Faster Engraftment and Immune Reconstitution after Haploidentical Allogenic Hematopoietic Cell Transplantation with CD3/CD19 Depleted as Compared to CD34 Selected Grafts.

Abstract

Haploidentical allogeneic hematopoietic cell transplantation (HHCT) using megadoses of CD34-selected hematopoietic stem cells (HSC) is complicated by slow engraftment and delayed immune reconstitution leading to intensive transfusional support, high risk of rejection and high incidence of life threatening infections. Graft CD3/CD19 depletion on a CliniMACS device results in grafts not only containing CD34+ stem cells but also CD34 negative progenitors, natural killer-, dendritic- and facilitating-cells, potentially leading to improved engraftment and immune reconstitution.We report a retrospective comparative study of eleven HHCTs with CD34 selected HSC (CD34) and seven HHCTs with CD3/CD19 depleted grafts (CD3/CD19) performed sequentially at a single institution with a median follow-up > 1 year. Conditioning was 12 Gy TBI, cyclosphosphamide (120 mg/kg) and ATG with or without either etoposide (40 mg/kg) or thiotepa (10mg/kg) in the CD34 group. All patients in the CD3/CD19 group received fludarabine (200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2) and OKT-3 (5 mg/day, day −5 to +14). No postgrafting immunosuppression was used. Only the CD34 group received G-CSF posttransplant. Median age was 30 (range, 19–47) years in the CD34 group compared to 37 (range, 31–58) years in the CD3/CD19 group. Diagnoses in the CD34 group included acute myeloid leukaemia (AML, n=3), acute lymphoblastic leukaemia (ALL, n=3), chronic myeloid leukaemia (CML, n=2), and one patient each with Non-Hodgkin's lymphoma, myelodysplastic syndrome and paroxysmal nocturnal hemoglobinuria. Diagnoses in the CD3/CD19 group were AML (n=3), ALL(n=3), and multiple myleoma (n=1). Graft composition was comparable with a median of 9,6x10E6 CD34+ cells/kg and 2,2x10E4 CD3+ cells/kg in the CD34 group versus 7,6x10E6 CD34+ cells/kg and 1,3 x10E4 CD3+ cells/kg in the CD3/CD19 group. The grafts in the CD3/CD19 group, however, contained significantly more CD34 negative cells (99 versus 3 %, p=<0.0001) such as NK-cells, monocytes and granulocytes. Engraftment in the CD3/19 group was significantly faster than in the CD34 group, with a median time to >500 neutrophils/μL of 13 versus 19 days (p=<0.0265) and a median time to >20000 platelets/μL of 13 versus 35 days (p=<0.0001). There was also a significant faster recovery of NK-cells with a median day 100 CD56+ count of 1808 versus 209 cells/μL (p=0.0413). The number of CD3+ cells on day 100 showed no significant difference. No cases of graft rejection have been observed in both groups. Transfusional requirements in the CD3/19 group were lower with a median of 11 versus 35 days with platelet support (p=0.039). There was no significant difference in the incidence of GVHD which was ≤ II in both groups. We observed a lower incidence of bacterial infections in the CD3/C19 group. In conclusion, CD3/19 depleted grafts allow haploidentical hematopoietic cell transplantation with faster engraftment and NK-cell reconstitution leading to a lower rate of bacterial infections and less transfusional requirements.