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

Abstract

Background: Posttransplantation cyclophosphamide (PTCy) limits severe acute and chronic graft-versus-host disease (GVHD) and facilitates engraftment, permitting HLAmatched 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/ml) 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

Immune reconstitution after T-cell replete HLA haploidentical hematopoietic stem cell transplantation using high-dose post-transplant cyclophosphamide

“…In myeloablative conditioning (MAC) haploHSCT with PTCy, CD8 + T cells neared normal levels by 60 days and achieved them by 180 days post-transplant. 63 This CD4+ and especially CD8+ T cell recovery was comparable with that after T cell–replete BM allografting using standard GVHD prophylactic regimens. 64 The generation of new naïve T cells by resumed thymic output did not begin until day 90 post-haploHSCT, and CD4+ thymic emigrant T cell or naïve T cells were absent during this time period.…”

Early viral reactivation despite excellent immune reconstitution following haploidentical Bone marrow transplant with post‐transplant cytoxan for sickle cell disease

“…It has been postulated that PTCy permits naïve and non‐activated memory cells to reconstitute in the later post‐transplant period, allowing for late protection against infectious events . In addition, the high early viral reactivation incidence has been attributed to low numbers of adoptively transferred memory T cells in the early phase after haplo‐BMT, contributing to a deficiency in cell‐mediated immunity, though with rapid recovery based on selective deletion of alloreactive rather than pathogen‐specific immune cells with PTCy . The rate of improvement characteristically increased for each subset (CD4, CD8, CD19, NK) after a median of 6 months, which correlated with the cessation of immunosuppression.…”

“…10,12 In addition, the high early viral reactivation incidence has been attributed to low numbers of adoptively transferred memory T cells in the early phase after haplo-BMT, contributing to a deficiency in cell-mediated immunity, though with rapid recovery based on selective deletion of alloreactive rather than pathogen-specific immune cells with PTCy. 10,41,42 The rate of improvement characteristically prospective studies. 21,22 A key and unexpected finding in our study was an increased incidence of early viral reactivations and infections before day + 100, which occurred in 70% (16/23) of patients, including 43% (10/23) with multiple viral reactivations or infections, the majority of which were due to CMV.…”

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

“…In the setting of T-cell replete haplo-HCT with both GIAC and PTCy-based protocols, CD8 + T cells recovered earlier than CD4 + T cells (158,(181)(182)(183). Faster CD8 + T cell recovery at day +90 correlated with higher CD3 + cells in the graft but was not associated with a higher incidence of GVHD (184).…”

“…Indeed, Peccatori and colleagues reported an expansion of Treg after haplo-HCT using a combination of ATG, sirolimus and MMF as GVHD prophylaxis (190). Moreover, in the Baltimore experience with a cohort of patients undergoing MAC haplo-HCT using PTCy, MMF, and tacrolimus-based GVHD prophylaxis, Tregs achieved normal donor levels at all time-points examined (day +30, +90, +180, and +365) (181). Finally, in haplo-HCT using the GIAC protocol, patients with a higher day +30 percentage of naive Treg, defined as CD4 + CD25 + CD45RA + , had a significantly lower incidence of grades II-IV acute GVHD (191).…”