The Two-Step Approach to Haploidentical Transplant: Can Altering Timing in the Conditioning Regimen Increase Graft Versus Tumor Effects?

In the two-step approach to haploidentical hematopoietic stem cell transplantation (HI-HSCT), following conditioning, recipients receive the lymphoid portion of their graft (“DLI”) containing a fixed dose of 2 x 10 8/kg CD3+ cells (Step 1 of the transplant). After the DLI, a 2 day period of alloreactivity and haploimmunostorm occurs which resolves with the administration of Cyclophosphamide (CY) for GVHD prophylaxis/rejection prevention. After the completion of CY, a CD34-selected donor product is infused (Step 2 of the transplant). It has been postulated that a rapid reduction in quantity and a functional impairment of alloreactive T cells by CY contributes to the establishment of tolerance between the donor and recipient immune systems. Based on their degree of disease burden at HSCT, a potentially important difference between patients undergoing HI-HSCT is the percentage of graft versus tumor (GVT) versus graft versus host (GVH) reactive T cells that are likely to become activated during the haploimmunostorm, and as a result of this activation, their subsequent inhibition by CY. In the initial two-step trial (2006-2010-initial group), relapsed disease was the major barrier to long-term survival (OS). In the follow-up trial (2013-2016-later group), extra time between the end of conditioning and the DLI was added to allow for a greater reduction in disease burden prior to the introduction of the DLI (Figure). We hypothesized that by allowing more of the malignancy to die off, less GVT specific T-cells in the DLI would become activated prior to CY administration. The result would be the avoidance of suppression of these cells by CY resulting in reduced relapse rates.