T cell-depleted partial matched unrelated donor transplant for advanced myeloid malignancy: KIR ligand mismatch and outcome

Abstract

To evaluate the applicability of high-dose conditioning, CD34 selection, and enhanced natural killer (NK) cell alloreactivity reported as promising after haploidentical transplantation, we tested the same strategy for patients with advanced/high-risk myeloid leukemia lacking either related or well-matched unrelated donors (URD). In a prospective multicenter clinical trial using pretransplantation conditioning of thiotepa (5 mg/kg/day × 2), fludarabine (40 mg/mg/M(2)/day × 5), and total body radiation (800 cGy) plus thymoglobulin (2.5 mg/kg/day × 2), as well as a CD34 selected filgrastim stimulated peripheral blood graft from a partial matched URD, we treated 24 patients. The patients (median age 40 [range: 22-61]) were mismatched at 1-3 of 10 HLA loci with their donors; all were mismatched at HLA-C. Thirty-seven percent were ethnic or racial minorities. Twenty-one of 24 engrafted promptly with 1 primary graft failure and 2 early deaths. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) (34%, 95% confidence interval [CI], 14-54%), chronic GVHD (20%, 95% CI, 2%-38%), and relapse (26%, 95% CI, 8%-84%) were unaffected by KIR ligand donor:recipient mismatch (n = 5) versus KIR ligand match (n = 19). Only 3 (12%) had grade III-IV GVHD. Nonrelapse occurred in 17% (95% CI, 30%-31%) by 100 days and in 35% (95% CI, 15%-55%) by 1 year. Two-year survival and leukemia-free survival were each 40% (95% CI, 21%-59%) and was similar in KIR ligand matched or mismatched patients. Infections, mostly in the first 2 months, were frequent, and were the cause of death in 5 patients (35% of deaths). T cell recovery and NK cell proliferation and functional maturation were not altered by KIR ligand match or mismatch status. For these high-risk patients, this high intensity regimen and T depleted approach yielded satisfactory outcomes, but logistical difficulties in arranging URD grafts for patients with high-risk, unstable leukemia limited accrual. Improvements in peritransplantation disease control and additional measures to augment the allogeneic graft-versus-leukemia effect are still required.

Figure 1

Cumulative incidence of acute and chronic GVHD, relapse and NRM

Figure 2

Survival (A) and Leukemia Progression-Free Survival (B) after partial matched URD HCT

Figure 3

Lymphocyte recovery after HCT. Circulating lymphocyte subsets (T cells, B cells, NK cells) in KIR-ligand matched (A) and KIR-ligand mismatched (B) HCT. The recovery pattern and timing was similar in both cohorts and recovered to near normal (similar to pre-HCT donor and recipient measures) by 6–9 months after HCT. Subset numbers were similar in both cohorts studied. Absolute lymphocyte numbers were not available at all timepoints thus absolute lymphocyte subset numbers are not shown.

Figure 4

Lymphocyte cytolysis of K562 in post-HCT samples. Shown are the % lysis (effector:target 20:1) of K562 targets by lymphocytes collected from HCT donor and recipients over time post-HCT. Recovery of lytic activity was good beyond day 28 post HCT and was similar in recipients of KIR-ligand matched and mismatched HCT.