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B. Dholaria et al.
Figure 1. Proposed treatment algorithm of therapeutic, pre-emptive and prophylactic donor-lymphocyte infusion (DLI) following T-cell replete haploidentical hematopoietic cell transplantation (HCT). HLA: human leukocyte antigen; MRD: minimal residual disease; GvHD: graft-versus-host disease; TKI: tyrosine kinase inhibitor.
specific MRD management strategies. DLI should not be used in patients who have converted to host chimerism due to increased risk of marrow aplasia.49 An alternative strategy for such patients would be to undergo a second allo-HCT from the same or from a different donor. It is important to weigh the risk of GvHD and marrow aplasia versus the potential benefit of reducing the disease relapse when considering pre-emptive DLI for MRD or MC.
Prophylactic haplo-donor-lymphocyte infusion
Prophylactic DLI from a matched donor has been stud- ied in patients with high-risk myeloid malignancies and was associated with improved disease-specific outcomes and low NRM.11,50,51 It can contribute to immune reconsti- tution and reduce the risk of infection,52 which is a major challenge after a T-cell depleted haplo-HCT. A matched- pair analysis by the EBMT showed improved OS in high- risk AML recipients who received prophylactic DLI from a matched donor (70% vs. 40% in controls; P=0.027).53 Inclusion criteria differ among published studies in their definition of high-risk disease. Most reports included patients with primary induction failure acute leukemia, high disease risk index, active disease before allo-HCT or the presence of high-risk mutations (i.e. TP53, ASXL1, RUNX1) in myeloid malignancies.54-57 One of the first experiences with prophylactic haplo-DLI was in the set- ting of autologous-HCT. Nagler et al. reported outcomes of 26 patients who received multiple haplo-DLI (with/without IL-2) after an autologous-HCT. This approach was feasible in inducing GvHD, but higher cell doses led to increased toxicity.58 The timing of prophylac- tic-DLI is also important as decreasing the interval
between allo-HCT and DLI will likely increase the risk of aGvHD.13 The activity of ATG, given as a part of condi- tioning, may persist for weeks, and residual ATG may negatively impact prophylactically infused donor lym- phocytes.59 At the same time, the administration of haplo- DLI as early as d+45 was feasible in single center stud- ies.32,56 It may be reasonable to administer prophylactic haplo-DLI before d+90 given that median time to relapse after allo-HCT is approximately three months.
Prophylactic donor-lymphocyte infusion in T-cell depleted haplo-hematopoietic cell transplantation
Early experience with prophylactic haplo-DLI was with T-cell-depleted haplo-HCT where donor lymphocytes were infused after a CD34+ cell-selected graft to enhance immune reconstitution.60-62 Perruccio et al. showed that infusion of donor-derived non-alloreactive T cells specific for cytomegalovirus (CMV) and aspergillus resulted in the rapid development of T-cell responses against these pathogens without inducing GvHD.63 Another prospec- tive study utilized CD8+ T-cell depleted DLI, which resulted in aGvHD in 26% of patients with 2-year PFS of 45%.62 Donor-derived T regulatory cells (Tregs), co-infused with conventional T cells (Tcons) were shown to protect recipients against GvHD.64 In a prospective study, patients received Tregs (d -4) followed by a megadose of CD34+cells and Tcons on d0 from a haploidentical donor without any post-transplant immunosuppression. Only 15% of the patients developed ≥grade 2 aGvHD and DFS was 56% at 18 months.61 In another prospective study by Gilman et al., 34 pediatric patients were infused an unma- nipulated prophylactic haplo-DLI with MTX between d+30 and d+42 after a T-cell depleted/CD34+ selected haplo-HCT. The intervention was safe and 2-year NRM
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haematologica | 2020; 105(1)