Prophylactic and pre-emptive donor lymphocyte infusion in patients with acute myeloid leukemia and myelodysplastic syndrome: validation of current recommendations and proposal of a modified outcome assessment

Abstract

Prophylactic and pre-emptive donor lymphocyte infusion (pro/preDLI) is used to prevent hematologic relapse of acute myeloid leukemia and myelodysplastic syndromes after allogeneic stem cell transplantation. Given the lack of prospective trials, outcome reports, risk factor analyses and published recommendations on DLI administration have had to rely on information from registry studies, frequently limited by inconsistent reporting and missing data. We, therefore, performed an extensive review of the charts of recipients of pro/preDLI in two German centers to investigate the clinical applicability of current guidelines in a well-defined cohort. Furthermore, as the outcome after pro/preDLI is unsatisfactorily described by conventional parameters, we constructed a model for "treatment success", defined as leukemia-free survival without intensive immunosuppressive treatment for graft-versus-host disease (GvHD). Eighty-three patients had received DLI: proDLI (N=36), preDLI for incomplete chimerism (N=27) and preDLI for persisting minimal residual disease/molecular relapse (N=20). According to current guidelines concerning initial T-cell doses and timing of DLI, 42% of patients had received DLI as recommended (standard intensity), whereas 30% had received DLI at lower cell doses and/or at a later timepoint (low intensity) and 28% had received DLI at higher cell doses and/or at an earlier timepoint (high intensity). Two-year rates of overall survival, leukemia-free survival, relapse incidence and non-relapse mortality within the entire cohort were 80%, 67%, 27% and 8%, respectively. One-year rates of high-grade acute/chronic GvHD were 34% and 27%, respectively, among all patients and 53% and 33% after high-intensity DLI. One-year treatment success rates were 72% and 69% after low- and standard-intensity DLI, respectively, in contrast to 34% after high-intensity DLI. Apart from advanced disease at the time of allogeneic stem cell transplantation, high-intensity DLI was the major risk factor for lower overall survival (hazard ratio [HR]=6.12), lower leukemia-free survival (HR=5.43), higher acute GvHD (HR=2.51), and lower treatment success (HR=0.41), supporting adherence to current recommendations.

Figure 1.

Structure of the multistate model. At time of their first donor lymphocyte infusion (DLI), all patients started in a state of being alive, without graft-versus-host disease (GvHD) and without relapse (1). From there, patients could transition into the following states: standard-dose immunosuppression (IS) for GvHD (2), relapse (5) or being alive without having received IS for GvHD nor experiencing relapse (6). Although clinically possible, a transition between state (1) and non-relapse mortality (NRM) (4) was not modeled because this transition was not observed in our cohort. Possible transitions for patients in the non-absorbing state (2) included either stop IS or ongoing low-dose IS (3), NRM (4) or relapse (5). From the non-absorbing state (3), patients could pass to relapse (5) or NRM (4). Patients with a relapse (non-absorbing) could only transition to leukemia-associated death (LAD) (7). The cumulative incidence of treatment success was assessed in a competing risk model with relapse, death or standard-dose IS regarded as competing events.

Figure 2.

Overall and leukemia-free survival, cumulative incidence of relapse, and non-relapse mortality by indication for donor lymphocyte infusion. DLI: donor lymphocyte infusion; MDR: minimal residual disease or molecular relapse.

Figure 3.

Overall and leukemia-free survival, cumulative incidence of relapse, and non-relapse mortality by donor lymphocyte infusion intensity. See Methods section for definitions of donor lymphocyte infusion intensity. DLI: donor lymphocyte infusion.

Figure 4.

Multistate model for the analysis of clinical events over time after prophylactic or pre-emptive donor lymphocyte infusions. The green areas represent states fulfilling the criteria for treatment success, defined as being alive, without relapse and with no or only low-dose immunosuppression for graft-versus-host disease. LAD: leukemia-associated death; NRM: non-relapse mortality; IS: immunosuppression; DLI: donor lymphocyte infusion.