Abstract
Donor lymphocyte infusion (DLI) is a key strategy for the treatment of AML relapse after allogeneic hematopoietic cell transplantation (allo-HCT) and has been used for either prophylactic, pre-emptive, or therapeutic purposes. However, the prognosis of these patients remains dismal even after DLI infusion (2-year overall survival, ~25%), and the efficacy is achieved at the cost of toxicities such as graft-versus-host (GVH) disease. Attempts to optimize DLI efficacy and safety, such as dose/timing modification and the use of cytoreduction, before DLI have been performed previously. Recently, a great number of novel targeted and immunomodulatory agents have emerged. Some of them, such as hypomethylating agents, FLT3 and Bcl-2 inhibitors, have been used in combination with DLI, aiming to enhance the graft-versus-leukemia effect. Moreover, manipulation of the DLI graft through cell selection (e.g., donor NK cells) or cell engineering (donor CAR-T cells) has shown potentially superior anti-tumor effects but less GVH effect than conventional DLI in clinical trials. This review summarizes the recent advances on the use of DLI for the prophylaxis/treatment of AML relapse and discusses future strategies which may further improve the treatment efficacy.
Highlights
Allogeneic hematopoietic cell transplantation remains the therapy with the highest chance of long-term remission for acute myeloid leukemia (AML), especially for those in first complete remission (CR1) who belong to the European LeukemiaNet (ELN) intermediate or highrisk prognostic groups, those who remain measurable residual disease (MRD)-positive after induction therapy as well as those beyond CR1 [1]
We reported the use of low-dose cyclosporine A (CsA) (1 to 2 mg/kg/day) after donor lymphocyte infusion (DLI) for 3 to 4 weeks after prophylactic mDLI in the G-CSF/anti-thymocyte globulin (ATG)-based allo-HCT protocol, and the cumulative incidence (CI) of grade II–IV DLI-associated acute GVHD (aGVHD) was 17.6% [34]
It is recommended to use prophylactic/pre-emptive DLIs especially in high-risk AML after allo-HCT since therapeutic DLI for overt relapse is related to a lower chance of disease control
Summary
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the therapy with the highest chance of long-term remission for acute myeloid leukemia (AML), especially for those in first complete remission (CR1) who belong to the European LeukemiaNet (ELN) intermediate or highrisk prognostic groups, those who remain measurable residual disease (MRD)-positive after induction therapy as well as those beyond CR1 [1]. Gao et al compared haploidentical and matched-sibling mDLI, followed by lowdose CsA (median: 2.3◊107 CD3+ cells/kg for the entire cohort), in high-risk AML defined by progressive disease at transplant, CR1 achievement with ≥3 cycles of chemotherapy, or those carrying TP53, DNMT3a, TET2, or FLT3-ITD gene mutations They observed a higher 100-day grade II–IV aGVHD CI (60 vs 31%) and worse 1-year NRM (28 vs 0%) in the haplo than the matched-sibling cohort, indicating a potentially higher toxicity for haplo than matched-sibling DLI [75]. The 2-year CI of grade I–III aGVHD was 31.5% [36] In another retrospective study analyzing 77 high-risk AML/MDS patients based on unfavorable genomic or clinical status at transplantation (AML, n = 54; MDS, n = 23), prophylactic or pre-emptive azacitidine combined with DLI achieved a 2-year CI of relapse of 22%, and the CIs of grade II–IV acute GVHD and cGVHD were 27.4 and 45%, respectively [77].
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