Abstract
Murine models of HCT established that nonablative conditioning using low doses of irradiation targeted to lymphoid tissues (TLI) and depletive anti-T cell antibodies protects against GVHD by skewing residual host T cell subsets to favor regulatory natural killer T cells that suppress GVHD by polarizing donor T cells toward secretion of non-inflammatory cytokines such as IL-4. We recently translated the murine protocol to a clinical study of 37 patients (pts) using nonmyeloablative TLI and ATG host conditioning with HLA matched related (MRD) and unrelated (URD) donors, and showed a marked reduction in the incidence of acute GVHD (aGVHD) while retaining graft anti-tumor activity (Lowsky et al., NEJM2005; 353). We now report the clinical outcomes following HCT of a larger set of pts using the same TLI and ATG regimen. Seventy consecutive pts with hemato-lymphoid malignancies (46 with lymphoid malignancies and 24 with acute leukemias) received MRD (38) or URD (32) G-CSF mobilized HCT. Of the 46 pts with lymphoid malignancies, 40 (87%) had advanced stage disease, 25 (54%) had relapsed after a prior autologous transplant, 31 (67%) were in partial remission (PR) at the start of the allogeneic transplant regimen, 6 (13%) had progressive disease (PD) and 9 (20%) were in a complete remission (CR). Of the 24 pts with acute leukemia 13 (54%) were in a first CR, 8 (33%) in second CR or beyond, and 3 (13%) were not in remission at the start of the transplant regimen. Sixty-eight of the 70 (97%) pts achieved multilineage donor cell engraftment within 56 days post transplantation. All pts were monitored for manifestations of aGVHD using standard scoring scales during the first 100 days after transplantation. Among the 38 recipients of an MRD graft aGVHD was grade 0 in 36 (95%) pts and grade I in 2 (5%) pts. Among the 32 pts that received grafts from an URD aGVHD was scored as grade 0 in 24 (75%) pts, grade I in 5 (16%) pts, grade II in 2 (6%) pts, and grade III in 1 (3%). All cases of aGVHD were treated to resolution. Thirty-seven of 38 (97%) pts with grafts from a MRD survived more than 100 days and were at risk for chronic GVHD (cGVHD). Among these, 26 (70%) had no cGVHD, 4 (11%) had limited cGVHD and 7 (19%) extensive cGVHD. Twenty-eight pts with grafts from URDs were at risk for cGVHD; 19 (68%) had no cGVHD, 3 (11%) had limited cGVHD and 6 (21%) had extensive cGVHD. Among the 46 transplant recipients with lymphoid malignancies, the follow-up ranged from 1674 to 197 days; 12 of these patients died and six were from disease relapse. The Kaplan-Meier (K-M) actuarial event free survival (EFS) at 3 years is 43%. EFS for patients that relapsed with lymphoma after failing a prior autologous transplant (n=25) was not different compared to patients that did not have a prior autologous transplant (n=21) as 6 events occured in both groups. The period of observation for the 24 pts with acute leukemia ranged from 190 to 1631 days; 10 of 11 pts died from disease relapse. The K-M actuarial EFS at 3 years is 50%. These data confirm the low incidence of acute and chronic GVHD using the TLI and ATG regimen in patients receiving grafts from MRD and URD. The low incidence of disease relapse in this group of patients with high-risk disease demonstrates the retention of graft anti-tumor activity.
Post-autologous transplant maintenance therapies in lymphoid malignancies: are we there yet?