Prophylactic Donor Lymphocyte Infusion Research Articles

Improving outcomes of hematopoietic stem cell transplant for leukemia in children and young adults in resource-limited setting

IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach in patients with relapsed and high-risk leukemia. This retrospective analysis aimed to investigate outcomes and risk factors associated with HSCT in children and young adults with hematological malignancies in a resource-limited setting. MethodsWe retrospectively evaluated 48 pediatric and young adult patients diagnosed with hematological malignancies who underwent HSCT at our institution between April 2017 and Jan 2023. ResultThe median age of the cohort was 10 years (6 months - 21 years), and the majority of patients underwent transplants for acute lymphoblastic leukemia (ALL) (n = 24; 50 %) and acute myeloid leukemia (n = 18; 37.5%). Median time to neutrophil and platelet engraftment were 15 days (range 9–28) and 18 days (range 9–40), respectively. One patient had primary graft failure. Cytomegalovirus reactivation occurred in 21 patients (43.8%). Seventeen patients received escalated donor lymphocyte infusion (DLI). With a median follow-up of 902 days (52–2490), the probability of event free survival and overall survival (OS) was 65.9% and 69.4%. OS for lymphoid and myeloid malignancies were 64.7% and 75.2%, respectively. Kaplan-Meier probabilities of OS for patients in first complete remission (CR), CR2, CR3, or with refractory disease were 80%, 76.2%, 0%, and 40%, respectively (p = 0.02). OS of the patients undergoing matched sibling donor (n = 17) or haploidentical HSCT (n = 31) was 70.6% and 69%, respectively (p = 0.989). ConclusionsOur study demonstrates excellent outcomes of patients with hematological malignancies undergoing allogeneic HSCT with similar outcomes in HLA-identical sibling donors and haploidentical first-degree family donors. Prophylactic DLI might be considered in patients with high-risk leukemia to prevent relapse, including ALL.

Randomized Trial of Prophylactic Donor Lymphocyte Infusion with Positively Selected CD4+ T Cells after HLA-Identical Allogeneic Stem Cell Transplantation

Introduction Allogeneic stem cell transplantation (alloSCT) can cure patients with hematological malignancies by T-cell mediated alloreactivity against patient hematopoiesis, the graft-versus-leukemia (GvL) effect. GvL can coincide with graft-versus-host disease (GvHD) when donor T cells target non-hematopoietic tissues. Increase of donor chimerism in bone marrow (BM) or peripheral blood (PB) after alloSCT indicates GvL response. After T-cell depleted alloSCT, donor lymphocyte infusion (DLI) can restore GvL. Dose and timing of DLI influence the degree of alloreactivity. Low dose of unmodified DLI as low as 0.3x10 6 T cells/kg 3 months after alloSCT appeared not to cause GvHD. (Zouwen et al. Ann Hematol, 2023) We hypothesized that infusion of a higher dose of purified CD4+ donor T cells would not cause GvHD, while inducing GvL by selective targeting of the MHC class II positive hematopoietic cells. Method A randomized controlled phase 2 trial was conducted in patients with hematological malignancies after HLA-identical sibling alloSCT with alemtuzumab added to the graft. Patients without GvHD or relapse were randomized at 2.5 months for prophylactic DLI with 1.0x10 6/kg CD4+ T cells (CD4+ DLI) 3 months after alloSCT or conventional care without DLI (CC). Both groups were eligible for prophylactic unmodified DLI at 6 months. Cumulative incidence (CI) of GvHD requiring immunosuppressive treatment 3 months after randomization was the primary endpoint. Changes in the trajectory of chimerism in BM and subsets in PB (CD4+ T cells, CD8+ T cells, NK cells, B cells and monocytes) were compared by means of mixed effects beta regression as secondary endpoints. Results 66 patients were included (table 1). CI of GvHD did not differ between groups (CD4+DLI: 6.1% vs CC: 9.1%, Gray's test p>0.9). Relapse was comparable (CD4+DLI: 15% vs CC: 12%), although heterogeneity of diseases prevented a formal comparison. In the CD4+ DLI group, BM chimerism was full donor (FD, >95% donor) at baseline in 23/33 patients, while 10/33 had mixed chimerism (MC, ≤95%). In the CC group, 23/33 were FD and 10/33 MC. Some patients with MC at baseline converted to FD in both groups (CD4+ DLI: 1/10 vs CC: 1/10). Changes in BM chimerism did not differ between CD4+ DLI and CC (p = 0.9). Chimerism of B cells, NK cells and monocytes in PB resembled bone marrow chimerism with most patients being FD at baseline. Changes in chimerism did not differ between CD4+ DLI and CC (p = 1.0, 0.5 and 0.9 for B cells, NK cells and monocytes respectively). In the CD4+ DLI group, 25/30 evaluable patients were MC in the CD4+ T-cell subset in PB at baseline. 3 month after randomization 7/25 had converted to FD, 17/25 remained MC and 1/25 was unevaluable. Of the 17 patient who remained MC, CD4+ donor chimerism increased (absolute increase >5%) in 13, decreased (>5%) in 2 and was stable in 2. In the CC group, 26/32 were MC in CD4+ T cells at baseline, of which 6 converted to FD, 18 remained MC and 2 were unevaluable. Of the 18 patients remaining MC, CD4+ chimerism increased in 5, decreased in 9 and remained stable in 4. The CD4+ donor chimerism increased significantly after CD4+ DLI compared to CC (p = 0.01) (Figure 1). In the CD4+ DLI group, 23/29 evaluable patients were MC in the CD8 subset at baseline. 7/23 converted to FD, 15/23 remained MC and 1 was unevaluable. Of these 15 MC patients at 3 months, 9 had increasing, 5 stable and 1 decreasing donor chimerism after 3 months. In CC, 22/31 were MC at baseline. 4/22 converted to FD at 3 months and 17/22 remained in MC. Of the 17 MC patients, 6 had increasing, 3 decreasing and 8 stable chimerism. The CD8+ donor chimerism increased significantly in the CD4+ DLI group compared to CC (p = 0.03). Conclusion CD4+ selected DLI at a dose of 1x10 6 CD4+/kg 3 months after HLA identical T-cell depleted alloSCT did not cause GvHD. Chimerism in BM leukocytes, B cells, NK cells or monocytes did not indicate GvL mediated by CD4+ DLI, possibly because most patients were already FD at baseline. CD4+ and CD8+ T-cell donor chimerism increased significantly after CD4+ DLI, suggesting a GVL-effect - earlier demonstrated in vitro for 4 selected patients. (Van Balen et al. Front Immunol, 2018) However, most patients did not convert to FD in the T-cell compartment, suggesting the GvL-effect of CD4+ DLI was limited. We considered this GvL-effect insufficient to prevent relapse and stress the importance of CD8+ donor T cells as main drivers of alloreactivity after DLI following HLA-identical alloSCT.

Donor Lymphocyte Infusion for Prophylaxis and Treatment of Relapse in Pediatric Hematologic Malignancies after Allogeneic Hematopoietic Stem Cell Transplant.

Donor lymphocyte infusion (DLI) is effective for managing patients with hematologic malignancies after allogeneic hematopoietic stem cell transplant (HSCT). However, few studies have explored its optimal use in pediatric populations. Herein, we report our single-center experiences of DLI and factors for predicting its outcomes. This retrospective study included pediatric patients who had received DLI (between June 1998 and December 2022) after allogeneic HSCT. Data regarding patient characteristics, preDLI disease status, and DLI characteristics were collected. The primary outcomes were overall survival (OS), event-free survival (EFS), and graft-versus-host-disease (GVHD) development. The study cohort comprised 17 patients with acute leukemia, 3 with chronic leukemia, and 3 with lymphoma. Prophylactic, preemptive, and therapeutic DLI were used in 7, 7, and 9 patients, respectively. Patients' median age and DLI dose were 9 years and 4.6 × 10 7 CD3 + cells/kg, respectively. The 5-year OS, EFS, and non-relapse mortality were 43.5%, 38.3%, and 13.3%, respectively. Approximately 39% of the patients developed Grade III or IV acute GVHD, whereas moderate/severe chronic GVHD (cGVHD) occurred in 30% of the evaluable patients. Patients' disease status before HSCT (p = 0.009) and DLI (p = 0.018) were the key factors influencing EFS. The implementation of a dose escalation schedule was associated with a marginal reduction in the risk of moderate/severe cGVHD (p = 0.051). A DLI dose of ≥5 × 10 7 CD3 + cells/kg was significantly associated with a high moderate/severe cGVHD risk (p = 0.002) and reduced OS (p = 0.089). Patients' disease status before HSCT and DLI may help predict EFS. The use of DLI as a prophylactic and preemptive modality leads to a favorable 5-year EFS. To safely deliver DLI in children, clinicians must maintain vigilant monitoring and prepare patients in advance when escalating the dose to ≥5 × 10 7 CD3 + cells/kg.

Prophylactic donor lymphocyte infusion after haploidentical hematopoietic cell transplantation and post-transplant cyclophosphamide for treatment of high-risk myeloid neoplasms in children: A retrospective study.

Post-transplant cyclophosphamide (PTCy) has been recommended for prevention of graft-versus-host disease (GvHD) following haploidentical hematopoietic cell transplantation (haplo-HCT) for treatment of malignant blood diseases, but disease relapse remains a problem. Although donor lymphocyte infusion (DLI) is reported to be effective for treating post-transplantation relapse, the efficacy and safety of prophylactic-DLI (pro-DLI) post haplo-HCT, and PTCy in pediatric patients with hematological malignancies is unknown. We retrospectively analyzed the outcomes of 54 pediatric patients with high-risk myeloid neoplasms who received a PTCy regimen for GvHD prophylaxis and pro-DLI after haploidentical peripheral blood stem cell transplantation. The high-risk myeloid neoplasms in this cohort included acute myeloid leukemia (n=46) and myelodysplastic syndromes (n=8). Median follow-up was for 19.7 (range: 3.4-46.6) months. The cumulative incidences of grade II-IV and III-IV acute GvHD were 37.0% (95% CI: 22.7%-48.7%) and 16.7% (95% CI: 6.1%-26.0%), respectively. There were no graft-failure events, and the 2-year rate of moderate/severe chronic GvHD was 8.1% (95% CI: 0%-16.7%). The 2-year non-relapse mortality, relapse, disease-free survival, GvHD-free relapse-free survival, and overall survival rates were 5.1% (95% CI: 0%-11.7%), 16.6% (95% CI: 5.3%-26.6%), 78.9% (95% CI: 68.0%-91.6%), 62.2% (95% CI: 49.4%-78.3%), and 87.3% (95% CI: 78.3%-97.4%), respectively. Prophylactic donor lymphocyte infusion in the setting of haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide appears to be effective and safe in pediatric patients with high-risk myeloid neoplasms.

The graft-versus-leukemia effect of prophylactic donor lymphocyte infusions after allogeneic stem cell transplantation is equally effective in relapse prevention but safer compared to spontaneous graft-versus-host disease.

Therapeutic donor lymphocyte infusions (tDLI) are used to reinforce the graft-versus-leukemia (GvL) effect in relapse after allogeneic stem cell transplantation (alloSCT). In contrast, the role of prophylactic DLI (proDLI) in preventing leukemia relapse has been less clearly established, although supported by retrospective, case-control, and registry analyses. We report a prospective, monocentric, ten year cohort of patients with high risk acute leukemias (AL) or myelodysplasia (MDS) in whom proDLI were applied beyond day +120 post alloSCT to compensate for lack of GvL.272 consecutive allotransplanted AL or MDS patients in complete remission and off immunosuppression at day +120 were stratified according to the prior appearance of relevant GvHD (acute GvHD °II-IV or extensive chronic GvHD) as a clinical indicator for GvL. Escalating doses of unmodified proDLI were applied to 72/272 patients without prior relevant GvHD. Conversely, 157/272 patients with prior spontaneous GvHD did not receive proDLI, nor did 43/272 patients with contraindications (uncontrolled infections, patient refusal, DLI unavailability).By day 160-landmark analysis (median day of first DLI application), proDLI recipients had significantly higher five-year overall (OS) and disease free survival (DFS) (77% and 67%) than patients with spontaneous GvHD (54% and 53%) or with contraindications (46% and 45%) (p=0.003). Relapse incidence for patients with proDLI (30%) or spontaneous GvHD (29%) was significantly lower than in patients with contraindications (39%; p=0.021). With similar GvHD incidence beyond day +160, non-relapse mortality (NRM) was less with proDLI (5%) than without proDLI (18%; p=0.036).In conclusion, proDLI may be able to compensate for lack of GvL in alloSCT recipients with high risk AL or MDS.

Pre-emptive and prophylactic donor lymphocyte infusion following allogeneic stem cell transplantation.

Donor lymphocyte infusion (DLI) is an allogenic immunotherapy used after allogeneic hematopoietic stem cell transplantation. DLI takes advantage of the graft-versus-tumor effect induced by the infused CD3 + T cells, but may induce graft-versus-host disease. To date, DLI has been attempted to prevent hematological relapse after allogeneic hematopoietic stem cell transplantation in patients with mixed chimerism and molecular relapse (pre-emptive DLI), and as maintenance therapy in patients with high-risk hematological malignancies (prophylactic DLI). DLI response and efficacy depend on patient, disease, and DLI factors. This review discusses the efficacy and risks of DLI, with a focus on pre-emptive and prophylactic use.

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

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.

Efficacy of Azacitidine and Prophylactic Donor Lymphocyte Infusion after HSCT in Pediatric Patients with Acute Myelogenous Leukemia: A Retrospective Pre-Post Study

Pediatric patients with acute myeloid leukemia (AML) who undergo allogeneic hematopoietic stem cell transplantation (HSCT) continue to have high rates of relapse. In 2018, Phoenix Children's Hospital started using post-HSCT maintenance therapy in patients with AML in attempt to decrease the number of relapses after HSCT. This therapy consisted of the hypomethylating agent azacitidine (AZA; 6 cycles starting on day +60) and prophylactic donor lymphocyte infusion (DLI; 3 escalating doses beginning after day +120). We aimed to compare 2-year leukemia-free survival (LFS) post-HSCT between patients with AML who received post-HSCT maintenance therapy with AZA and prophylactic DLI and historical control patients who did not receive post-HSCT therapy. This retrospective pre-post study was conducted at Phoenix Children's Hospital and included patients with AML who underwent HSCT between January 1, 2008, and May 31, 2022. We compared LFS, overall survival (OS), and immune reconstitution patterns post-HSCT between patients with AML who received post-HSCT maintenance therapy with AZA and prophylactic DLI (postintervention group) and historical control patients who did not receive this post-HSCT maintenance therapy (preintervention group). Sixty-three patients were evaluable. After excluding 7 patients who died or relapsed prior to day +60, 56 patients remained, including 39 in the preintervention group and 17 in the postintervention group. The median age at transplantation was 9.1 years in the preintervention group and 11 years in the postintervention group (P=.33). The 2-year LFS was 61.5% in the preintervention group, compared to 88.2% in the postintervention group (P=.06). The 2-year OS was 69.2% in the preintervention group and 88.2% in the postintervention group (P=.15). The rates of CD3+CD4+ T cell and CD19+ B cell recovery were faster in the preintervention group compared to the postintervention group (P = .004 and .0006, respectively). In this limited retrospective study, post-HSCT maintenance therapy using AZA and prophylactic DLI was well tolerated; however, its efficacy is yet to be fully determined.

On Behalf of the SFGM-TC: Prophylactic Donor Lymphocyte Infusion in Patients Treated with Allogeneic Stem-Cell Transplantation for High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia

Introduction: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Unfortunately, it is still associated with a significant risk of relapse due to mechanisms of escape from the control of alloreactive T cells. Repetitive adjuvant donor lymphocyte infusion (DLI), termed prophylactic DLI (proDLI), as an effective strategy in preventing relapse is still debated. Methods: We performed a retrospective multicenter study to evaluate the efficacy of proDLI in allografted AML and MDS. We identified 56 patients treated with proDLI (DLI planned in full chimeras without any sign of disease relapse) and matched them to 167 patients in control group, (DLI performed for mixed chimerism or positive minimal residual disease) based on similar age, initial disease, cytogenetic prognosis, and conditioning intensity. Results: In univariate analysis, the incidence of severe aGVHD at 100 days and incidence of all grades of chronic GVHD 1 year after allo-HSCT were similar in the two groups. We also observed a trend of higher 3-year RI (52.61% [95% confidence interval 25.99–79.23]) in the proDLI group versus the control group (29.31% [20.28–38.34], p = 0.067). However, 3-year overall survival (p = 0.892), progression-free survival (p = 0.239), and nonrelapse mortality (p = 0.343) were similar between the two groups. In multivariate analysis, the only factor influencing overall and progression-free survival was anti-thymocyte globulin administration during the conditioning regimen. Conclusion: The proDLI strategy had an acceptable toxicity profile but did not improve patient outcomes compared to the pre-emptive strategy.

Competitive Repopulation and Allo-Immunologic Pressure Determine Chimerism Kinetics after T Cell-Depleted Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusion

After allogeneic stem cell transplantation (alloSCT), patient-derived stem cells that survived the pretransplantation conditioning compete with engrafting donor stem cells for bone marrow (BM) repopulation. In addition, donor-derived alloreactive T cells present in the stem cell product may favor establishment of complete donor-derived hematopoiesis by eliminating patient-derived lymphohematopoietic cells. T cell-depleted alloSCT with sequential transfer of potentially alloreactive T cells by donor lymphocyte infusion (DLI) provides a unique opportunity to selectively study how competitive repopulation and allo-immunologic pressure influence lymphohematopoietic recovery. This study aimed to determine the relative contribution of competitive repopulation and donor-derived anti-recipient alloimmunologic pressure on the establishment of lymphohematopoietic chimerism after alloSCT. In this retrospective cohort study of 281 acute leukemia patients treated according to a protocol combining alemtuzumab-based T cell-depleted alloSCT with prophylactic DLI, we investigated engraftment and quantitative donor chimerism in the BM and immune cell subsets. DLI-induced increase of chimerism and development of graft-versus-host disease (GVHD) were analyzed as complementary indicators for donor-derived anti-recipient alloimmunologic pressure. Profound suppression of patient immune cells by conditioning sufficed for sustained engraftment without necessity for myeloablative conditioning or development of clinically significant GVHD. Although 61% of the patients without any DLI or GVHD showed full donor chimerism (FDC) in the BM at 6 months after alloSCT, only 24% showed FDC in the CD4+ T cell compartment. In contrast, 75% of the patients who had received DLI and 83% of the patients with clinically significant GVHD had FDC in this compartment. In addition, 72% of the patients with mixed hematopoiesis receiving DLI converted to complete donor-derived hematopoiesis, of whom only 34% developed clinically significant GVHD. Our data show that competitive repopulation can be sufficient to reach complete donor-derived hematopoiesis, but that some alloimmunologic pressure is needed for the establishment of a completely donor-derived T cell compartment, either by the development of GVHD or by administration of DLI. We illustrate that it is possible to separate the graft-versus-leukemia effect from GVHD, as conversion to durable complete donor-derived hematopoiesis following DLI did not require induction of clinically significant GVHD.

Prophylactic Donor Lymphocyte Infusion in Patients after Allogeneic Stem Cell Transplantation with Post-Transplant Cyclophosphamide Is Associated with Low Relapse Risk and Excellent Survival in Patients below 65 Years with Acute Myeloid Leukemia and High-Risk Myelodysplasia

BackgroundPost-transplant cyclophosphamide (PTCy) effectively prevents graft-versus-host-disease (GVHD) in allogeneic stem cell transplantation (alloSCT) with matched related and matched unrelated donors resulting in low risk of non-relapse mortality (NRM) (<10%). However, PTCy-alloSCT is associated with high relapse rates of approximately 20-30% after 1 year and 30-40% after 2 years (Gooptu et al. Blood 2021, Ruggeri et al. J Hemat Oncol 2018). Prophylactic donor lymphocyte infusion (DLI) may reduce relapse, although it may increase the risk of GVHD. AimTo provide evidence for reduction of relapse and improvement of survival by combining allogeneic SCT with PTCy and subsequent standardized prophylactic donor lymphocyte infusions (DLI) in a cohort of patients with acute myeloid leukemia (AML) and high risk myelodysplasia (MDS). Patients and MethodsSixty-five patients with AML (n=50) or high risk MDS (n=15) received myeloablative (n=15) or reduced-intensity (n=50) alloSCT with a matched related (n=8) or 9/10 (n=19) or 10/10 (n=38) matched unrelated donor. Based on modified ELN criteria, 10 AML patients were intermediate risk and 40 poor risk. GVHD prophylaxis consisted of PTCy, mycophenolate until day +30, and tacrolimus tapered from +70 (related or 10/10 unrelated) or day +90 (9/10 unrelated). All patients were planned to receive DLI at 6 months after transplantation at a dose of 3 x 10^6 CD3+ cells/kg in related and 1.5 x 10^6 CD3+ cells/kg in unrelated alloSCT. In poor risk patients (poor risk AML and high risk MDS) additional low dose DLI (0.3 or 0.15 x 10^6 CD3+ cells/kg in related and unrelated alloSCT, respectively) was planned one month after tacrolimus tapering (i.e. 3-4 months after alloSCT). In poor risk patients with a sensitive molecular or immunophenotypical minimal residual disease (MRD) marker (<0.1%) low dose DLI was not administered but MRD monitored; only in case of MRD positivity at 2 or 4 months additional low dose DLI was given. ResultsOf the 65 patients, 49 received standard dose DLI at 6 months after alloSCT (75%), either as a first dose at 6 months (40%), or as a second DLI after a low dose DLI at 3-4 months after alloSCT (35%). Reasons for not receiving standard dose DLI were NRM (5%), GVHD (9%), relapse (9%) and donor-related (2%). Of the 22 poor risk patients with a sensitive MRD marker, 15 received the first DLI at 6 months; 6 received both low dose DLI and 6 month DLI because of MRD positivity at 2 or 4 months after alloSCT; one patient did not receive prophylactic DLI because of systemic relapse at day 105. With a median follow up of 400 days (range 183-814), 12 patients developed systemic relapse. Most relapses (67%) occurred very early after transplant (median 110 days, range 63 to 165 days), before low dose DLI could be effectively given. These early relapses occurred significantly more in patients >= 65 years (88%) than <65 years (p=0.01 Fisher's exact). Overall survival at 1 year was 95% (95% CI 89-100%) in patients <65 (n=42), significantly higher than the 68% (95% CI 49-95%) in patients >=65 (n=23) (p=0.01). Relapse rate at 1 year was 5% (95% CI 1-15%) in patients <65, significantly lower than the 37% (95% CI 25-58%) in patients >=65 (p=0.001). Grade 2-4 acute and chronic GVHD incidence at 1 year was low (6% (95% CI 2-14%) and 11% (2.5-25%), respectively). Survival at 1 year was similar (p=0.35) in poor risk patients without MRD marker (80%, 95% CI 67-96%), poor risk with MRD marker (95%, 95% CI 87-100%) and intermediate risk (86%, 95% CI 63-100%). For these groups relapse risk was also similar: 18% (95% CI 7-33%), 16% (95% CI 3-36%) and 11% (95% CI 5-41%), respectively. ConclusionsThis study is the first to demonstrate feasibility of prophylactic DLI after PTCy-alloSCT with a low associated risk of GVHD. The observed low incidence of relapse at 1 year after transplantation (5%) of patients aged <65 years appears to be substantially less than the reported risk without pre-planned DLI (20-30%). Although the value of early DLI administration (around 3-4 months) is still unclear, standard dose DLI administration at 6 months appears feasible in intermediate risk patients and poor risk patients with sensitive MRD markers. Early relapses after alloSCT, at a time point before early DLI could be effective, caused the inferior survival of patients aged >= 65 years. The results of this study can serve as a reference for designing future prophylactic cellular interventions in the PTCy-alloSCT setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sequential Use of Flamsa, FLAG, CLAG or TEC-Based Conditioning Regimen Followed By Allogeneic Hematopoietic Transplantation Results in Favorable Outcome for High Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome and Myeloproliferative Neoplasia Patients: 15 Year Follow-up of the Multicenter Study in Singapore

Introduction: Allogeneic hematopoietic cell transplant (allo-HCT) is an effective consolidative treatment for patients with certain hematological malignancies and gives the best outcome when done in remission. However, patients with refractory acute myeloid leukemia (AML) or some myeloproliferative neoplasia (MPN) and myelodysplastic syndrome (MDS) deemed unable to achieve remission with standard induction are often excluded from allo-HCT with conventional conditioning regimen as pre-transplant remission could not be achieved. Recently, a sequential transplant approach, as developed by the Munich group, comprising of intensive cytoreductive chemotherapy FLAMSA (Fludarabine/Amsacrine/Cytarabine) to decrease leukemia cell burden shortly prior to conditioning regimen, has been successfully used for high-risk (HR) AML/MDS with promising results. Methods: We studied 72 patients (median age 51 years, range 17-68) with HR AML (n=57), as defined by refractory, relapsed disease, secondary leukemia, complete remission with adverse-risk cytogenetics according to ELN criteria, or high/very risk refined Disease Risk Index (DRI), MPN (n=3) and HR MDS (n=12) according to IPSS-R, undergoing allo-HCT using the sequential transplant approach in 2 transplant centers in Singapore between January 2009 and July 2022. The sequential transplant approach combined a cytoreductive chemotherapy, which consisted of either FLAMSA (n=21), FLAG [Fludarabine/Cytarabine/Granulocyte Colony Stimulating Factor (GCSF)] +/- Idarubicin (n=30), CLAG (Clofarabine +/- Cytarabine +/- GCSF) (n=18), or TEC (Thiotepa, Etoposide, Cyclophosphamide) (n=3) followed by reduced intensity (RIC) (n=61) or myeloablative (MAC) (n=11) conditioning regimen. All patients received peripheral blood stem cell from matched related donors (MRD) (n=36), mismatched related donors (MMRD) (n=7), matched unrelated donors (MUD) (n=21), or mismatched unrelated donors (MMURD) (n=8). Post-grafting immunosuppression consisted of calcineurin inhibitor and mycophenolate mofetil (MMF) in all patients. Thymoglobulin and post-transplant cyclophosphamide were added for GVHD prophylaxis for MUD/MMURD and MMRD transplant, respectively. One MMRD had selective ex vivo T-cell depleted transplant followed by MMF as GVHD prophylaxis. Results: The median time to neutrophil > 1000/μL was 11 days (range, 8-25). With a median follow-up duration of 51 months (range, 1-148), the Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 5 years were 42% (95% CI, 30-54) and 32% (95% CI 20-44), respectively. The cumulative incidence of relapse and non-relapse mortality (NRM) at 2 years were 47% (95% CI, 35-59) and 16% (95% CI, 9-26), respectively. Patients receiving FLAG, CLAG or TEC-based sequential regimen showed a trend towards lower NRM and relapse compared to FLAMSA-based regimen, although the difference was not statistically significant. This translated into a more favorable 5-year LFS (40% vs 13%, p=0.04), but no statistically significant difference in 5-year OS (42% vs 40%, p=0.56). Patients with refractory disease (n=49) were at higher risk of relapse compared to patients whom had achieved at least a partial remission prior to sequential allo-HCT (n=17) (2-year cumulative incidence of relapse: 59.0% vs 34.0%, p=0.02). This resulted in an inferior 5-year OS (31% vs 66%; p=0.02) and LFS (20% vs 75%, p<0.01). On multivariable analysis, only refined DRI showed significant impact on OS (p=0.01) and LFS (p=0.02) but had no significant impact on NRM and relapse. The 5-year OS for patients with intermediate/high risk and very high risk DRI were 51% and 21% (p<0.01), and the corresponding 5-year LFS were 42% and 10% (p<0.01), respectively (Figure 1 and Figure 2). Conclusions: Sequential transplant conditioning with FLAMSA, FLAG, CLAG or TEC-based cytoreductive regimen followed by allo-HCT is an effective strategy in overcoming the dismal prognosis of HR AML, MDS and MPN, including patients with high risk DRI, and enabling favorable long-term disease-free survival. More studies on effective strategies such as optimising the conditioning regimen intensity or post-transplant maintenance therapy with prophylactic donor lymphocyte infusion, are needed to further eliminate the risk of relapse, without increasing risk of treatment-related toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Optimized therapeutic strategy for patients with refractory or relapsed acute myeloid leukemia: long-term clinical outcomes and health-related quality of life assessment.

Patients with refractory or relapsed acute myeloid leukemia (AML) have poor survival, necessitating the exploration of optimized therapeutic strategy. Here, we aimed to investigate clinical outcomes and health-related quality of life (HR-QoL) after total therapy, which included allogeneic hematopoietic stem cell transplantation (allo-HSCT), and prophylactic donor lymphocyte infusion (DLI) in the early phase after transplantation, followed by multiple measurable residual disease (MRD) and graft-versus-host disease (GvHD)-guided DLIs. Consecutive patients who had refractory or relapsed AML and had received non-T-cell-depleted allo-HSCT at Peking University Institute of Hematology were included in the study. If the patients achieved complete remission at 30 days after transplantation and had no evidence of relapse, severe infection, organ failure, and active GvHD at the time of planned DLI, prophylactic DLI was administered at 30 days after transplantation for human leukocyte antigen (HLA)-matched related HSCT or at 45-60 days after transplantation for haploidentical or unrelated HSCT. Subsequently, multiple DLIs were administered based on MRD results and whether they developed GvHD after transplantation. A total of 105 patients were eligible. Eighty-seven patients received prophylactic DLI (group B), while 18 did not receive prophylactic DLI (group A). Among 105 patients, the cumulative incidence of grade 2-4 acute GvHD and chronic GvHD was 40.6% (95% confidence interval [CI] = 30.6%-50.6%) and 73.3% (95% CI = 67.4%-79.2%), respectively. The cumulative incidence of relapse (CIR), transplant-related mortality (TRM), and leukemia-free survival (LFS) at 5 years after transplantation were 31.5% (95% CI = 21.9%-41.1%), 22.1% (95% CI = 11.3%-32.9%), and 46.4% (95% CI = 36.8%-56.0%), respectively. In group B, the CIR, TRM, and LFS at 5 years after transplantation were 27.6% (95% CI = 17.6%-37.6%), 21.6% (95% CI = 11.2%-32.0%), and 50.8% (95% CI = 40.0%-61.6%), respectively. At the end of follow-up, 48 patients survived, and more than 90% of survivors had satisfactory recoveries of HR-QoL. Our study indicated that total therapy is not only associated with decreased CIR, comparable TRM, and better long-term LFS, but also with satisfactory HR-QoL for refractory or relapsed AML, compared with those of standard of care therapy reported previously. Therefore, total therapy may be an optimized therapeutic strategy for refractory or relapsed AML.

Relapse after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia: an overview of prevention and treatment.

Despite therapeutic progress in acute myeloid leukemia (AML), relapse post-allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a major challenge. Here, we aim to provide an overview of prevention and treatment of relapse in this population, including cell-based and pharmacologic options. Post-transplant maintenance therapy is used in patients who have undetectable measurable residual disease (MRD), while pre-emptive treatment is administered upon detection of MRD. Prompt transfusion of prophylactic donor lymphocyte infusion (DLI) was found to be effective in preventing relapse and overcoming the negative impact of detectable MRD. In addition, patients with persistent targetable mutations can benefit from targeted post-transplant pharmacological interventions. IDH inhibitors have shown promising results in relapsed/refractory AML. Hypomethylating agents, such as decitabine and azacitidine, have been studied in the post-allo-HSCT setting, both as pre-emptive and prophylactic. Venetoclax has been shown effective in combination with hypomethylating agents or low-dose cytarabine in patients with newly diagnosed AML, especially those unfit for intensive chemotherapy. FLT3 inhibitors, the topic of another section in this review series, have significantly improved survival in FLT-3-ITD mutant AML. The role of other cell-based therapies, including CAR-T cells, in AML is currently being investigated.

P1332: PROMISING OUTCOME OF PATIENTS OLDER THAN 70 YEARS WHO UNDERWENT PERIPHERAL BLOOD HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACUTE MYELOID LEUKEMIA OR HIGH RISK MYELODYSPLASTIC SYNDROME

Background: Allogeneic stem cell transplantation is a curative option of patients older than 60 years of age with AML and high risk MDS. In this situation, the development of haploidentical transplantation (Haplo-SCT) using post transplantation cyclophosphamide (PT-Cy) allowed extending the feasibility of Allo-HSCT. However, there is few data specifically focusing on Haplo-SCT in patients over 70 years of age with AML and MDS, for whom the benefit-risk balance of Haplo-SCT is still a matter of debate. Aims: To evaluate the outcome of patients older than 70 years with AML or high risk MDS who underwent Haplo-SCT. Methods: This retrospective study included consecutive AML or MDS patients older than 70 years who received first Haplo-SCT from 2013 to 2021 in our center. All patients had the same transplantation modalities: 1) Non-myeloablative conditioning regimen as described by the Baltimore’s group (Fludarabine, cyclophosphamide and 2-Gray TBI); 2) Peripheral blood stem cells (PBSC) as graft source; 3) GVHD prophylaxis using PT-Cy, cyclosporine A and mycophenolate mofetil; 4) G-CSF from day+5 to neutrophil recovery. Prophylactic donor lymphocyte infusion (DLI) was initially planned after day+60 in absence of GVHD. Results: We analyzed 45 patients who met inclusion criteria, 23 with AML and 22 with MDS. The median age was 72 years (range: 70-75). HCT-CI was >= 3 in 22 patients (49%). At the time of Haplo-SCT, 22/23 AML patients were in CR (17 CR1 and 5 CR2) and one patient had refractory AML. Disease status at Haplo-SCT was CR, PR, marrow CR and active disease in 12, 2, 1 and 7 patients, respectively. All patients received pre transplantation treatment with intensive chemotherapy and/or azacytidine, except one MDS patients who underwent upfront Haplo-SCT. Disease risk index was high or very high in 11 patients (24%), and intermediate in 34 patients (76%). Median follow up using the reverse Kaplan Meier method was 36 months (95%CI: 25-43). Grade 2-4 and 3-4 acute GVHD at day+100 was 33% and 7%, respectively. There was no early death (at day+100: OS=100%; NRM=0%). At 3 years after Haplo-SCT, the cumulative incidence of all grades and moderate to severe chronic GVHD was 37% and 28%. Half of the cases of chronic GVHD occurred after prophylactic DLI. The 3-year cumulative incidence of NRM was 20%. In AML patients, the 3-year CIR, PFS and OS were 17%, 61% and 64% respectively. Corresponding values for MDS patients were 26%, 56% and 66%, respectively. Ten patients received prophylactic DLI. Among them, one died from late NMR (urothelial metastatic cancer after 2 years post Haplo-SCT) and one patient relapsed and subsequently died from AML (complex karyotype, CR2). The 8 remaining patients who received prophylactic DLI are still disease free at last follow up. As surrogate marker of quality of life, we evaluated the prevalence of GVHD and immunosuppressive treatment (IST) in disease free patients. At 2 years after Haplo-SCT, 87% of disease free patients are living without GVHD and without IST. Summary/Conclusion: Haplo-SCT in patients older than 70 years with AML or high risk MDS is feasible without early NRM. The use of PBSC and prophylactic DLI may explain the low incidence of relapse and long-term survival. Our results support that selected patients older than 70 years can achieve promising outcomes after non-myeloablative Haplo-SCT using PBSC, confirming that age by itself and the absence of an HLA-matched donor should not be considered as firm contraindication for transplantation.

P1381: EARLY FULL DONOR CHIMERISM AFTER FLAMSA RIC BASED ALLOGENEIC HSCT BUT NOT PRESENCE OF MORPHOLOGICAL REMISSION ASSOCIATES WITH OUTCOMES IN R/R AML PATIENTS

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is still the only potentially curative treatment for patients (pts) with high-risk acute myeloid leukemia (AML). Despite recent advances, a significant number of pts are primary refractory or have early relapse (r/r) with <6 months (m) remission duration. One strategy to improve the outcomes of r/r AML is to perform HSCT after aplasia-inducing chemotherapy. Here, we report on a series of pts receiving a sequential chemotherapy regimen (fludarabine 30 mg/m2, amsacrine 100 mg/m2, cytarabine 2 g/m2 (FLAMSA)) and reduced-intensity conditioning (RIC) followed by HSCT as well as prophylactic donor lymphocyte infusions (DLI) as described by Schmid et al (JCO 2005). Aims: We aimed to retrospectively analyze the outcome of 82 consecutive pts with r/r AML who underwent FLAMSA RIC based HSCT between 2006 and 2020 at our center. Methods: Median age of the 82 pts was 55 years (y) and 38 pts (46%) were male. ELN risk and revised MRC prognostic classification at diagnosis were favorable in 8% and 4%, intermediate in 28% and 56%, and adverse in 64% and 40% of the pts, respectively. Median time from diagnosis to HSCT was 5 months. At the time of HSCT, only 3 pts (3%) were in complete remission (CR). RIC following the FLAMSA chemotherapy was 4Gy TBI and cyclophosphamide (73%), busulfan and cyclophosphamide (11%), melphalan (13%) or 2Gy TBI only (2%). 95% of pts received peripheral blood stem cells and 5% bone marrow (BM) from a matched unrelated donor (MUD, 63%), matched sibling donor (MSD, 10%), mismatch unrelated donor (MMUD, 23%) or a haploidentical donor (4%). Immunosuppression (IS) consisted of cyclosporine A, mycophenolate mofetil and antithymocyte globuline (MUD and MMUD only) or post transplantation cyclophosphamide, tacrolimus and MMF (haplo-donors only). 12 pts (15%) received ≥ 1 DLI preemptively past d+120 as planned. Results: Median overall survival (OS) and event-free survival (EFS) were 276 and 135 days (d). 33 pts (39%) had an OS >1y, and 22 (27%) an event free survival (EFS) >1y. 49 pts (59%) relapsed within the 1st y. Age at HSCT, type of AML (de novo vs secondary), remission status at time of HSCT, ratio of blasts in blood to bone marrow, donor type, type of RIC, mismatch and MRC risk classification had no significant impact on OS and EFS, whereas the number of treatment lines before HSCT significantly influenced OS (p=.05). Pts with ELN favorable/intermediate risk had longer EFS (p=.04, Figure 1A), but not OS (p=.12). On d+28 after HSCT, 43 pts (52%) had reached morphologic leukemia free state (MLFS), CR with incomplete count recovery (CRi) or CR, which was not associated with better OS or EFS (Figure 1B). In contrast, pts (n=49, 60%) with a donor chimerism (DC) ≥98% in BM had a significantly longer EFS (p<.01, Figure 1C) and OS (p<.01) than those with <98%. At d+100 32 pts (39%) were in MLFS, CRi or CR, and had a significant better for EFS (p<.01, Figure 1D) and OS (p<.05). Pts with a d+100 DC ≥98% in BM also had improved EFS (p=.02, Figure 1E) but not OS (p=.16). Acute Graft-versus-Host-Disease (GvHD) °II-IV occurred in 21 pts (26%). 13 pts (16%) developed any grade of chronic GvHD. Incidence of GvHD did not increase after DLI. Image:Summary/Conclusion: Despite the poor prognosis of r/r AML, a significant number of pts after FLAMSA RIC HSCT survived >1 y. Except ELN risk classification, there was no strong outcome predictor prior to HSCT. D+28 DC but not morphological remission in BM identifies pts at high risk for relapse after HSCT, allowing for additional post-HSCT strategies.

P1365: DONOR LYMPHOCYTE INFUSION IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: RESULTS FROM A RETROSPECTIVE STUDY

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a therapeutic option with curative intent in hematological malignancies. Despite improvements in alloHSCT, relapse of the underlying disease is still one of the main causes of mortality. Donor lymphocyte infusion (DLI) is an immunotherapy that can be used after alloHSCT in patients with high-risk disease (prophylaxis), mixed donor chimerism or minimal residual disease (preemptive) and relapse (therapeutic). Donor derived graft versus tumor effects induce a durable remission after DLI. Aims: To characterize the use of DLI as prophylaxis, preemptive or therapeutic strategy in alloHSCT and evaluate overall survival (OS). Methods: A retrospective unicenter study was conducted to evaluate the use of DLIs in a cohort of 50 patients (91 DLIs), treated in a Bone Marrow Transplantation Unit, between January 2005 and December 2021. The chi-square test (categorical variables) and t-test or Wilcoxon-Mann-Whitney test (continuous variables) were used. OS was estimated according to Kaplan-Meier and compared by the log-rank test. Statistical analysis was made using SPSS28®. Results: Our cohort showed male predominance (n= 29, 58%) and a median age of 40 years (4-65), with 4 pediatric patients. Patients were affected by acute myeloid leukemia (n=20), acute lymphoblastic leukemia (n=12), chronic myeloproliferative leukemia (n=6), Hodgkin lymphoma (n=2), myelodysplastic/myeloproliferative syndrome (n=4), non-Hodgkin lymphoma (n=3), chronic lymphocytic leukemia (n=1), mixed phenotype leukemia, (n=1), multiple myeloma (n=1). Conditioning regimen was myeloablative in 19 (38%) patients and reduced-intensity in 31 (62%). All 50 donors were HLA-matched, and 8 (16%) were HLA-matched unrelated (MUR). DLIs use was prophylactic in 2 (4%) patients, preemptive in 7 (14%) and therapeutic in 41 (82%) patients. The median number of DLI/patient was 1 (1-8) and the median dose of total CD3+ cells infused was 1,0x107/Kg (0,1-13,48). The median time between alloHSCT and the first DLI was 17 months (1-133). Complete Response (CR) was defined by completed donor chimerism or no MRD detected. CR was maintained in 1/2 (50%) patients undergoing prophylactic DLIs. Patients who received preemptive and therapeutic DLIs achieved CR in 2/7 (29%) and 9/41 (22%) cases, respectively. Overall, 11 patients (22%) developed GVHD after DLIs. Presence of GVHD was associated with higher number of DLIs (2,45 vs 1,64) and with CR (p=0,041) No significant differences were observed in age (p=0,154), number of CD3+ infused (p=0,414), DLIs strategy (p=0,433), time between alloHSCT to first DLI (p=0,668) and CR. Death occurred in 30 (60%) patients. OS survival was defined as time from date of first DLI to date of last follow-up (FU) or date of death. With a median FU of 141 months, the OS was superior in patients who achieved CR compared to relapsed patients (34 months), Log-rank p=0.109. OS was significantly superior in preemptive and prophylaxis DLIs compared with therapeutic DLIs (Log-rank p<0,01). Overall, 8/19 (42%) patients are currently alive in CR. Summary/Conclusion: DLI has been widely applied to the therapeutic intervention, with promising results in prevention and preemptive strategy. Although with the limits of a relatively small and heterogeneous cohort, we describe our experience in the use of DLI and demonstrate that it is an effective prophylactic and preemptive treatment option in alloHSCT patients. Prospective studies on homogeneous patient cohorts are needed improve the effectiveness of DLI.

Time‐dependent analysis of adoptive immunotherapy following sequential FLAMSA‐reduced intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with high‐risk myeloid neoplasia

Prophylactic donor lymphocyte infusions (DLI) are part of the sequential FLAMSA-reduced intensity conditioning (RIC) regimen to cure high risk myeloid neoplasia with allogeneic hematopoietic stem cell transplantation (HSCT). Although DLI themselves carry significant risks, their prophylactic use has not been analyzed in a time-dependent manner. One hundred and fourteen patients underwent FLAMSA-RIC HSCT between 2013 and 2020. Next to Kaplan-Meier estimation of overall, disease-free, and graft-versus-host relapse-free survival (OS, DFS, GRFS), cumulative incidences of relapse and death in remission were calculated in a competing risk model. Additionally, the contribution of prophylactic and preemptive DLI as time-dependent covariates was assessed using a time-varying model toward DFS (Simon-Makuch method, Mantel-Byar test). At 2years, OS was 45.2% [95% CI 36.7-55.7%], DFS 31.8% [95% CI 24-42.2%] and GRFS 11.3 [95% CI 6.5-19.8]. Neither prophylactic nor preemptive DLI showed a significant influence on DFS when considered time-dependent covariates (Mantel-Byar, p=.3). This was further corroborated in competing risk analysis with DLI as time-dependent covariates. Both prophylactic and preemptive DLI miss significance in their impact on survival within a high-risk cohort in a time-varying model. Controlled trials to address the impact of postgrafting immunotherapy approaches are needed.

Sequential Conditioning Regimen with Thiotepa in Allogeneic Hematopoietic Cell Transplantation for the Treatment of Refractory Myeloid Malignancies

IntroductionThe outcome of conventional allogeneic hematopoietic cell transplantation (HCT) for the treatment of patients with refractory myeloid malignancies remains poor. Thiotepa-based sequential conditioning has shown promising results for various refractory hematological malignancies (Duléry R et al. Biol Blood Marrow Transplant. 2018; 24(5):1013-1021). However, no study has evaluated the outcome of this sequential approach specifically in refractory myeloid malignancies. The optimal dose of chemotherapeutic agents used in the conditioning regimen and the feasibility of this sequential approach in patients aged 60 years and above also need to be assessed.MethodsAll consecutive patients with refractory myeloid malignancy who underwent allogeneic HCT with a thiotepa-based sequential conditioning regimen in Saint Antoine hospital between April 2013 and October 2020 were included. The sequential approach consisted of a broad spectrum cytoreduction with thiotepa, etoposide, and cyclophosphamide (TEC) from day -15 to -10. Then, after a 3-day rest, a reduced-intensity conditioning (RIC) regimen was administered with fludarabine 150 mg/m 2, intravenous busulfan 6.4 mg/kg and thymoglobulin 5 mg/kg from day -6 to -2. From 2013 to 2018, doses of thiotepa (10 mg/kg), etoposide (400 mg/m 2) and/or cyclophosphamide (1600 mg/m 2) could be reduced in patients older than 60 years or with comorbidities. Since September 2018, the use of a reduced TEC-RIC regimen (thiotepa at 5 mg/kg, etoposide 300 mg/m 2 and cyclophosphamide 1200 mg/m 2 from day -13 to -10) became the new standard of care for all patients. After transplant, patients could receive a hypomethylating agent or targeted therapy to prevent relapse. Prophylactic donor lymphocyte infusions were given to enhance the graft-versus-leukemia effect, in the absence of contraindication. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and mycophenolate mofetil for all patients. Post-transplant cyclophosphamide was added in the case of haploidentical HCT.ResultsSeventy-one patients (median age 61 years, range 15-76) were included. Diagnoses comprised acute myeloblastic leukemia (n=65) and myelodysplastic syndrome/chronic myelomonocytic leukemia (n=6). Donors were haploidentical (n=36), matched related (n=13), unrelated (n=21) and umbilical cord blood (n=1). A reduced TEC-RIC was administrated to 43 (61%) patients, a full dose TEC-RIC to 18 (25%), and a TEC-RIC with a dose reduction only for thiotepa to 10 (14%). With a median follow-up of 45.4 months (95% CI: 36.7-63.6), the 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) were 51%, 41%, and 24%, respectively. Patients receiving a reduced TEC-RIC had a lower cumulative incidence of acute and chronic GVHD (acute grade II-IV GVHD: 14%, acute grade III-IV GVHD: 0%, chronic GVHD: 19%) than the other patients (acute grade II-IV GVHD: 29%, acute grade III-IV GVHD: 18%, chronic GVHD: 29%). The outcomes were not significantly different according to the TEC dose in terms of relapse incidence, OS, and PFS, although the NRM was lower with the reduced TEC-RIC (21% versus 28%, p=0.72). Most notably, patients aged 60 years and above had a 2-year OS and PFS of 48% and 39%, respectively, with no significant difference compared to patients younger than 60 years (Figure).ConclusionOur findings endorse the feasibility and efficacy of a thiotepa-based sequential approach for refractory myeloid malignancies undergoing HCT. The dose reduction did not compromise disease control and expanded the transplant option to older patients, ineligible for a higher dose regimen. Thus, a reduced TEC-RIC sequential regimen can be proposed for selected patients older than 60 years and allows promising outcomes for the treatment of refractory myeloid malignancies. [Display omitted] DisclosuresDuléry: Gilead: Other: travel support and meeting fees; Takeda: Consultancy; Novartis: Honoraria. Malard: Therakos/Mallinckrodt: Honoraria; Biocodex: Honoraria; Astellas: Honoraria; JAZZ pharmaceuticals: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Legrand: Servier: Consultancy. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Labopin: Jazz Pharmaceuticals: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Comparison of Prophylactic and Preemptive Donor Lymphocyte Infusion in Patients with Very High Risk Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Relapse remains to be the biggest problem for patients with very high risk acute leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Donor lymphocyte infusion (DLI) has been widely applied to the prevention and preemptive intervention of relapse post-transplantation. However, the optimal time to implement DLI in patients with a high risk of relapse remains controversial. During August 1, 2014 and August 30, 2020, four hundred and thirty-one consecutive acute leukemia patients with very high-risk features underwent allo-HSCT in our center. Ninety-five patients received prophylactic DLI (pro-DLI) while one hundred and fifty-five patients received preemptive DLI (pre-DLI). Patients were stratified into five risk groups by the disease-risk stratification system (DRSS) which recently introduced by European Society for Blood and Marrow Transplantation: low risk (N=44), intermediate-1 (N=67), intermediate-2 (N=60), high (N=36), and very high (N=43). In the very high group, patients who received pro-DLI achieved higher 3-year overall survival (OS) (50.8% versus 31.8%, P=0.05), leukemia-free survival (LFS) (52.5% versus 31.6%, P=0.03) and graft-versus-host disease (GVHD)-free and relapse-free survival (GRFS) (47.9% versus 31.6%, P=0.04) compared with pre-DLI. Pro-DLI cohort was associated with a trend of lower 3-year cumulative rates of relapse (42.8% versus 57.9%, P=0.12) and non-relapse mortality (NRM) (4.6% versus 10.5%, P=0.43). In the subgroup of intermediate-2 and high (N=96), pro-DLI cohort was associated with superior survival and relapse rate, though without statistical significance. Further analysis was conducted separately between patients with positive minimal residual disease (MRD) and negative MRD pre-transplant in intermediate-2/high subgroup. In the patients with positive MRD before all-HSCT, pro-DLI achieved significant higher 3-year OS (66.7 % versus 26.2%, P=0.028), PFS (68.6 % versus 24.7%, P=0.015) and GRFS (68.6 % versus 14.4%, P=0.007), along with lower cumulative of relapse (31.4 % versus 59.3%, P=0.1) and NRM (0 versus 16%, P=0.1) compared with pre-DLI. However, pro-DLI patients was associated with inferior OS (52.7 % versus 77.8%, P=0.046), PFS(54.8 % versus 75.3%, P=0.247) and NRM (25% versus 3%, P=0.02) in patients with negative MRD. In addition, no difference was found in patients in the group of low and intermediate-1 risk. Taken together, we recommend early pro-DLI in patients of very-high risk group and positive MRD of intermediate-2/high group. Pre-DLI given timely after MRD turning positive achieved better outcome in the remaining patients. DisclosuresNo relevant conflicts of interest to declare.