In utero hematopoietic cell transplantation (IUHCT) with maternal cells was safe in two fetuses with alpha thalassemia major (ATM), according to interim results of a phase I clinical trial presented by Renan Sper, PhD, from the University of California, San Francisco, at the virtual 62nd ASH Annual Meeting and Exposition.
Alpha thalassemia major is caused by the lack of alpha globin in fetal and adult hemoglobin, Dr. Sper explained in his presentation. This leads to fetal anemia and hydrops fetalis, a syndrome marked by extreme edema. Treatment options include blood transfusions before and after birth or postnatal HCT, which can be associated with significant treatment-related toxicity.
“Because of the in utero clinical manifestation of ATM, IUHCT using maternal hematopoietic stem cells may present an attractive treatment option that takes advantage of the fetal tolerance developed to maternal allo-antigens during pregnancy,” he said explained. This approach also could eliminate the need for conditioning regimens, and their associated toxicities, used in a postnatal HCT.
“Fetuses can be ‘educated’ to tolerate new kinds of cells before birth,” lead study author Tippi MacKenzie, MD, from the University of California, San Francisco, told ASH Clinical News. “One of the beauties of using maternal hematopoietic cells is that the fetuses should already be tolerant to those cells because of trafficking between the mother and the fetus before birth.”
This trial included fetuses with ATM between 18 to 26 weeks’ gestation without other major anomalies. Nineteen patients have been evaluated; 15 terminated the pregnancy, two did not meet inclusion window, and two were transplanted and have completed the 1-year follow-up.
For the procedure, 300 mL of maternal bone marrow was harvested. CD34+ cells were selected and transplanted into the fetus via the umbilical vein along with standard in utero transfusions (IUTs). IUTs were repeated every 3 weeks until delivery. Patient 1 was transplanted at 23 weeks with 1×108 CD34+ cells/kg plus 1×107 T cells/kg. Patient 2 was transplanted at 25 weeks with a lower dose of 5×107 CD34+ cells/kg plus 5×106 T cells/kg.
Both patients received four additional in utero transfusions until birth. Both were born with no complications, no neurologic signs, and no evidence of graft-versus-host disease.
A comparison of cord blood samples with healthy controls indicated no changes in percentage of hematopoietic stem cells, while indicating a nearly 100-fold increase in percentage of erythrocyte progenitor cells expressed in CD71 and CD235A. According to Dr. Sper, this indicated changes in peripheral erythropoiesis.
“In patient 1, we detected multilineage chimerism levels between 1% and 4% within the first 4 months of life, reducing to microchimerism levels by 9 months of age,” Dr. Sper said, which supports the investigators’ hypothesis that IUHCT of maternal cells would result in multilineage cell chimerism. “In patient 2, we observed overall lower chimerism levels compared with patient 1.”
Next, to test their hypothesis that IUHCT would lead to sustained immunotolerance to maternal allo-antigens, the researchers performed mixed lymphocyte reactions using patient T cells with maternal antigen presenting cells (APCs) or third-party APCs. In patient 1, no T cell expansion was observed when exposed to maternal cells, but was responsive to third-party APCs, which was suggestive of sustained immunotolerance to maternal allo-antigens. However, patient 2 experienced T cell expansion and did not develop sustained immunotolerance. Patient 1’s tolerance appeared to last for the entire first year after the transplant, which leaves the opportunity for a booster transplant, Dr. MacKenzie reported.
While the trial is ongoing and these results will need to be confirmed in larger studies, the researchers deemed the approach tolerable. No safety events were reported in the 2 patients who had been transplanted. These findings give clinicians the opportunity to transplant these patients before birth, leading to meaningful levels of engraftment, hematopoiesis, and tolerance.
The authors report no relevant conflicts of interest.
MacKenzie TC, Frascoli M, Sper R, et al. In utero stem cell transplantation in patients with alpha thalassemia major: interim results of a phase 1 clinical trial. Abstract #1698. Presented at the 2020 American Society of Hematology Annual Meeting, December 6, 2020.