A 2-Step Approach to Haploidentical Versus Matched Related Hematopoietic Stem Cell Transplantation (HSCT): Equivalent Early Immune Reconstitution with Comparable Outcomes

Haploidentical (HI) HSCT enfranchises patients (pts) who have no HLA matched donor. In the 2-step approach to HI HSCT, a large fixed dose of allogeneic T cells are infused after conditioning, followed 2 days later by cyclophosphamide (CY) to induce bidirectional tolerance. A CD34 selected stem cell product is infused after CY. CY eradicates only activated T cells, supporting post HSCT immune reconstitution (IR) and low rates of GVHD. Given the favorable results with this approach in HI HSCT, we applied the regimen to MR HSCT. Delivering a fixed dose of donor T cells within the same 2 step regimen provides a level baseline from which to evaluate whether HI HSCT is inherently inferior to MR HSCT. Thus, we compared IR and clinical outcomes of patients undergoing HI HSCT versus MR HSCT using this approach.

Flow cytometric assessment of T-cell subsets was used to measure IR at day (D) +28 and +90 in pts undergoing HI and MR HSCT. Pts were evaluable for IR analysis if they had full donor chimerism, had no evidence of disease, and were fully engrafted. All trials utilized the 2 step approach. The MA conditioning regimen was 12 Gy of TBI over 4 days. 2 MR HSCT pts received a reduced intensity conditioning with Fludarabine/Cytarabine and 2 Gy of TBI. Conditioning was immediately followed by an infusion of 2 x 10⁸ CD3+ cells/kg donor T cells (step 1).  CY 60 mg/kg/d x 2 was given starting 2 days after the T cell infusion. Tacrolimus and MMF were begun on day -1. A CD 34 selected product was infused on day 0 (step 2).

Both HI and MR showed equivalent early IR in all T-cell subsets with no statistical differences between them. There were no deaths from infections or GVHD. GVHD was controlled in all cases with steroids and/or photopheresis. Each group had 1 mortality from regimen related toxicity. No rejections or engraftment failures were observed. CMV reactivation was higher in the HI group, with no CMV organ disease. After a median follow up of 18 months (range 2-60), both HI and MR HSCT had similar survival rates, 83% and 78% respectively.

Using the same 2 step approach, which allows uniform T cell dosing, comparable outcomes were seen in terms of IR, significant GVHD, incidence of regimen-related mortality and survival in HI vs MR HSCT recipients, albeit with higher CMV reactivation.  The establishment of this "level playing field" in terms of non-relapse mortality, allows for future inquiries which compare graft versus tumor effects between the 2 donor sources with less confounding influences.

	HI HSCT (%)	MR HSCT (%)
Number	29	23
Age (range)	49 (21-65)	49 (27-64)
Sex (M/F)	19/10	17/6
Median CD34 cells (x 106/kg)	4.7	4.32
Disease
AML/MDS	16 (55)	11 (48)
ALL	11 (38)	5 (22)
NHL	2 (7)	7 (30)
Conditioning
MA	29 (100)	21 (91)
RIC	0	2 (9)
Outcomes:
Median ANC recovery -days	11	11
Median Platelet recovery- days	17	18
aGVHD III-IV	3 (10)	1 (4)
cGVHD	5 (12)	1 (4)
CMV Reactivation	10 (35)	4 (17)
Deaths	5 (17)	5 (22)
Cause of Death:
Infection	0	0
Relapse	4 (14)	4 (17)
Toxicity	1 (3)	1 (4)
GVHD	0	0