of Health Consensus Criteria		Day+ 180, + 1 year and +2 years post-transplant
Overall Survival		Up to 2 years post-transplant
Disease-Free Survival		Up to 2 years post-transplant
Event-Free Survival		Up to 2 years post-transplant
Disease Relapse		Up to 2 years post-transplant
Persistent post-immunosuppressant mixed chimerism	Between 5% and 95% donor chimerism at two years post- transplant, at least 6 months post- immunosuppressant	Up to 2 years post-transplant
Persistent immunosuppressant -dependent mixed chimerism	Between 5% and 95% donor chimerism at two years post- transplant and on immunosuppressant	+2 years post-transplant
Complete chimerism: >95% donor chimerism		+2 years post-transplant
Primary donor graft failure: Defined as < 5% donor chimerism by Day + 30 post- transplant		Day +30 post-transplant
Secondary donor graft failure: Defined as < 5% donor chimerism beyond Day +30 in patients with prior documentation of ≥ 5% donor cells by Day +30		> Day + 30 up to 2 years post-transplant
Donor chimerism in blood		Day +30, Day +60, Day +100, Day+180, and +1 yr, +1.5 yr, +2yr post-transplant
Donor chimerism in bone marrow		Day + 100, Day + 180 and + 1 yr post-transplant
Percent HbS levels		Baseline, and then Day + 30, Day + 100, Day + 180, +1 yr, +1.5, +2yr post-transplant

Other Outcome Measures

Outcome Measure	Time Frame
Ratio donor: recipient de novo thymic T cells	Up to 2 years post-transplant
Ratio donor: recipient FoxP3+ regulatory T cells	Up to 2 years post-transplant
Tolerance status of donor: recipient type T cells	Up to 2 years post-transplant

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: California Institute for Regenerative Medicine (CIRM)
• Investigators: Principal Investigator: Joseph Rosenthal, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2019
• Primary Completion (Estimated): January 25, 2027
• Study Completion (Estimated): January 25, 2027

Study Registration Dates

• First Submitted: August 10, 2017
• First Submitted That Met QC Criteria: August 10, 2017
• First Posted (Actual): August 15, 2017

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Thalassemia; Sickle Cell Disease; Anemia, Sickle Cell; Hemoglobinopathies; Sickle Cell Disorders; Haploidentical Transplant; Nonmyeloablative Conditioning; CD4+ T cell; CD4+ T cell-depleted Hematopoietic Cell Transplant; Mixed Chimerism
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Thalassemia; Hemoglobinopathies; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fatty Acids; Lipids; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Acids, Acyclic; Carboxylic Acids; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Pyrimidine Nucleosides; Pyrimidines; Macrolides; Lactones; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Nucleosides; Biological Products; Complex Mixtures; Deoxyribonucleosides; Caproates; Immune Sera; Coformycin; Formycins; Cyclophosphamide; Mycophenolic Acid; Tacrolimus; Antilymphocyte Serum; Pentostatin; thymoglobulin; Pharmaceutical Preparations
• Other Study ID Numbers: 16453

Drug and device information, study documents

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