Feasibility, safety, and efficacy of early prophylactic donor lymphocyte infusion after T cell-depleted allogeneic stem cell transplantation in acute leukemia patients

Annals of Hematology https://doi.org/10.1007/s00277-023-05145-1 ORIGINAL ARTICLE Feasibility, safety, and efficacy of early prophylactic donor lymphocyte infusion after T cell‑depleted allogeneic stem cell transplantation in acute leukemia patients Boris van der Zouwen1 · E. A. S. Koster1 · P. A. von dem Borne1 · L. E. M. Oosten1 · M. W. I. Roza‑Scholten2 · T. J. F. Snijders3 · D. van Lammeren4 · P. van Balen1 · W. A. F. Marijt1 · H. Veelken1 · J. H. F. Falkenburg1 · L. C. de Wreede2 · C. J. M. Halkes1 Received: 7 January 2023 / Accepted: 21 February 2023 © The Author(s) 2023 Abstract Prophylactic donor lymphocyte infusion (DLI) starting at 6 months after T cell-depleted allogeneic stem cell transplantation (TCD-alloSCT) can introduce a graft-versus-leukemia (GvL) effects with low risk of severe graft-versus-host-disease (GvHD). We established a policy to apply low-dose early DLI at 3 months after alloSCT to prevent early relapse. This study analyzes this strategy retrospectively. Of 220 consecutive acute leukemia patients undergoing TCD-alloSCT, 83 were prospectively classified to have a high relapse risk and 43 were scheduled for early DLI. 95% of these patients received freshly harvested DLI within 2 weeks of the planned date. In patients transplanted with reduced intensity conditioning and an unrelated donor, we found an increased cumulative incidence of GvHD between 3 and 6 months after TCD-alloSCT for patients receiving DLI at 3 months compared to patients who did not receive this DLI (0.42 (95%Confidence Interval (95% CI): 0.14–0.70) vs 0). Treatment success was defined as being alive without relapse or need for systemic immunosuppressive GvHD treatment. The five-year treatment success in patients with acute lymphatic leukemia was comparable between high- and non-high-risk disease (0.55 (95% CI: 0.42–0.74) and 0.59 (95% CI: 0.42–0.84)). It remained lower in high-risk acute myeloid leukemia (AML) (0.29 (95% CI: 0.18–0.46)) than in non-high-risk AML (0.47 (95% CI: 0.42–0.84)) due to an increased relapse rate despite early DLI. Keywords Prophylactic donor lymphocyte infusion · Allogeneic stem cell transplantation · Graft-versus-host-disease · Treatment success Introduction Allogeneic stem cell transplantation (alloSCT) is a curative treatment option for acute leukemia patients by donorderived T cell responses against recipient hematopoietic * Boris van der Zouwen 1 Department of Hematology, Leiden University Medical Center, C2R, 2300 RC, Leiden 9600, The Netherlands 2 Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands 3 Department of Hematology, Medical Spectrum Twente, Enschede, The Netherlands 4 Department of Hematology, HagaZiekenhuis, The Hague, The Netherlands cells including the malignant cells, also known as the graftversus-leukemia (GvL) effect [1–4]. GvL is frequently associated with graft-versus-host disease (GvHD), i.e., donor T cell responses against nonhematopoietic recipient tissues. GvHD requiring systemic immunosuppression (sIS) carries significant morbidity and mortality [5]. Of all patients receiving alloSCT for acute leukemia, 30% to 70% require treatment for chronic GHVD, often for longer than 2 years [6–9]. GvHD risk can significantly be reduced by depletion of donor T cells, but T cell depletion (TCD) is associated with an increased relapse rate, especially in high-risk leukemia patients [10–13]. Donor lymphocyte infusion (DLI) after TCD-alloSCT is applied to achieve a persistent GvL response without induction of severe GvHD [12, 14, 15]. The rationale to postpone this DLI is to wait for a less proinflammatory environment than present at the time of the 13 Vol.:(0123456789) Annals of Hematology transplantation, which gradually occurs after definitive donor hematopoiesis has been established, tissue damage has been repaired, and recipient antigen-presenting cells (APC) have been partially replaced by donor APC [16]. Other factors that can influence the magnitude of the donor-derived immune response after DLI include the number of infused effector cells and the degree of genetic disparity between patient and donor [17]. Our center previously reported that most patients with acute leukemia experience persistent remission without the need of sIS for chronic GvHD after receiving prophylactic DLI at 6 months after TCD-alloSCT [18]. However, relapses before this DLI occurred in patients with high-risk acute leukemia [19]. Therefore, we adjusted our treatment algorithm in 2007 by adding an extra prophylactic low-dose DLI at 3 months after TCD-alloSCT for this patient group [20]. The aim of this early DLI was to lower the risk of recurrence of leukemia prior to standard prophylactic DLI at 6 months without inducing a significant increase in the risk of severe GvHD. In this study, we investigated the feasibility, toxicity and long-term efficacy of a strategy in which an early low-dose DLI was scheduled after TCD-alloSCT for all acute leukemia patients with a high early relapse risk and no previous GvHD. Materials and methods Study population and prophylactic DLI strategy All consecutive patients who underwent TCD-alloSCT with a 9/10 or 10/10 HLA-matched donor for acute leukemia in complete remission (CR) at the Leiden University Medical Center (LUMC) between January 2007 and December 2015 were included in this study. All patients gave written informed consent for treatment, data collection, and scientific evaluation before transplantation. The study was approved by the LUMC Ethics Committee. Data were analyzed as of February 2021. Patients who were transplanted for AML after a myeloproliferative disease or were planned to receive experimental cell products after transplantation as part of a clinical trial were excluded from this analysis. Since 2007, all patients with acute leukemia were scheduled to receive prophylactic DLI, defined as an infusion that is planned to be administered at a prescheduled time point after TCD-alloSCT to patients without a hematological relapse, independently of chimerism status [21]. All patients were planned to receive 1.5 or 3 × 106 CD3 cells/kg, for unrelated and matched sibling patient-donor combinations, respectively at 6 months. Patients who developed GvHD before this timepoint, did not receive DLI as the occurrence of GvHD was interpreted as indication of an alloimmune 13 response. High-risk leukemia patients were scheduled to receive a low-dose prophylactic DLI at 3 months after transplantation as well (0.15- or 0.3 × 106 CD3 cells/kg, for unrelated and matched sibling patient-donor combinations, respectively) [20]. Since DLI is standard care in this strategy, donors are informed that a request for T cell apheresis would probably follow some months after the donation of the stem cells. T cell apheresis for multiple DLI products was performed immediately prior to the first DLI. Fresh donor T cells were administered as the 1 st DLI, and remaining T ce (...truncated)