Clinical trial NCT02986698: In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
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
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: California Institute for Regenerative Medicine (CIRM)
First posted: 2016-12-08
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Maximum age (years): 26
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 description: 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.

Eligibility criteria: Inclusion Criteria:

* 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
* adequate bone marrow harvest from maternal participant is a condition for inclusion

Exclusion Criteria:

* Fetal Subject Exclusion Criteria: Fetal participants will be excluded if they have a second major anatomic anomaly (not related to the underlying thalassemia) that contributes a significant morbidity or mortality risk, or echocardiogram or ultrasound findings that indicate a high risk of fetal demise after fetal intervention.
* Maternal Subject Exclusion Criteria: Maternal participants will be excluded if they have one or more morbidities that would preclude bone marrow harvest and fetal intervention including, but not limited to, morbid obesity with BMI \> 35, maternal cardiac disease, mirror syndrome, symptomatic maternal anemia, or if they develop preterm premature rupture of membranes (PPROM) or active preterm labor (PTL).

Primary outcomes:
measure: Maternal participant tolerance of bone marrow harvest
timeFrame: 5 year recruitment phase to include time of bone marrow harvest through 30 days after delivery
measure: Safety of in utero hematopoietic stem cell transplantation when performed at the same time as in utero blood transfusion for the fetal participant
timeFrame: 5 year recruitment plus 1 year data collection phase to include time of IUHCT through 1 year after delivery
Secondary outcomes:
measure: Adequate bone marrow harvest from the maternal participant
timeFrame: 5 year recruitment phase
measure: successful engraftment
timeFrame: 5 year recruitment plus data collection phase to include time of IUHCT through 1 year after delivery
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California
state: California
Study officials:
affiliation: University of California, San Francisco
name: Tippi Mackenzie, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.