Extensive multilineage analysis in patients with mixed chimerism after allogeneic transplantation for sickle cell disease: insight into hematopoiesis and engraftment thresholds for gene therapy

Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease may provide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lacking. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T-lymphocytes, monocytes, granulocytes and red blood cells. Thirty-four patients with mixed chimerism and ≥12 months of follow-up were included. A selective advantage of donor red blood cells and their progenitors/precursors led to full chimerism in mature red blood cells (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism 10g/dL) and 3 with AS donors (hemoglobin <10g/dL). However, only one vaso-occlusive crisis occurred with 68.7% HbS. Except in the patients with lowest chimerism, the donor engraftment was lower for T cells than for the other lineages. In a context of mixed chimerism after hematopoietic stem cell transplantation for sickle cell disease, myeloid (rather than T cell) engraftment was the key efficacy criterion. Results show that myeloid chimerism as low as 30% was sufficient to prevent vaso-occlusive crisis in transplants from an AA donor but not constantly from an AS donor. However, the correction of hemolysis requires higher donor chimerism levels (i.e. ≥50%) in both AA and AS recipients. In the future, this group of patients may need a different therapeutic approach.