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At least 20% donor myeloid chimerism is necessary to reverse the sickle phenotype after allogeneic HSCT

Courtney D. Fitzhugh, Stefan Cordes, Tiffani Taylor, Wynona Coles, Katherine Roskom, Mary Link, Matthew M. Hsieh and John F. Tisdale

Key Points

  • Results based on our allogeneic model suggest genetic strategies aimed at correcting at least 20% of HSCs are necessary to reverse SCD.

  • A minority of donor myeloid cells is adequate because of the vast differences in RBC survival between donor and recipient.

Abstract

Novel curative therapies using genetic transfer of normal globin-producing genes into autologous hematopoietic stem cells (HSCs) are in clinical trials for patients with sickle cell disease (SCD). The percentage of transferred globin necessary to cure SCD is currently not known. In the setting of allogeneic nonmyeloablative HSC transplants (HSCTs), stable mixed chimerism is sufficient to reverse the disease. We regularly monitored 67 patients after HSCT. After initially robust engraftment, 3 of these patients experienced declining donor myeloid chimerism (DMC) levels with eventual return of disease. From this we discovered that 20% DMC is necessary to reverse the sickle phenotype. We subsequently developed a mathematical model to test the hypothesis that the percentage of DMC necessary is determined solely by differences between donor and recipient red blood cell (RBC) survival times. In our model, the required 20% DMC can be entirely explained by the large differences between donor and recipient RBC survival times. Our model predicts that the requisite DMC and therefore necessary level of transferred globin is lowest in patients with the highest reticulocyte counts and concomitantly shortened RBC lifespans.

  • Submitted March 8, 2017.
  • Accepted August 22, 2017.
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