Clinical Trial: In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: A Single-Center, Non-Randomized Study of the Safety and Efficacy of In Utero Hematopoietic Stem Cell Transplantation for the Treatment of Fetuses With Alpha Thalassemia Major

Brief Summary: The investigators aims to evaluate the safety of in utero hematopoietic stem cell transplantation in fetuses with alpha-thalassemia major performed at the time of in utero transfusion of red blood cells.

Detailed Summary:

Alpha thalassemia major (ATM) is almost universally fatal in utero and represents an orphan disease with an unmet need for effective therapies. The only current treatment to allow the fetus to be born is to perform in utero transfusions (IUT) of red blood cells to treat the anemia and avoid the complications of hydrops and fetal demise. Often, affected pregnancies undergo elective termination after diagnosis. Cases with prenatal diagnosis of ATM who receive IUT and survive to birth will ultimately require lifelong monthly blood transfusions or bone marrow transplant, if a suitable donor is identified.

This is a phase 1 clinical trial to demonstrate the safety, feasibility and efficacy of performing in utero stem cell transplantation on fetuses affected with ATM. The investigators aim to recruit ten participants with a prenatal diagnosis of ATM. Participants will undergo bone marrow harvest and an in utero transfusion combined with maternal stem cells. Transplanting maternal cells into the fetus takes advantage of existing maternal-fetal tolerance during pregnancy. Hematopoietic stem cell (HSC) transplantation into the fetus takes advantage of the developing fetal immune system to induce tolerance to the transplanted cells without using conditioning or immunosuppression. Performing stem cell transplantation at the same time as IUT minimizes any additional procedural risk to the fetus.

The investigators hope to demonstrate that it is safe and feasible to perform in utero stem cell transplantation. Additionally, the investigators want to demonstrate postnatal chimerism of maternal cells so that, if a bone marrow transplant remains necessary after delivery, conditioning and immune suppression will not be required.

Current Primary Outcome:

• Maternal participant tolerance of bone marrow harvest [ Time Frame: 5 year recruitment phase to include time of bone marrow harvest through 30 days after delivery ]
  Maternal participant tolerance of bone marrow harvest defined as not requiring interventions for preterm labor, bleeding, infection or prolonged hospitalization.
• Safety of in utero hematopoietic stem cell transplantation when performed at the same time as in utero blood transfusion for the fetal participant [ Time Frame: 5 year recruitment plus 1 year data collection phase to include time of IUHCT through 1 year after delivery ]
  safety for fetal participant defined by survival 24 hours after procedure, fetal survival till birth, neonatal survival through discharge of hospitalization and no evidence of graft versus host disease

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Adequate bone marrow harvest from the maternal participant [ Time Frame: 5 year recruitment phase ]
  This is defined as approximately 200-300 cc of bone marrow from which 10^7-10^9 CD34+ cells/kg fetal weight with 10^5-10^7 CD3+ cells/kg fetal weight will be isolated.
• successful engraftment [ Time Frame: 5 year recruitment plus data collection phase to include time of IUHCT through 1 year after delivery ]
  The primary efficacy endpoint is successful engraftment of maternal bone marrow- derived CD34+ hematopoietic stem cells measured by establishment of maternal participant donor cell chimerism equal to or greater than 1% donor cells in the circulation of the fetal recipient. Chimerism will be determined in cord blood at birth, or at a corrected gestational age of 40 weeks, if there is preterm delivery, followed weekly for the first 4 weeks of life, and monthly for one year in the infant to monitor the stability of engraftment.

Original Secondary Outcome: Same as current

Information By: University of California, San Francisco

Dates:
Date Received: December 5, 2016
Date Started: July 2017
Date Completion: February 2024
Last Updated: May 3, 2017
Last Verified: May 2017