Immunohaematological complications in patients with sickle cell disease after haemopoietic progenitor cell transplantation: a prospective, single-centre, observational study

Abstract

Background: Haemopoietic progenitor cell (HPC) transplantation can cure sickle cell disease. Non-myeloablative conditioning typically results in donor-derived erythrocytes and stable mixed chimerism of recipient-derived and donor-derived leucocytes. Exposure to donor antigens from the HPC graft and new red cell antibodies induced by transfusion can lead to immunohaematological complications. We assessed the incidence of such complications among HPC transplant recipients with sickle cell disease.

Methods: The study population was all patients with sickle cell disease enrolled before March 31, 2015, in the three clinical trials of non-myeloablative HPC transplantation at the National Institutes of Health. We assessed formation of new red cell antibodies after transplantation and red cell incompatibility between donors and recipients.

Findings: 61 patients were enrolled, 42 were HLA matched and 19 were haploidentical. Nine (15%) had immunohaematological complications. Before HPC transplantation, three patients had antibodies incompatible with their donors. After HPC transplantation, new red cell antibodies were seen in six patients (11 alloantibodies and two autoantibodies), among whom three developed antibodies incompatible with donor or recipient red cells and three developed compatible antibodies. The clinical course of complications was highly variable, from no severe effects attributable to antibodies, to sustained reticulocytopenia, to near-fatal haemolysis. We found no significant correlation between immunohaematological complications and graft failure, graft rejection, or death.

Interpretation: Clinical effects ranged from seemingly not clinically important to potentially fatal. In patients with sickle cell disease, donor and recipient red cell phenotypes should be carefully assessed before transplantation to minimise and manage the risk of immunohaematological complications.

Funding: Intramural Research Program and National Institutes of Health.

Figure 1:

Alloantibody formation

Figure 2:. Transfusion support and clinical outcomes in engrafted patients by alloantibody status

The 47 patients who maintained their grafts long term were divided into five groups: those with no alloantibodies (n=28); those with alloantibodies at enrolment that were either compatible (n=11) or incompatible (n=3) with their donors; and those who developed new alloantibodies after enrolment that were either compatible (n=2) or incompatible (n=3) with donor and recipient. The number of RBCs transfused after enrolment (A), time to transfusion independence (B), and time to engraftment (C) were compared across the five subgroups. Each circle represents one patient, horizontal bars show the median, and vertical bars indicate the first and third quartiles. For detailed data and statistics see the appendix (p 5). RBCs=red blood cells.

Figure 3:. Reticulocyte concentrations in patients with sustained reticulocytopenia

41 patients with haemopoietic progenitor cell engraftment and no red cell incompatibility experienced low reticulocyte concentrations around 10 days after transplantation that generally returned to normal concentrations by day 50. Three patients developed sustained reticulocytopenia, of whom two had pre-existing antibodies and one developed a new antibody incompatible with donors. Reticulocyte concentrations were >3 SD below control (14-day moving average of reticulocyte counts in 41 patients with red cell incompatability and sustained engraftment) at day 90. Reticulocytes recovered in two of these patients after >180 days, and in one after >2 years.