Comparable and Robust Immune Reconstitution after HLA-Haploidentical or HLA-Matched Allogeneic Transplantation (BMT) Utilizing Posttransplantation Cyclophosphamide

Background: Posttransplantation cyclophosphamide (PTCy) limits severe acute and chronic graft-versus-host disease (GVHD) and facilitates engraftment, permitting HLA-matched donor (MD) BMT without additional GVHD prophylaxis and the safe performance of HLA-haploidentical (haplo) BMT. Low rates of transplant related mortality, infection, and post-transplant lymphoproliferative disorders (PTLD) support that PTCy based immunosuppression allows favorable immune recovery. However limited data exist regarding immune reconstitution after haplo or MD BMT utilizing PTCy.

Methods: We assessed immune recovery in 71 patients undergoing myeloablative (MA) haplo BMT with PTCy (50mg/kg on days +3 and +4), mycophenolate mofetil (MMF) (days +5-35), and tacrolimus (days +5-180) as GVHD prophylaxis and 73 patients undergoing MA MD BMT with PTCy as sole GVHD prophylaxis. Flow cytometric immunophenotyping was performed on peripheral blood samples collected serially at predetermined time points.

Results: Immune reconstitution was not statistically different after HLA-matched related and HLA-matched unrelated BMT; therefore these groups are reported together. By 1 year after haplo and MD BMT, median ALCs were in the normal range (1100-4800 cells/µl) and B-cell counts were higher than those in normal donors. NK cells reached normal donor numbers by 6 months. In patients without GVHD, NK recovery was rapid, reaching normal donor levels at 2-3 months. Results were similar after MD and haplo BMT. However, CD4⁺ and CD8⁺ T-cell counts at 1 month were statistically significantly lower after haplo BMT (p<0.0001 for both). At 1 year median CD4⁺ T-cell counts were 227 and 286 after MD and haplo BMT, respectively.  Both values were significantly lower than median donor counts (632, p<0.0001).  Median CD8⁺ T-cells at 6 months and 1 year were not significantly different when compared with normal donors.  However, there was a trend towards lower total CD8⁺ T-cell counts at all time points after haplo compared with MD BMT. Phenotypic effector memory (EM) and terminally differentiated effector memory T-cells (TEMRAs), particularly within the CD8⁺ fraction, recovered rapidly after haplo or MD BMT. Yet, phenotypically naïve cells remained low throughout the first post-BMT year. Consistent with our prior reports, Tregs comprised a larger portion of CD4⁺ T-cells after MD or haplo BMT compared with donor patterns (p<0.0001).

Conclusion: Haplo and MD BMT led to comparable reconstitution of NK and B-cells; however CD4⁺ and CD8⁺ T-cell recovery lags early after haplo BMT. This delay is likely attributable to the addition of MMF and tacrolimus, which may be mitigated by discontinuation of MMF at Day 35, resulting in equivalent CD4⁺ T-cell and CD8⁺ T-cell counts by 3 and 6 months, respectively. Ultimately, excellent immune reconstitution by 1 year supports the low rates of PTLD and infectious deaths after haplo or MD BMT with PTCy.