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

NCT02986698 | Terminated Phase 1 FDA Drug

• 1 other identifier: 16-21157
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Alpha Thalassemia Major; Hemoglobinopathy; with Thalassemia; Hemoglobinopathies; Fetal Anemia; Fetal Hydrops; Alpha; Thalassemia; Thalassemia Major; Thalassemia Alpha; A-Thalassemia

Keywords

intrauterine transfusion; in utero human stem cell transplantation

Outcome Measures

Primary Outcomes (2)

• Maternal participant tolerance of bone marrow harvest

  Maternal participant tolerance of bone marrow harvest defined as not requiring interventions for preterm labor, bleeding, infection or prolonged hospitalization.

  5 year recruitment phase to include time of bone marrow harvest through 30 days after delivery

• Safety of in utero hematopoietic stem cell transplantation when performed at the same time as in utero blood transfusion for the fetal participant

  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

  5 year recruitment plus 1 year data collection phase to include time of IUHCT through 1 year after delivery

Secondary Outcomes (2)

• Adequate bone marrow harvest from the maternal participant

  5 year recruitment phase

• successful engraftment

  5 year recruitment plus data collection phase to include time of IUHCT through 1 year after delivery

Study Arms (1)

in utero hematopoietic stem cell transplantation

EXPERIMENTAL

Perform in utero hematopoietic stem cell transplantation at the time of intrauterine transplantation in fetuses with alpha-thalassemia major. The cellular product is: Semi-allogeneic, Related, Maternal Bone Marrow-Derived, Miltenyi CliniMACS Plus enriched CD34+ hematopoietic stem cells administered in utero at a dose of 1 x 10\^7-10\^9 cells/kg fetal weight with equal to or less than 1% CD3+ T cells (equivalent to 10\^5-10\^7 T cells/kg fetal weight) in a final volume of 2-5ml suspended in 5% human serum albumin in Normosol buffer (Hospira, Inc.). Stem cells will be administered immediately before the red blood cells intravenously via the umbilical vein during the clinically indicated IUT. All participants will receive one dose of stem cells but may receive additional transfusions as clinically indicated.

Biological: in utero hematopoietic stem cell transplantation

Interventions

in utero hematopoietic stem cell transplantation BIOLOGICAL

This is a phase 1 safety study to demonstrate it is safe for both the mother and fetus to perform In utero hematopoietic stem cell transplantation of maternal derived stem cells at the time of intrauterine transplantation of red blood cells to treat fetuses affected with alpha-thalassemia major.

in utero hematopoietic stem cell transplantation

Eligibility Criteria

• Age: 18 Weeks - 26 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male or female fetuses from 18 weeks and 0/7 days to 26 weeks 0/7 days gestation with a diagnosis of alpha-thalassemia major by chorionic villus sampling (CVS), amniocentesis, cordocentesis or by identification of parents as genetic carriers, and identification of fetal anemia or signs of impending hydrops, for whom parents elect to pursue in utero transfusion, and are willing to undergo subsequent IUT for the remainder of gestation.
• parents must consent to fetal autopsy in the event of a fetal demise

Sponsors & Collaborators

• University of California, San Francisco: lead
• California Institute for Regenerative Medicine (CIRM): collaborator

Study Sites (1)

University of California

San Francisco, California, 94158, United States

Location

Related Publications (10)

• Kreger EM, Singer ST, Witt RG, Sweeters N, Lianoglou B, Lal A, Mackenzie TC, Vichinsky E. Favorable outcomes after in utero transfusion in fetuses with alpha thalassemia major: a case series and review of the literature. Prenat Diagn. 2016 Dec;36(13):1242-1249. doi: 10.1002/pd.4966. Epub 2016 Dec 7.

  PMID: 27862048 BACKGROUND

• Derderian SC, Jeanty C, Walters MC, Vichinsky E, MacKenzie TC. In utero hematopoietic cell transplantation for hemoglobinopathies. Front Pharmacol. 2015 Jan 12;5:278. doi: 10.3389/fphar.2014.00278. eCollection 2014.

  PMID: 25628564 BACKGROUND

• Vichinsky E. Advances in the treatment of alpha-thalassemia. Blood Rev. 2012 Apr;26 Suppl 1:S31-4. doi: 10.1016/S0268-960X(12)70010-3.

  PMID: 22631041 BACKGROUND

• MacKenzie TC. Fetal Surgical conditions and the unraveling of maternal-fetal tolerance. J Pediatr Surg. 2016 Feb;51(2):197-9. doi: 10.1016/j.jpedsurg.2015.10.059. Epub 2015 Nov 4.

  PMID: 26653947 BACKGROUND

• MacKenzie TC, David AL, Flake AW, Almeida-Porada G. Consensus statement from the first international conference for in utero stem cell transplantation and gene therapy. Front Pharmacol. 2015 Feb 10;6:15. doi: 10.3389/fphar.2015.00015. eCollection 2015. No abstract available.

  PMID: 25713535 BACKGROUND

• Jeanty C, Derderian SC, Mackenzie TC. Maternal-fetal cellular trafficking: clinical implications and consequences. Curr Opin Pediatr. 2014 Jun;26(3):377-82. doi: 10.1097/MOP.0000000000000087.

  PMID: 24759226 BACKGROUND

• Nijagal A, MacKenzie TC. Clinical implications of maternal-fetal cellular trafficking. Semin Pediatr Surg. 2013 Feb;22(1):62-5. doi: 10.1053/j.sempedsurg.2012.10.011.

  PMID: 23395148 BACKGROUND

• Nijagal A, Flake AW, MacKenzie TC. In utero hematopoietic cell transplantation for the treatment of congenital anomalies. Clin Perinatol. 2012 Jun;39(2):301-10. doi: 10.1016/j.clp.2012.04.004. Epub 2012 May 8.

  PMID: 22682381 BACKGROUND

• Nijagal A, Wegorzewska M, Le T, Tang Q, Mackenzie TC. The maternal immune response inhibits the success of in utero hematopoietic cell transplantation. Chimerism. 2011 Apr;2(2):55-7. doi: 10.4161/chim.2.2.16287.

  PMID: 21912720 BACKGROUND

• Borges B, Canepa E, Chang IJ, Herzeg A, Lianoglou B, Kishnani PS, Harmatz P, MacKenzie TC, Cohen JL. Prenatal Delivery of Enzyme Replacement Therapy to Fetuses Affected by Early-Onset Lysosomal Storage Diseases. Am J Med Genet C Semin Med Genet. 2025 Jan 31:e32132. doi: 10.1002/ajmg.c.32132. Online ahead of print.

  PMID: 39891377 DERIVED

MeSH Terms

Conditions

Thalassemia; Hemoglobinopathies; Hydrops Fetalis; alpha-Thalassemia; beta-Thalassemia

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Erythroblastosis, Fetal; Fetal Diseases; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Immune System Diseases; Edema; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Tippi Mackenzie, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Surgery

Study Record Dates

• First Submitted: December 5, 2016
• First Posted: December 8, 2016
• Study Start: October 5, 2017
• Primary Completion: April 30, 2024
• Study Completion: December 31, 2024
• Last Updated: January 27, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)