Stem Cell Transplant a Promising Option in Sickle Cell Anemia

By Reuters Staff

January 23, 2019

NEW YORK (Reuters Health) - Matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) is a promising option for children with sickle cell anemia (SCA) requiring chronic transfusion due to elevated transcranial Doppler velocity (TCD), a study from France suggests.

High TCD velocities increase the risk of stroke in children with SCA. Regular red blood cell transfusions, and in appropriate cases switching to hydroxyurea after at least one year of transfusion therapy, reduce TCD velocities and stroke risk, but less is known about the effect of MSD-HSCT on TCD velocities.

To investigate, Dr. Francoise Bernaudin from Intercommunal Hospital Center in Creteil and colleagues compared cerebrovascular outcomes in children with SCA and abnormal TCD velocities undergoing MSD-HSCT or standard care (transfusions or transfusions followed by hydroxyurea).

Children younger than age 15 were eligible to participate if they were receiving transfusions for abnormal TCD velocities and had at least one sibling without SCA. Familial HLA testing was done after study enrollment, and treatment allocation was based on availability of a matched sibling donor.

Treatment consisted of myeloablative HSCT with busulfan, cyclophosphamide, and rabbit antithymocyte globulin for children with a matched sibling donor. Children without a donor had regular transfusions to keep the hemoglobin S level below 30% and total hemoglobin level between 9 and 11 g/dL, with the option to switch to hydroxyurea.

At one year, in a propensity-matched sample of 25 children in each group, the highest TCD velocity (the primary outcome) was significantly lower in the MSD-HSCT group than in the standard care group (129.6 vs 170.4 cm/s; P<0.001), according to the January 22 JAMA online report.

This finding persisted at three years, with significantly lower TCD velocities in the MSD-HSCT group compared with standard care group (112.4 vs 156.7 cm/s; P=0.001).

Also, at one year, 80% of children who received MSD-HSCT had developed normal velocities versus 48% of children in the standard care group (P=.045). There were no strokes or deaths in either group, and no patient experienced chronic graft-vs-host disease.

The investigators note that normalization of TCD velocity has generally been considered a surrogate marker of decreased stroke risk but whether this is actually the case remains to be determined. "Nevertheless, no infarct or stenosis occurred after MSD-HSCT, whereas these did occur in 9% and 6% of patients, respectively, in the standard care group," they report.

"Further research is warranted to assess the effects of MSD-HSCT on clinical outcomes and over longer follow-up," the investigators conclude in their article.

In an editorial, Dr. Janet Kwiatkowski of the hematology division at Children's Hospital of Philadelphia in Pennsylvania says these findings indicate that MSD-HSCT is a "promising treatment option" for patients with SCA who require chronic transfusion therapy.

Dr. Kwiatkowski agrees with the French team that it remains unknown whether reduction in TCD velocities translates into reduced risk of stroke – "the true outcome of interest." The ideal study would compare rates of overt stroke. "However, because the rate of stroke is low in children receiving transfusions for primary stroke prevention, such a study would require a large sample size with many years of follow-up, which likely is not feasible."

"Importantly," MSD-HSCT was generally well tolerated and associated with significantly higher quality of life at three years relative to standard care, Dr. Kwiatkowski says.

"MSD-HSCT is difficult initially but in the long term allows for fewer medical appointments and hospitalizations as well as discontinuation of daily medications, which likely translates into improved quality of life over time. Thus, even if stroke rate were equal between the treatment groups, quality of life is better with MSD-HSCT, a major factor for children with many years of life ahead," Dr. Kwiatkowski writes. The MSD-HSCT group also had better control of iron burden, which should help avoid long-term morbidity associated with iron overload, she points out.

The study was sponsored by the Assistance Publique-Hôpitaux de Paris and supported by an institutional grant from the French Ministry of Health.


JAMA 2019.