CAF Interviews Dr. Tippi MacKenzie on First Ever Clinical Trial Involving In Utero Stem Cell Transplantation for Alpha-thalassemia Major (ATM)

October 19, 2017 –The University of California, San Francisco (UCSF) is currently recruiting participants for the first ever clinical trial performing in utero stem cell transplantations on fetuses affected with alpha-thalassemia major (ATM). CAF speaks with Dr. Tippi MacKenzie, a pediatric and fetal surgeon at UCSF Benioff Children’s Hospital who is leading this clinical trial as the principal investigator.

Tippi MacKenzie, M.D., with patient

CAF: How severe is a prenatal diagnosis of alpha thalassemia major (ATM)? What percentage of these fetuses survive without treatment?

TM: Alpha thalassemia major is almost uniformly fatal in utero without intervention. These fetuses develop severe anemia which results in a condition called “hydrops” that includes heart failure.

CAF: What treatments are currently available to allow fetuses diagnosed with ATM to survive and be born? How effective are these treatments? What complications are associated with these treatments?

TM: When a prenatal diagnosis of ATM is confirmed, pregnancy management options include close fetal monitoring, pregnancy termination, or fetal intervention with in utero transfusions. These transfusions are designed to treat the fetal anemia and can result in the birth of a healthy baby with good neurological outcomes. However, the surviving patients will continue to require lifelong blood transfusions, or a stem cell transplant. Our group is now starting a clinical trial of combining in utero transfusions with a stem cell transplant with the hope that this will become a single, definitive treatment.

CAF: Your phase 1 clinical trial is currently recruiting participants and will demonstrate the safety, feasibility and efficacy of performing in utero stem cell transplantation on fetuses affected with ATM. The maternal participant will undergo bone marrow harvest. The harvested maternal stem cells will then be transplanted into the fetus via an in utero transfusion (IUT). Is this correct?

TM: Yes, that is correct. The stem cells are harvested from the mother because the fetus will tolerate the mother’s stem cells during pregnancy and will therefore not require any immune suppression.

CAF: What are the expected benefits of IUT of stem cells and how do these benefits compare with the benefits of IUT of red blood cells?

TM: In utero transfusions of red blood cells are a short-term measure to correct the fetal anemia. They have been successful in protecting the fetus from the effects of anemia until birth. However, babies born after transfusions will still require life-long therapy with continued blood transfusions, or a stem cell transplant. The in utero stem cell transplantation, if successful, could result in a more definitive therapy since the patient could then make his or her own functioning red blood cells from the transplanted stem cells. Even if there are not enough surviving stem cells to fully replace all red blood cells, the patient can get a “booster” stem cell transplant after birth, which is usually safer than a brand-new stem cell transplant.

CAF: What are the risks to the fetuses undergoing this trial?

TM: It is important to consider potential risks for both the fetus and the mother. For the fetus, there is a risk from the transplantation procedure which involves a needle stick into the umbilical vein; in some cases, this procedure could result in the fetus needing to be delivered earlier, or not surviving. Since these fetuses already require this needle stick for the blood transfusion, we think adding the stem cell transplant adds only a minimal risk. There is a chance that the stem cells will not survive and the baby will continue to need blood transfusions or another stem cell transplant after birth. There is also a small chance that the transplanted cells could react against the fetus (graft vs host disease), although this has not been seen in the preclinical studies. There is also a chance that the babies may be born extremely early, and require a long period in the hospital, and perhaps not survive. Each family will need to weigh the risks of doing nothing (which almost always results in fetal demise) with a fetal intervention.

CAF: What are the risks to the maternal participant undergoing this trial?

TM: The main risk for the mother is due to the bone marrow harvest that is necessary to obtain the stem cells. The stem cells are harvested from the hip, under anesthesia, and mothers could experience bleeding, infection, and pain after the procedure. There may be risks of anesthesia during pregnancy, which is a consideration for all cases of fetal intervention. They may also become anemic after donating their bone marrow and may need a blood transfusion. Mothers may also have complications after the in utero transfusion/transplantation procedure, which involves placing a needle through the amniotic sac into the fetus’ umbilical cord. This could result in an infection or complications leading to preterm labor. Mothers who carry fetuses with severe anemia can have other pregnancy complications and the hope is that the fetal transfusion could protect from those complications.

CAF: What is the eligibility criteria for participants of this trial?

TM: For this trial, we will include fetuses who have anemia because of underlying alpha thalassemia major, at 18-25 weeks of gestation. Because it is important to transplant enough cells, we can only include patients who have adequate numbers of stem cells harvested from the mother’s bone marrow. If a fetus has other severe problems that will make it unlikely for them to survive, they would not be offered this therapy. Maternal inclusion criteria are similar to those used in other fetal therapies such as not having signs of preterm labor.

CAF: How many participants will be recruited and what is the length of time they can expect to be involved in the trial? Will all treatments be conducted at UCSF?

TM: We are hoping to recruit 10 participants and will follow them for at least 1 year after the . The initial in utero transplantation will be at UCSF. However, the fetuses in the study will continue to require in utero transfusions every 3 weeks until birth. If a family lives far away, they will be able to go home if there is a provider skilled in performing these in utero transfusions. Follow up for the infant will be either at their home institution or at UCSF.

CAF: Who are the other members of your team working on this clinical trial?

TM: We have a wonderful team of providers skilled in the multiple aspects of care our families will need. For example, Dr. Elliott Vichinsky is a hematologist with extensive experience with this disease. Dr. Juan Gonzalez is a maternal-fetal medicine expert with experience in fetal blood transfusions. Dr. Chris Dvorak is a pediatric hematologist whose team will manage the bone marrow harvest and the processing of those cells for infusion back into the fetus. Kristen Gosnell, our research nurse, will oversee the care of our families through our Fetal Treatment Center. Billie Lianoglou, our genetic counselor, will work with families and referring providers to confirm the diagnosis of alpha thalassemia. Romobia Hutchinson, our program manager, will oversee other aspects of the clinical trial. Finally, there are numerous research faculty and postdoctoral fellows who will be responsible for studying how the stem cells survive in each patient and determine whether we need to make any changes to the transplantation protocol as we begin to obtain results.

CAF: Is there anything else you would like to share with the thalassemia community?

TM: For many years, patients with alpha thalassemia major were not given any options other than pregnancy termination. However, it appears that meaningful survival is possible with fetal transfusions and these are being offered more frequently. We are excited to offer this new therapy of combining the transfusions with a stem cell transplantation since it offers the possibility of a more definitive therapy. We are excited to hear from the community about your opinions about this treatment option.

Additional information for those interested in participating in this clinical trial can be found by clicking this link.

The Cooley’s Anemia Foundation provides information on select clinical trials that may be of interest to the thalassemia population. This information is provided for educational purposes only and does not imply an endorsement of any trial. Patients who are considering participating in a clinical trial and do not know what questions to ask may want to consult with CAF Patient Outreach Director Sandy Gilbert ( who can help them determine what questions they should ask the investigators to determine if a trial is right for them.

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