Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation with High Dose, Post-Transplantation Cyclophosphamide

Abstract

Allogeneic stem cell transplantation (SCT) from an HLA-haploidentical relative provides a potentially curative treatment option for hematologic malignancies patients who lack a suitably HLA-matched donor. The greatest challenge to performing HLA-haploidentical SCT has been high rates of graft failure and severe graft-versus-host disease (GVHD). Our group has been exploring high dose, post-transplantation cyclophosphamide (Cy) as prophylaxis of GVHD after nonmyeloablative, HLA-haploidentical bone marrow transplantation, or mini-haploBMT. Among 210 recipients of mini-haploBMT, 87% of patients have experienced sustained donor cell engraftment. The cumulative incidences of grades II-IV acute GVHD and chronic GVHD are 27% and 13%, respectively. Five-year cumulative incidence of non-relapse mortality is 18%, relapse is 55%, and actuarial overall survival and event-free survivals are 35% and 27%, respectively. These outcomes suggest that mini-haploBMT with post-transplantation Cy is associated with acceptably low toxicities and can provide longterm survival, if not cure, for many patients with advanced hematologic malignancies.

Virus infection in HLA-haploidentical hematopoietic stem cell transplantation: incidence in the context of immune recovery in two different transplantation settings

“…Further, resistance to PTCY seems to be mediated by the presence of the enzyme ALDH (aldehyde-dehydrogenase), thus leading to a selective killing of naive T cells lacking ALDH, while memory T cells providing antiviral immunity can be spared [44,45]. This is also clinically supported by an observation by Munchel and colleagues, who detected a donor-derived immunity against CMV returning by day +60 in 70 % of their patients after TCR/PTCY haplo-HSCT with an improved recovery of memory T cells resulting in decreased infection-related mortality [46].…”

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

“…A similar concept involves administering cyclophosphamide (50 mg/kg) to patients for 2 days starting 3 days after haplo-HSCT from T-cell replete donors to eliminate alloreactive T cells while sparing nonalloreactive/quiescent donor T cells. [29][30][31][32][33] This selective depletion is simpler than the genetic modification described here, and appears to effectively prevent GVHD. However, because every patient is treated with cyclophosphamide irrespective of GVHD, unnecessary depletion of critical T-cell subsets may occur, potentially delaying immune reconstitution and increasing opportunistic infections.…”

Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene

“…For the moment, we believe such a conclusion would be premature: the patient numbers are small, the trial was uncontrolled, and the great majority of enrolled patients had lymphoid malignancies or biphenotypic leukemia, for which there is little good evidence for a substantive contribution from a graft-versus leukemia effect of donor T cells. 8,9,[43][44][45][46][47] This possibility will, however, need to be considered in the design of largescale studies.…”