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1.
Fludarabine-treosulfan versus fludarabine-melphalan or busulfan-cyclophosphamide conditioning in older AML or MDS patients - A clinical trial to registry data comparison
Beelen, D. W., Iacobelli, S., Koster, L., Eikema, D. J., van Biezen, A., Stölzel, F., Ciceri, F., Bethge, W., Dreger, P., Wagner-Drouet, E. M., et al
Bone marrow transplantation. 2024
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Editor's Choice
Abstract
A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.
PICO Summary
Population
Adults aged 50-70 years with primary or secondary AML in complete remission or MDS, receiving a peripheral blood allogeneic transplant (n=1220)
Intervention
Participants in the MC-FludT.14/L trial who received fludarabine-treosulfan conditioning (FluTreo, n=252)
Comparison
Propensity-score matched patients identified from the EBMT registry (n=968) who received fludarabine/melphalan (FluMel, n=338) or busulfan/cyclophosphamide (BuCy, n=630) regimens
Outcome
In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n=110) or BuCy (n=78). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel and BuCy. Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel and BuCy. For MDS patients, no endpoint differences between FluTreo and FluMel (n=30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n=25) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA.
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Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma
Locke, F. L., Filosto, S., Chou, J., Vardhanabhuti, S., Perbost, R., Dreger, P., Hill, B. T., Lee, C., Zinzani, P. L., Kröger, N., et al
Nature medicine. 2024
Abstract
The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10(-9) for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10(-9) for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
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Validation of the transplant conditioning intensity (TCI) index for allogeneic hematopoietic cell transplantation
Spyridonidis, A., Labopin, M., Gedde-Dahl, T., Ganser, A., Stelljes, M., Craddock, C., Wagner-Drouet, E. M., Versluis, J., Schroeder, T., Blau, I. W., et al
Bone marrow transplantation. 2023
Abstract
The intensity of the conditioning regimen given before allogeneic hematopoietic cell transplantation (allo-HCT) can vary substantially. To confirm the ability of the recently developed transplant conditioning intensity (TCI) score to stratify the preparative regimens of allo-HCT, we used an independent and contemporary patient cohort of 4060 transplant recipients with acute myeloid leukemia meeting inclusion criteria from the discovery study (allo-HCT in first complete remission, matched donor), but who were allografted in a more recent period (2018-2021) and were one decade older (55-75 years, median 63.4 years), we assigned them to a TCI category (low n = 1934, 48%; intermediate n = 1948, 48%, high n = 178, 4%) according to the calculated TCI score ([1-2], [2.5-3.5], [4-6], respectively), and examined the validity of the TCI category in predicting early non-relapse mortality (NRM), 2-year NRM and relapse (REL). In the unadjusted comparison, the TCI index provided a significant risk stratification for d100 and d180 NRM, NRM and REL risk. In the multivariate analysis adjusted for significant variables, there was an independent association of TCI with early NRM, NRM and REL. In summary, we confirm in contemporary treated patients that TCI reflects the conditioning regimen related morbidity and anti-leukemic efficacy satisfactorily and across other established prognostic factors.
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Allogeneic hematopoietic stem cell transplantation for NK/T-cell lymphoma: an international collaborative analysis
Berning, P., Schmitz, N., Ngoya, M., Finel, H., Boumendil, A., Wang, F., Huang, X. J., Hermine, O., Philippe, L., Couronné, L., et al
Leukemia. 2023;:1-10
Abstract
Natural killer/T-cell lymphomas (NKTCL) represent rare and aggressive lymphoid malignancies. Patients (pts) with relapsed/refractory disease after Asparaginase (ASPA)-based chemotherapy have a dismal prognosis. To better define the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), we conducted a retrospective analysis of data shared with the European Society for Blood and Marrow Transplantation (EBMT) and cooperating Asian centers. We identified 135 pts who received allo-HSCT between 2010 and 2020. Median age was 43.4 years at allo-HSCT, 68.1% were male. Ninety-seven pts (71.9 %) were European, 38 pts (28.1%) Asian. High Prognostic Index for NKTCL (PINK) scores were reported for 44.4%; 76.3% had >1 treatment, 20.7% previous auto-HSCT, and 74.1% ASPA-containing regimens prior to allo-HSCT. Most (79.3%) pts were transplanted in CR/PR. With a median follow-up of 4.8 years, 3-year progression-free(PFS) and overall survival were 48.6% (95%-CI:39.5-57%) and 55.6% (95%-CI:46.5-63.8%). Non-relapse mortality at 1 year was 14.8% (95%-CI:9.3-21.5%) and 1-year relapse incidence 29.6% (95%-CI:21.9-37.6%). In multivariate analyses, shorter time interval (0-12 months) between diagnosis and allo-HSCT [HR = 2.12 (95%-CI:1.03-4.34); P = 0.04] and transplantation not in CR/PR [HR = 2.20 (95%-CI:0.98-4.95); P = 0.056] reduced PFS. Programmed cell death protein 1(PD-1/PD-L1) treatment before HSCT neither increased GVHD nor impacted survival. We demonstrate that allo-HSCT can achieve long-term survival in approximately half of pts allografted for NKTCL.
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5.
Long-Term Survivors After Failure of CAR-T Cell Therapy for Large B-Cell Lymphoma: A Role for Allogeneic Hematopoietic Cell Transplantation? A GLA/DRST Analysis
Derigs, P., Bethge, W. A., Krämer, I., Holtick, U., von Tresckow, B., Ayuk, F., Penack, O., Vucinic, V., von Bonin, M., Baldus, C., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND The outcome of patients with large B-cell lymphoma (LBCL) who relapse or progress after CD19-directed CAR-T cell therapy administered as salvage therapy beyond the second treatment line is poor. However, a minority of patients become long-term survivors despite CAR-T failure. The German Lymphoma Alliance (GLA) has proposed a hierarchical management algorithm for CAR-T failure in LBCL, aiming at allogeneic hematopoietic cell transplantation (alloHCT) as definite therapy in eligible patients. PURPOSE The purpose of this study was to investigate characteristics, relapse patterns and management strategies in long-term survivors after CAR-T failure with particular focus on feasibility and outcome of alloHCT. STUDY DESIGN Retrospective analysis of all evaluable patients with relapse/progression event (REL) observed in a previous reported GLA sample (Bethge et al, Blood 2022) between November 2018 and May 2021. RESULTS REL occurred in 214 of 356 patients (60%) having undergone CAR-T for LBCL in the previous GLA study. For 143 of these 214 patients (67%) an evaluable dataset was available. 26 of 143 patients (18%) survived 12 months or longer from REL, 109 (76%) died within the first year after REL, and 8 patients (6%) were alive but had not reached the 12-months landmark. Long-term survivors had more favorable pre-CAR-T features, had a longer interval between CAR-T and REL, and had more often received a tumor biopsy post CAR-T failure, whereas the choice of the first salvage regimen had no impact. AlloHCT was feasible in 40 of 53 patients (75%) intended and resulted in a 12-month post-transplant overall survival of 36% in those patients who underwent transplant with sensitive or untreated REL. CONCLUSIONS AlloHCT after CAR-T failure in LBCL is feasible and may be an important contributor to long-term survival although selection bias has to be taken into account. Thus, alloHCT should be considered as a reasonable treatment option in eligible patients in this setting. Since the overall outlook after CAR-T failure nevertheless remains poor, novel effective therapeutic approaches are needed, either for allowing long-term disease control per se, or for improving the preconditions for successful alloHCT.
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6.
Impact of disease burden on clinical outcomes of AML patients receiving allogeneic hematopoietic cell transplantation: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Abou Dalle, I., Labopin, M., Kröger, N., Schroeder, T., Finke, J., Stelljes, M., Neubauer, A., Blaise, D., Yakoub-Agha, I., Salmenniemi, U., et al
Bone marrow transplantation. 2023
Abstract
Pre-transplant detectable measurable residual disease (MRD) is still associated with high risk of relapse and poor outcomes in acute myeloid leukemia (AML). We aimed at evaluating the impact of disease burden on prediction of relapse and survival in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT) in first remission (CR1). We identified a total of 3202 adult AML patients, of these 1776 patients were in CR1 and MRD positive and 1426 patients were primary refractory at time of transplant. After a median follow-up of 24.4 months, non-relapse mortality and relapse rate were significantly higher in the primary refractory group compared to the CR1 MRD positive group (Hazards Ratio (HR) = 1.82 (95% CI: 1.47-2.24) p < 0.001 and HR = 1.54 (95% CI: 1.34-1.77), p < 0.001), respectively. Leukemia-free survival (LFS) and overall survival (OS) were significantly worse in the primary refractory group (HR = 1.61 (95% CI: 1.44-1.81), p < 0.001 and HR = 1.71 (95% CI: 1.51-1.94), p < 0.001, respectively). Our real-life data suggest that patients in CR1 and MRD positive at time of transplant could still be salvaged by allo-HCT with a 2-year OS of 63%, if negative MRD cannot be obtained and their outcomes are significantly better than patients transplanted with active disease.
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The European landscape on allogeneic haematopoeietic cell transplantation in Chronic Lymphocytic Leukaemia between 2009 and 2019: a perspective from the Chronic Malignancies Working Party of the EBMT
Tournilhac, O., van Gelder, M., Eikema, D. J., Zinger, N., Dreger, P., Bornhäuser, M., Vucinic, V., Scheid, C., Cornelissen, J. J., Schroeder, T., et al
Bone marrow transplantation. 2023;:1-4
Abstract
Allogeneic transplantation (allo-HCT) is a curative treatment in CLL whose efficacy including the most severe forms had led to the 2006 EBMT recommendations. The advent after 2014 of targeted therapies has revolutionized CLL management, allowing prolonged control to patients who have failed immunochemotherapy and/or have TP53 alterations. We analysed the pre COVID pandemic 2009-2019 EBMT registry. The yearly number of allo-HCT raised to 458 in 2011 yet dropped from 2013 onwards to an apparent plateau above 100. Within the 10 countries who were under the EMA for drug approval and performed 83.5% of those procedures, large initial differences were found but the annual number converged to 2-3 per 10 million inhabitants during the 3 most recent years suggesting that allo-HCT remains applied in selected patients. Long-term follow-up on targeted therapies shows that most patients relapse, some early, with risk factors and resistance mechanisms being described. The treatment of patients exposed to both BCL2 and BTK inhibitors and especially those with double refractory disease will become a challenge in which allo-HCT remains a solid option in competition with emerging therapies that have yet to demonstrate their long-term effectiveness.
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8.
Impact of conditioning regimen intensity on outcomes of second allogeneic hematopoietic cell transplantation for secondary acute myelogenous leukemia
Nagler, A., Peczynski, C., Dholaria, B., Labopin, M., Valerius, T., Dreger, P., Kröger, N., Reinhardt, H. C., Finke, J., Franke, G. N., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Limited data is available on factors impacting the outcomes of second hematopoietic cell transplantation (HCT2) in patients with secondary acute myeloid leukemia (sAML). This study aimed to assess HCT2 outcome for sAML comparing reduced-intensity (RIC) to myeloablative (MAC) conditioning. Two hundred and fifteen patients were included: RIC (n = 134), MAC (n = 81). The median follow-up was 41.1 (95% CI: 26.7-69.3) and 28.5 (95% CI: 23.9-75.4) months, respectively. At two years, the relapse incidence (RI) was 58.3% versus 51.1% in RIC and MAC, respectively. The 2-year leukemia free survival (LFS) was 26.6% versus 26%, and the graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was 16.4% versus 12.1%, while OS was 31.4% and 39.7%, for RIC and MAC respectively. MVA showed a significantly lower RI [hazard ratio (HR) = 0.46 (95% CI, 0.26-0.8, p = 0.006)] and improved LFS [HR = 0.62 (95% CI, 0.39-0.98, p = 0.042)] with MAC versus RIC. The choice of conditioning regimen did not impact non-relapse mortality [HR = 1.14 (95% CI, 0.52-2.5, p = 0.74)], overall survival (OS) [HR = 0.72 (95% CI, 0.44-1.17, p = 0.18)] or GRFS [HR = 0.89 (95% CI, 0.59-1.36, p = 0.6)]. In conclusion, MAC was associated with a lower RI and superior LFS. These results support the use of MAC for eligible patients with sAML who are being considered for HCT2.
PICO Summary
Population
Adult patients with relapsed secondary acute leukaemia (sAML) receiving a second hematopoietic cell transplant (HCT2) from mulitple centre registries across Europe (n=215)
Intervention
Reduced-intensity pre-HCT2 conditioning (RIC, n=134)
Comparison
Myeloablative pre-HCT2 conditioning (MAC, n=81)
Outcome
Median follow-up was 41.1 (RIC, 95% CI: 26.7-69.3) and 28.5 (MAC, 95% CI: 23.9-75.4) months. At two years, the relapse incidence (RI) was 58.3% versus 51.1% in RIC and MAC, respectively. The 2-year leukemia free survival (LFS) was 26.6% versus 26%, and the graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was 16.4% versus 12.1%, while OS was 31.4% and 39.7%, for RIC and MAC respectively. Multivariate analysis showed a significantly lower RI [hazard ratio (HR) = 0.46 (95% CI, 0.26-0.8)] and improved LFS [HR = 0.62 (95% CI, 0.39-0.98)] with MAC versus RIC. The choice of conditioning regimen did not impact non-relapse mortality [HR = 1.14 (95% CI, 0.52-2.5)], overall survival (OS) [HR = 0.72 (95% CI, 0.44-1.17)] or GRFS [HR = 0.89 (95% CI, 0.59-1.36)].
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Thiotepa-fludarabine-treosulfan conditioning for 2nd allogeneic HCT from an alternative unrelated donor for patients with AML: a prospective multicenter phase II trial
Finke, J., Schmoor, C., Stelljes, M., Burchert, A., Dreger, P., Hegenbart, U., Wagner-Drouet, E. M., Bornhäuser, M., Sohlbach, K., Schub, N., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Therapeutic options for patients with AML relapsing after allogeneic HCT range from chemotherapy or hypomethylating agents with or without donor lymphocyte infusions to a 2nd allogeneic HCT. Available data are based on retrospective single center or registry studies. The aim of this multicenter trial was to investigate prospectively intensive conditioning with Thiotepa, Fludarabine and Treosulfan (TFT) for 2nd allogeneic HCT from an alternative unrelated donor in patients with AML relapse > 6 months after a 1st allogeneic HCT. Primary endpoint was disease-free survival (DFS) at one year after 2nd HCT. 50 patients median age 53.5 years, in CR/PR (34%) or active relapse (66%) were included. 33 of 38 patients (86.8%) with available data achieved CR 100 days post transplant. 23 patients were alive and free of relapse at primary endpoint one year after 2nd HCT (DFS rate 0.46, 95%-CI (0.32-0.61). Three-year rates of DFS, relapse, non-relapse mortality, and overall survival were 0.24, 95%-CI (0.13-0.36); 0.36 (0.25-0.52); 0.40 (0.29-0.57); and 0.24 (0.13-0.37). Second HCT with TFT conditioning is feasible and has high anti-leukemic efficacy in chemosensitive or refractory AML relapse after prior allogeneic HCT. Still, relapse rates and NRM after 2nd allogeneic HCT remain a challenge. The trial is registered in the German Clinical Trials Registry (number DRKS00005126).
PICO Summary
Population
Participants with acute myeloid leukaemia (AML) relapsing after allogeneic transplant, from fourteen centres in Germany (n=50)
Intervention
Second allogeneic transplant from an alternative donor >6 months after 1st allogeneic transplant
Comparison
None
Outcome
50 patients median age 53.5 years, in CR/PR (34%) or active relapse (66%) were included. 33 of 38 patients (86.8%) with available data achieved CR 100 days post transplant. 23 patients were alive and free of relapse at primary endpoint one year after 2nd HCT (DFS rate 0.46, 95%-CI (0.32-0.61). Three-year rates of DFS, relapse, non-relapse mortality, and overall survival were 0.24, 95%-CI (0.13-0.36); 0.36 (0.25-0.52); 0.40 (0.29-0.57); and 0.24 (0.13-0.37). Second HCT with TFT conditioning is feasible and has high anti-leukemic efficacy in chemosensitive or refractory AML relapse after prior allogeneic HCT.
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10.
Comparison of autologous and allogeneic hematopoietic cell transplantation strategies in patients with primary plasma cell leukemia, with dynamic prediction modelling
Lawless, S., Iacobelli, S., Knelange, N. S., Chevallier, P., Blaise, D., Milpied, N., Foà, R., Cornelissen, J. J., Lioure, B., Benjamin, R., et al
Haematologica. 2022
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Free full text
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Editor's Choice
Abstract
Primary Plasma Cell Leukaemia (pPCL) is a rare and challenging malignancy. There is limited data regarding optimum transplant approaches. Therefore we undertook a retrospective analysis from 1998-2014 of 751 patients with Primary Plasma Cell Leukaemia (pPCL) undergoing one of four transplant strategies; single autologous transplant (single-auto), single allogeneic transplant (allo-first) or a combined tandem transplant either auto-allo or auto-auto. To avoid time bias multiple analytic approaches were employed including Cox models with time dependent covariates and dynamic prediction by landmarking. Initial comparisons were made between patients undergoing allo-first (n=70) versus auto first (n=681), regardless of subsequent administration of second transplant. The allo-first group had lower relapse rate (45.9%, 95%CI 33.2-58.6 vs. 68.4%, 64.4-72.4) but higher NRM (27%, 95%CI 15.9-38.1 vs 7.3%, 5.2-9.4) at 36 months. Allo-first had remarkably higher risk in the first 100 days for both OS and PFS. Autoallo (n=122) had no increased risk in the short term and significant benefit in PFS post-100 days compared to single auto (HR 0.69, 95%CI: 0.52-0.92, p=0.012). Auto-auto (n=117) was an effective option for patients achieving CR prior to first transplant, whereas in patients without CR prior to transplant our modelling predicted that auto-allo was superior. This is the largest retrospective study reporting on transplant in pPCL to date. We confirm significant mortality risk within the first 100 days for allo-first and suggest that tandem transplant strategies are superior. Disease status at time of transplant influences outcome, this knowledge may help guide clinical decisions on transplant strategy.
PICO Summary
Population
Adults with primary plasma cell leukaemia reported to the EBMT registry (n=751)
Intervention
Single allogeneic transplant (allo-first, n=70)
Comparison
Single autologous transplant (auto first, n=681). Then proceeding on to either a combined tandem transplant: auto-allo (n=122) or auto-auto (n=117), or no further transplant (auto only, n=442)
Outcome
Initial comparisons were made between patients undergoing allo-first (n=70) versus auto first (n=681), regardless of subsequent administration of second transplant. The allo-first group had lower relapse rate (45.9%, 95%CI 33.2-58.6 vs. 68.4%, 64.4-72.4) but higher non relapse mortality (27%, 95%CI 15.9-38.1 vs 7.3%, 5.2-9.4) at 36 months. Allo-first had remarkably higher risk in the first 100 days for both overall survival and progression-free survival (PFS). Auto-allo (n=122) had no increased risk in the short term and significant benefit in PFS post-100 days compared to single auto (HR 0.69, 95%CI: 0.52-0.92). Auto-auto (n=117) was an effective option for patients achieving complete response (CR) prior to first transplant, whereas in patients without CR prior to transplant our modelling predicted that auto-allo was superior.