A Blood Stem Cell Transplant for Sickle Cell Disease

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).

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

Primary outcomes

• 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 outcomes

• 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 [Up to 2 years post-transplant]: Between 5% and 95% donor chimerism at two years post- transplant, at least 6 months post- immunosuppressant
• Persistent immunosuppressant -dependent mixed chimerism [+2 years post-transplant]: Between 5% and 95% donor chimerism at two years post- transplant and on immunosuppressant
• 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 outcomes

• 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]

Sex: All, ages: 18 Years to 45 Years

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

• Joseph Rosenthal, MD, Principal investigator, City of Hope Medical Center