July 27, 2017
Alpha thalassemia major is usually fatal in utero and
there is an unmet need for effective therapies. The only
current treatment for supporting the fetus through
pregnancy is a fetal blood transfusion. Newborns need
chronic transfusions to replace their red blood cells. Stem
cell transplant after birth can cure the disease completely
but there can be significant complications and it is often
challenging to find a suitable stem cell donor.
Our team has developed a new strategy of
in utero stem cell transplantation with the
goal of curing the fetus before birth.
Thalassemia is a test case for in utero hematopoietic stem cell transplant
UCSF Benioff Children's Hospital Oakland and the Center for Maternal-Fetal Precision Medicine have begun enrollment for a clinical trial that will test the safety of combining in utero hematopoietic stem cell transplant with a fetal transfusion of red blood cells. This combination is aimed at treating and, possibly, curing Alpha Thalassemia Major, a blood disease that is often fatal in utero. This trial is the first of its kind in the world, and could also lead to treatments for other life-threatening blood diseases, such as sickle-cell anemia. A $12 million grant from the California Institute for Regenerative Medicine will fund this phase 1 clinical trial.
The study is led by pediatric and fetal surgeon Tippi MacKenzie, MD, of the UCSF Fetal Treatment Center, and Elliot Vichinsky, MD, who created the Northern California Comprehensive Thalassemia Center at UCSF Benioff Children's Hospital Oakland.
Leveraging Fetal Tolerance of Maternal Stem Cells
The trial's thesis is rooted in small and large animal studies that suggest the fetus is unlikely to reject the mother's stem cells at this stage of the pregnancy, as well as on work from other labs that has shown the fetus must become tolerant to the mother for a normal pregnancy to work. It is hoped that if the mother's stem cells successfully engraft in the fetus (even if at low levels)m the infant will not need immune suppression if a bone marrow transplant is necessary after delivery.
Lethal Disease on the Rise
In some regions of the world, Alpha Thalassemia Major is relatively common and almost always leads to fetal loss due to severe anemia. Over the past few decades, changing immigration patterns have contributed to an enormous increase in in the at-risk population in the U.S. If it is identified through early maternal screening or fetal monitoring, the fetus can now likely survive safely through pregnancy, because experienced perinatologists can transfuse red blood cells in utero. At UCSF, the Comprehensive Thalassemia Center is a pioneer in the use of genetic testing to identify fetuses with Alpha Thalassemia Major, and the Fetal Treatment Center performs the transfusions.
After birth, babies with Alpha Thalassemia Major need to undergo a lifetime of monthly transfusions. The other option is stem cell transplantation -- if a proper donor can be found. The challenge in transplantation after birth is that the baby's immune system matures, which causes considerable risk of rejection and graft-versus-host disease. To minimize this, the patients' immune system is suppressed with chemotherapy. This, in turn, is associated with risk of serious infection, marrow suppression, and drug toxicity.
The phase I trial builds on the UCSF clinical program to test whether an in utero transplantation at the time of fetal transfusion can lead to safe engraftment of the healthy stem cells in the ATM patient without the use of immunosuppression or chemotherapy and its complications.
How the Trial Works
If a family receives a diagnosis of Alpha Thalassemia Major in the fetus and has no other significant health risks, an interdisciplinary team will meet with them for a non-directive counseling session, during which clinicians present the medical, psychological, economic, and ethical risks and benefits of all potential actions. In addition to physicians, the team includes a bioethicist to help families and clinicians navigate the many ethical concerns, and a forensic scientist who can expertly detect whether the trial has reached an important threshold for the number of maternal cells engrafted in the fetus after birth. Patients also have access to a patient advisory group, which provides peer support through the decision-making process and beyond.
For those who enroll in the trial, the clinical team harvests and conditions the mother's stem cells and then delivers the stem cell transplant at the same time as the first intrauterine transfusion without performing additional fetal procedures.
For more information about the trial, please call 1-800-RX-FETUS (1-800-793-3887), send an email to fetus@ucsf.edu, or visit http://thalassemia.com/services-intrauterine-therapy.aspx or http://fetus.ucsf.edu/intrauterine-therapy-alpha-thalassemia-major. To learn more about alpha thalassemia, families or providers can call the Northern California Comprehensive Thalassemia Center at 510-428-3651 or visit our website at thalassemia.com.
This study, "In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)", is listed on ClinicalTrials.gov.
Updated 9/22/2017
