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A B S T R A C T CTLA4Ig attenuates T cell activation by co-stimulation blockade, but natural killer (NK) cells are not only resistant to CTLA4Ig, they also may demonstrate better antileukemia effect in the presence of CTLA4Ig. To explore this phenomenon we used sequential CTLA4Ig primed donor lymphocyte infusion (DLI) after post-transplant cyclophos-phamideÀbased haploidentical transplantation. Thirty patients (CTLA4Ig-DLI group) with advanced leukemia received CTLA4Ig on day À1 and subsequently on days +7, +21, and +35, followed 12 hours later by DLI of 1 to 10 £ 10 6 CD3 + T cells/kg containing .1 to 3.27 £ 10 6 /kg CD56 + NK cells, with low dose cyclosporine for 60 days. The incidences of acute graft-versus-host disease (GVHD), chronic GVHD and nonrelapse mortality (NRM) were 6.7%, 21%, and 4.5 %, respectively, with disease progression of 23.3% and overall survival of 79% at 18 months. Patients without disease progression had a significant early surge in CD56 dim CD16 + NK cells with lower NKG2A expression. CTLA4Ig primed DLI was associated with an upregulation of CD86 in mature NK cells that was not witnessed with CTLA4Ig administration alone. Thus, CTLA4Ig primed DLI resulted in early proliferation of mature NK cells with cytotoxic potential enabling early institution of adoptive immunotherapy to mitigate the risk of relapse in advanced leukemia with reduced GVHD and NRM.

We conducted a prospective study on T and natural killer (NK) cell subset composition of graft and transplant outcomes in T cell-replete haploidentical transplantation with a single dose of subcutaneous plerixafor (Px) added to granulocyte colony-stimulating factor (G-CSF)-based mobilization in allogeneic donors to collect 10 × 10/kg CD34 hematopoietic stem cells (HSCs) at single apheresis. Twnety-six donors received G-CSF + Px and 25 G-CSF alone for mobilization. Despite significantly lower peripheral blood (PB) CD34 HSCs on day 4 in the G-CSF + Px group (33 [range, 6-47] cells/µL versus 81 [range, 50-168] cells/µL in the G-CSF group; P = .0001), PB CD34 HSC count (median 136 versus 139 cells/µL) on day 5 as well as that in the graft (2.7 versus 2.3 × 10/mL, P = .1) were comparable between the 2 groups. The total nucleated cell count was higher (3.4 versus 3.1 × 10/mL, P = .05), but CD4 T cells (2.3 versus 2.7 × 10/mL, P = .09) were lower in the G-CSF group with mobilization of regulatory T cells being similar. NK cells were skewed toward the CD56/16 subset in both groups, varying significantly from the steady-state NK subset ratio in PB. The time to engraftment, incidences of acute and chronic graft-versus-host disease, nonrelapse mortality, and overall survival were also similar. Addition of single-dose Px to G-CSF mobilization improves CD34 recovery and does not significantly alter the T and NK cell composition of the graft, including regulatory T cells, with no adverse impact on transplant outcomes.

To understand the phenomenon of early alloreactivity (EA) in younger children undergoing post-transplantation cyclophosphamide (PTCy)-based haploidentical transplantation, we studied the graft composition and the immune reconstitution in 32 consecutive patients (aged 2 to 25 years) undergoing PTCy and T cell costimulation blockade based peripheral blood stem cell transplantation with emphasis on CD45RA subset of regulatory T cells (Tregs). All but 1 engrafted, and 14 patients experienced EA (acute graft-versus-host disease grades II to IV, n = 8; and post-transplantation hemophagocytic syndrome, n = 6) with a cumulative incidence of 43.7%; 42% developed mild chronic graft-versus-host disease. The overall survival was 70.2% with a nonrelapse mortality of 16.8% at a median of 19 months. Age < 10 years, donor age > 45 years, and poor recovery of Tregs correlated with EA. Not Tregs but higher CD45RA Tregs in the graft was associated with less EA (11.7% versus 32.5%, P = .0001). Higher donor age correlated with a lower CD45RA Tregs in the graft (P = .01). However, only higher CD45RA Treg percentage in the graft favorably impacted EA as well as nonrelapse mortality and overall survival. Our study demonstrates a critical role for CD45RA Tregs in determining EA and outcome after PTCy-based haploidentical peripheral blood stem cell transplantation, and the age-related physiologic decline in this population might be responsible for adverse impact of donor age.