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Repetitively Administered Low-Dose Donor Lymphocyte Infusion for Prevention of Relapse after Allogeneic Stem Cell Transplantation in Patients with High-Risk Acute Leukemia
Tsirigotis, P., Gkirkas, K., Kitsiou, V., Chondropoulos, S., Athanassiades, T., Thomopoulos, T., Tsirogianni, A., Stamouli, M., Karagiannidi, A., Siafakas, N., et al
Cancers. 2021;13(11)
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Editor's Choice
Abstract
BACKGROUND Patients with high-risk acute leukemia have a high risk of relapse after allogeneic stem cell transplantation (allo-SCT). In an effort to reduce the relapse rate, various therapeutic methods have been implemented into clinical practice. Among them, prophylactic donor lymphocyte infusion (pro-DLI) has shown significant efficacy. However, the widespread application of pro-DLI has been restricted mostly due to concerns regarding the development of graft versus host disease (GVHD). In the present study, we tested the safety and efficacy of a novel method of prophylactic-DLI based by repetitive administration of low lymphocyte doses. METHODS DLI was administered to patients with high-risk acute leukemia at a dose of 2 × 10(6)/kg CD3-positive cells. DLI at the same dose was repeated every two months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first. Forty-four patients with a median age of 53 years (range 20-67) who underwent allo-SCT between 2011 and 2020 were included in our study. Thirty-three patients with high-risk acute myeloid leukemia (AML) and 11 with high-risk acute lymphoblastic leukemia (ALL) after allo-SCT from a matched sibling (MSD, no = 38 pts) or a matched-unrelated donor (MUD, no = 6 pts) received pro-DLI. Twenty-three patients were in CR1, all with unfavorable genetic features; 12 patients were in CR2 or beyond; and 9 patients had refractory disease at the time of transplant. Ten out of 23 patients in CR1 had detectable minimal residual disease (MRD) at the time of allo-SCT. Disease risk index (DRI) was high and intermediate in 21 and 23 patients, respectively. Conditioning was myeloablative (MAC) in 36 and reduced intensity (RIC) in 8 patients, while GVHD prophylaxis consisted of cyclosporine-A in combination with low-dose alemtuzumab in 39 patients or with low-dose MTX in 5 patients, respectively. RESULTS Thirty-five patients completed the scheduled treatment and received a median of 8 DLI doses (range 1-35). Fifteen out of 35 patients received all planned doses, while DLI was discontinued in 20 patients. Reasons for discontinuation included GVHD development in nine, donor unavailability in seven, disease relapse in three, and secondary malignancy in one patient, respectively. Nine patients were still on treatment with DLI, and they received a median of four (range 2-12) doses. Fourteen percent of patients developed transient grade-II acute GVHD while 12% developed chronic GVHD post-DLI administration. Acute GVHD was managed successfully with short course steroids, and four out of five patients with cGVHD were disease-free and off immunosuppression. With a median follow-up of 44 months (range 8-120), relapse-free (RFS) and overall survival (OS) were 74%, (95% CI, 54-87%) and 78%, (95% CI, 58-89%) respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13% (95% CI, 4-28%). The cumulative incidence of relapse in patients with intermediate and high DRI is 7% and 15%, respectively. CONCLUSION Prolonged-up to three years-low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk acute leukemia. The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells. This novel strategy deserves testing in larger cohort of patients with high-risk acute leukemia.
PICO Summary
Population
Patients with high-risk acute leukemia who underwent allo-SCT between 2011 and 2020 (n=44)
Intervention
Donor lymphocyte infusion at a dose of 2 × 10(6)/kg CD3-positive cells, every two months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first.
Comparison
None
Outcome
35 patients completed the scheduled treatment and received a median of 8 DLI doses (range 1-35). 15 out of 35 patients received all planned doses, while DLI was discontinued in 20 patients. Reasons for discontinuation included GVHD development in 9, donor unavailability in 7, disease relapse in 3, and secondary malignancy in one patient, respectively. 9 patients were still on treatment with DLI, and they received a median of 4 doses. 14% of patients developed transient grade-II acute GVHD while 12% developed chronic GVHD post-DLI administration. Acute GVHD was managed successfully with short course steroids, and 4 out of 5 patients with cGVHD were disease-free and off immunosuppression. With a median follow-up of 44 months (range 8-120), relapse-free (RFS) and overall survival (OS) were 74%, and 78%, respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13%. The cumulative incidence of relapse in patients with intermediate and high DRI is 7% and 15%, respectively.
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Long-term results and GvHD after prophylactic and preemptive donor lymphocyte infusion after allogeneic stem cell transplantation for acute leukemia
Schmid, C., Labopin, M., Schaap, N., Veelken, H., Brecht, A., Stadler, M., Finke, J., Baron, F., Collin, M., Bug, G., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
We report on 318 patients with acute leukemia, receiving donor lymphocyte infusion (DLI) in complete hematologic remission (CHR) after allogeneic stem cell transplantation (alloSCT). DLI were applied preemptively (preDLI) for minimal residual disease (MRD, n?=?23) or mixed chimerism (MC, n?=?169), or as prophylaxis in high-risk patients with complete chimerism and molecular remission (proDLI, n?=?126). Median interval from alloSCT to DLI1 was 176 days, median follow-up was 7.0 years. Five-year cumulative relapse incidence (CRI), non-relapse mortality (NRM), leukemia-free and overall survival (LFS/OS) of the entire cohort were 29.1%, 12.7%, 58.2%, and 64.3%. Cumulative incidences of acute graft-versus-host disease (aGvHD) grade II-IV°/chronic GvHD were 11.9%/31%. Nineteen patients (6%) died from DLI-induced GvHD. Age =60 years (p?=?0.046), advanced stage at transplantation (p?=?0.003), shorter interval from transplantation (p?=?0.018), and prior aGvHD =II° (p?=?0.036) were risk factors for DLI-induced GvHD. GvHD did not influence CRI, but was associated with NRM and lower LFS/OS. Efficacy of preDLI was demonstrated by decreasing MRD/increasing blood counts in 71%, and increasing chimerism in 70%. Five-year OS after preDLI for MRD/MC was 51%/68% among responders, and 37% among non-responders. The study describes response and outcome of DLI in CHR and helps to identify candidates without increased risk of severe GvHD.
PICO Summary
Population
Patients with acute leukaemia in complete remission after allogeneic transplant (n=318)
Intervention
Donor lymphocyte infusion (DLI) for minimal residual disease (MRD, n=23) or mixed chimerism (MC, n=169), or as prophylaxis in high-risk patients with complete chimerism and molecular remission (proDLI, n=126).
Comparison
None
Outcome
Median interval from alloSCT to DLI1 was 176 days, median follow-up was 7.0 years. Five-year cumulative relapse incidence (CRI), non-relapse mortality (NRM), leukemia-free and overall survival (LFS/OS) of the entire cohort were 29.1%, 12.7%, 58.2%, and 64.3%. Cumulative incidences of acute graft-versus-host disease (aGvHD) grade II-IV°/chronic GvHD were 11.9%/31%. Nineteen patients (6%) died from DLI-induced GvHD. Age >/=60 years, advanced stage at transplantation, shorter interval from transplantation, and prior aGvHD =II° were risk factors for DLI-induced GvHD. GvHD did not influence cumulative relapse incidence, but was associated with NRM and lower LFS/OS. Efficacy of preDLI was demonstrated by decreasing MRD/increasing blood counts in 71%, and increasing chimerism in 70%. Five-year OS after preDLI for MRD/MC was 51%/68% among responders, and 37% among non-responders
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Association of Second Allogeneic Hematopoietic Cell Transplant vs Donor Lymphocyte Infusion With Overall Survival in Patients With Acute Myeloid Leukemia Relapse
Kharfan-Dabaja, M. A., Labopin, M., Polge, E., Nishihori, T., Bazarbachi, A., Finke, J., Stadler, M., Ehninger, G., Lioure, B., Schaap, N., et al
JAMA oncology. 2018
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Abstract
Importance: The optimal treatment approach to patients with acute myeloid leukemia (AML) who relapse after an allogeneic hematopoietic cell transplant (allo-HCT) remains elusive. No randomized clinical trial comparing survival outcomes of a second allo-HCT (allo-HCT2) vs donor lymphocyte infusion (DLI) has been conducted to date. Objective: To compare overall survival (OS) after an allo-HCT2 or DLI in relapsed AML after a first allo-HCT. Design, Setting, and Participants: A retrospective registry study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation involving 418 adults who received an allo-HCT2 (n = 137) or DLI (n = 281) for postallograft-relapsed AML. Analysis was assessed on the principle of intent-to-first received intervention. The data were collected from November 21, 2015, to May 15, 2017, and analysis was performed June 1, 2017. Main Outcomes and Measures: Number of patients with relapsed AML who are alive after 2 years and 5 years from receiving an allo-HCT2 or DLI. Results: Of the 418 patients, 228 (54.5%) were men; mean age was 46.2 years (interquartile range, 36.5-56.9 years). There was no apparent difference in OS whether an allo-HCT2 or DLI was prescribed (2-year OS with allo-HCT2, 26%; 5-year OS with allo-HCT2, 19%; 2-year OS with DLI, 25%; 5-year OS with DLI, 15%; P = .86). Overall survival was better if either of these procedures was offered when the patient was in complete remission (hazard ratio, 0.55; 95% CI, 0.41-0.74; P < .001). Conversely, OS was low for patients relapsing within less than 6 months after an allo-HCT1, regardless of the treatment prescribed (5-year OS: allo-HCT2, 9%; 95% CI, 1%-17% vs DLI, 4%; 95% CI, 1%-8%; P = .86). Conclusion and Relevance: Heterogeneity of the patient-, disease-, and treatment-related characteristics limit the ability to recommend one approach over another. Findings of this study highlight that best outcomes seem to be achieved in patients relapsing 6 or more months from an allo-HCT1 or those in complete remission at the time of either allo-HCT2 or DLI.
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Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation in acute leukaemia - a matched pair analysis by the Acute Leukaemia Working Party of EBMT
Schmid, C., Labopin, M., Schaap, N., Veelken, H., Schleuning, M., Stadler, M., Finke, J., Hurst, E., Baron, F., Ringden, O., et al
British journal of haematology. 2018
Abstract
Strategies for relapse prevention after allogeneic transplantation in acute leukaemia are warranted. A registry-based matched-pair analysis evaluated the efficacy of prophylactic donor lymphocyte infusion (proDLI). Adults receiving proDLI in complete remission (CR) and controls were pair-matched for age, diagnosis, cytogenetics, stage, donor, gender, conditioning and T-cell depletion. Eighty-nine pairs were identified (median follow-up: 6.9 years). Within the entire cohort, no difference was observed. However, among patients with high-risk acute myeloid leukaemia (AML) (unfavourable cytogenetics and/or transplanted beyond first CR), proDLI recipients had improved overall survival (69.8% vs. 40.2% in controls, P = 0.027). ProDLI has moderate efficacy, but can contribute to improved outcome in high-risk AML.