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Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study
Penack, O., Luft, T., Peczynski, C., Benner, A., Sica, S., Arat, M., Itäla-Remes, M., Corral, L. L., Schaap, N. P. M., Karas, M., et al
Journal for immunotherapy of cancer. 2024;12(1)
Abstract
BACKGROUND We previously reported that the "Endothelial Activation and Stress Index" (EASIX; ((creatinine×lactate dehydrogenase)÷thrombocytes)) measured before start of conditioning predicts mortality after allogeneic hematopoietic stem cell transplantation (alloSCT) when used as continuous score. For broad clinical implementation, a prospectively validated EASIX-pre cut-off is needed that defines a high-risk cohort and is easy to use. METHOD In the current study, we first performed a retrospective cohort analysis in n=2022 alloSCT recipients and identified an optimal cut-off for predicting non-relapse mortality (NRM) as EASIX-pre=3. For cut-off validation, we conducted a multicenter prospective study with inclusion of n=317 first alloSCTs from peripheral blood stem cell in adult patients with acute leukemia, lymphoma or myelodysplastic syndrome/myeloproliferative neoplasms in the European Society for Blood and Marrow Transplantation network. RESULTS Twenty-three % (n=74) of alloSCT recipients had EASIX-pre ≥3 taken before conditioning. NRM at 2 years was 31.1% in the high EASIX group versus 11.5% in the low EASIX group (p<0.001). Patients with high EASIX-pre also had worse 2 years overall survival (51.6% vs 70.9%; p=0.002). We were able to validate the cut-off and found that EASIX ≥3 was associated with more than twofold increased risk for NRM in multivariate analysis (HR=2.18, 95% CI 1.2 to 3.94; p=0.01). No statistically significant difference could be observed for the incidence of relapse. CONCLUSIONS The results of this study provide a prospectively validated standard laboratory biomarker index to estimate the transplant-related mortality risk after alloSCT. EASIX ≥3 taken before conditioning identifies a population of alloSCT recipients who have a more than twofold increased risk of treatment-related mortality.
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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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Allogeneic hematopoietic stem cell transplantation in patients aged 60-79 years in Germany (1998-2018): a registry study
Weller, J. F., Lengerke, C., Finke, J., Schetelig, J., Platzbecker, U., Einsele, H., Schroeder, T., Faul, C., Stelljes, M., Dreger, P., et al
Haematologica. 2023
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Editor's Choice
Abstract
Incidences of diseases treated with transplantation frequently peak at higher age. The contribution of age to total risk of transplantation has not been estimated amidst an aging society. We compare outcomes of 1,547 patients aged 70-79 and 9,422 patients aged 60-69 transplanted 1998-2018 for myeloid, lymphoid and further neoplasia in Germany. To quantify the contribution of population mortality to survival, we derive excess mortality based on a sex-, year- and age-matched German population in a multistate model that incorporates relapse and graft-versus-host-disease (GvHD). Overall, relapse-free (RFS) and GvHD-free-relapse-free survival (GRFS) is inferior in patients 70-79, compared to patients 60-69, with 36% [95%CI 34-39%] versus 43% [41-44%], 32% [30-35%] versus 36% [35-37%] and 23% [21-26%] versus 27% [26-28%] three years post-transplant (p<0.001). Cumulative incidences of relapse at three years are 27% [25-30%] (patients 70-79) versus 29% [29-30%] (60-69, p=0.71), yet the difference in non-relapse mortality (NRM, 40% [38-43%] versus 35% [34-36%] in 70-79 versus 60-69 aged patients, p<0.001) translates into survival differences. Median OS of patients surviving >1 year relapse-free is 6.7 (median, 95%CI 4.5-9.4, 70-79) versus 9 (8.4-10.1, 60-69) years since landmark. Three years after RFS of 1 year, excess NRM is 14% [95%CI 12-18%] in 70-79 versus 12% [11-13%] in 60-69, while population NRM is 7% [6-7%] versus 3% [3-3%]. Mortality for reasons other than relapse, GvHD or age is as high as 27% [24-29%] and 22% [22-23%] 4 years after transplantation. In conclusion, survival amongst older patients is adequate after allogeneic stem cell transplantation.
PICO Summary
Population
Adults aged 60 years and over, receiving first allogeneic transplant for any malignant disease, identified from the German registry for stem cell transplantation (n=10,969)
Intervention
Transplant aged 70-79 years (n=1,547)
Comparison
Transplant aged 60-69 years (n=9,422)
Outcome
Overall, relapse-free (RFS) and GvHD-free-relapse-free survival (GRFS) is inferior in patients 70-79, compared to patients 60-69, with 36% [95%CI 34-39%] versus 43% [41-44%], 32% [30-35%] versus 36% [35-37%] and 23% [21-26%] versus 27% [26-28%] three years post-transplant. Cumulative incidences of relapse at three years are 27% [25-30%] (patients 70-79) versus 29% [29-30%] (60-69), yet the difference in non-relapse mortality (NRM, 40% [38-43%] versus 35% [34-36%] in 70-79 versus 60-69 aged patients translates into survival differences. Median OS of patients surviving >1 year relapse-free is 6.7 (median, 95%CI 4.5-9.4, 70-79) versus 9 (8.4-10.1, 60-69) years since landmark. Three years after RFS of 1 year, excess NRM is 14% [95%CI 12-18%] in 70-79 versus 12% [11-13%] in 60-69, while population NRM is 7% [6-7%] versus 3% [3-3%]. Mortality for reasons other than relapse, GvHD or age is as high as 27% [24-29%] and 22% [22-23%] 4 years after transplantation.
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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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6.
Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline
Bayas, A., Berthele, A., Blank, N., Dreger, P., Faissner, S., Friese, M. A., Gerdes, L. A., Grauer, O. M., Häussler, V., Heesen, C., et al
Therapeutic advances in neurological disorders. 2023;16:17562864231180730
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Editor's Choice
Abstract
BACKGROUND While substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS), a high percentage of treated patients still show progression and persistent inflammatory activity. Autologous haematopoietic stem cell transplantation (AHSCT) aims at eliminating a pathogenic immune repertoire through intense short-term immunosuppression that enables subsequent regeneration of a new and healthy immune system to re-establish immune tolerance for a long period of time. A number of mostly open-label, uncontrolled studies conducted over the past 20 years collected about 4000 cases. They uniformly reported high efficacy of AHSCT in controlling MS inflammatory disease activity, more markedly beneficial in relapsing-remitting MS. Immunological studies provided evidence for qualitative immune resetting following AHSCT. These data and improved safety profiles of transplantation procedures spurred interest in using AHSCT as a treatment option for MS. OBJECTIVE To develop expert consensus recommendations on AHSCT in Germany and outline a registry study project. METHODS An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of virtual meetings. RESULTS We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS based on the Swiss criteria. Current data indicate that patients who are most likely to benefit from AHSCT have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM). CONCLUSION Further clinical trials, including registry-based analyses, are urgently needed to better define the patient characteristics, efficacy and safety profile of AHSCT compared with other high-efficacy therapies and to optimally position it as a treatment option in different MS disease stages. Autologous haematopoietic stem cell transplantation for multiple sclerosis Substantial progress has been made in the development of disease-modifying medications for multiple sclerosis (MS) during the last 20 years. However, in a relevant percentage of patients, the disease cannot completely be contained. Autologous haematopoietic stem cell transplantation (AHSCT) enables rebuilding of a new and healthy immune system and to potentially stop the autoimmune disease process for a long time. A number of studies documenting 4000 cases cumulatively over the past 20 years reported high efficacy of AHSCT in controlling MS inflammatory disease activity. These data and improved safety profiles of the treatment procedures spurred interest in using AHSCT as a treatment option for MS. An open call among MS neurologists as well as among experts in stem cell transplantation in Germany started in December 2021 to join a series of video calls to develop recommendations and outline a registry study project. We provide a consensus-based opinion paper authored by 25 experts on the up-to-date optimal use of AHSCT in managing MS. Current data indicate that patients are most likely to benefit from AHSCT if they are young, ambulatory, with high disease activity, that is, relapses or new magnetic resonance imaging (MRI) lesions. Treatment data with AHSCT will be collected within the German REgistry Cohort of autoLogous haematopoietic stem cell transplantation MS (RECLAIM). Further clinical trials including registry-based analyses and systematic follow-up are urgently needed to better define the optimal patient characteristics as well as the efficacy and safety profile of AHSCT compared with other high-efficacy therapies. These will help to position AHSCT as a treatment option in different MS disease stages. eng
PICO Summary
Population
An expert panel of multiple sclerosis (MS) neurologists in Germany (n=25)
Intervention
Development of a position paper and registry outline on the up-to-date optimal use of autologous transplant in in managing MS
Comparison
None
Outcome
Current data indicate that patients who are most likely to benefit from autologous transplantation have relapsing-remitting MS and are young, ambulatory and have high disease activity. Treatment data with AHSCT will be collected within the German REgistry Cohort of autologous haematopoietic stem CeLl trAnsplantation In MS (RECLAIM).
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Donor Selection for Allogeneic Hematopoietic Cell Transplantation
Fleischhauer, K., Tran, T. H., Meisel, R., Mytilineos, J., Dreger, P., Kröger, N.
Deutsches Arzteblatt international. 2023;(Forthcoming)
Abstract
BACKGROUND In Germany, each year over 3000 patients with malignant and non-malignant hematologic and systemic diseases are treated by allogeneic hematopoietic cell transplantation (HCT). Genetic donor-recipient disparities, especially those concerning variable human leukocyte antigens (HLA), mediate both an immunotherapeutic effect and the risk of damage to healthy tissues ("graft-versus-host disease"). The adoption of evidence-based strategies for donor selection has been crucial for the continuous improvement of survival rates after allogeneic HCT, with over 50% of patients transplanted for standard indications-such as early-stage acute myeloid leukemia-alive at three years post-transplant. METHODS The PubMed database was selectively searched for literature on immunogenetic and clinical factors relevant to allogeneic HCT, as part of the process of establishing a German consensus statement on HCT donor selection. RESULTS The most important factor in donor selection is a match for the five major HLA loci (HLA-A, -B, -C, -DR, -DQ), either in genetically HLA-identical siblings or in unrelated but fully HLA-compatible donors from international registries. Additional selection criteria for the latter include compatibility for the HLA-DP locus, donor age and sex, cytomegalovirus serostatus, and blood group. Related donors identical for only 50% of the HLA genes (haploidentical donors) as well as unrelated donors with a single HLA mismatch are both valid alternatives although they are associated with an up to 10% higher risk of mortality. CONCLUSION The refinement of donor selection strategies has been instrumental for the continuous improvement of patient survival rates after allogeneic HCT witnessed over the past decades. An interdisciplinary approach to donor selection based on up-to-date scientific evidence is crucial for optimizing patient outcomes.
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EASIX-1 year and late mortality after allogeneic stem cell transplantation
Kordelas, L., Terzer, T., Gooley, T. A., Davis, C., Sandmaier, B. M., Sorror, M. L., Penack, O., Schaeper, N. D. E., Blau, I. W., Beelen, D. W., et al
Blood advances. 2023
Abstract
Patients with haematological malignancies who survive the first year after allogeneic stem cell transplantation (alloSCT) without relapse have a substantial risk of non-relapse mortality (NRM), and predictive markers are missing. The Endothelial Activation and Stress Index (EASIX) predicts endothelial complications and NRM early after alloSCT. We hypothesised that EASIX assessed 1 year after alloSCT in disease-free survivors may predict late NRM. Relapse-free survivors at one year after alloSCT were retrospectively studied in two independent cohorts (training cohort: n=610, merged validation cohort: n=852). EASIX determined one year after alloSCT was correlated with overall survival (OS), NRM, and relapse. Serum endothelial and inflammatory markers were measured in the training cohort and correlated with EASIX-1y. EASIX-1year predicted OS and NRM but not relapse risk in both, training and validation cohort in univariable and multivariable Cox regression analyses. Brier score and c-index analyses validated the univariable EASIX effects. There was no significant interaction between EASIX-1year and incidence of chronic GvHD on OS. EASIX-1year predicted outcome irrespective of pre-existing comorbidities. Principal causes of NRM in both, training and validation cohorts were infections with and without GvHD, as well as cardiovascular complications. EASIX-1y correlated with sCD141 and interleukin-18, but not with C-reactive protein, suppressor of tumorigenicity (ST)-2, angiopoietin-2, CXCL9 or CXCL8. EASIX-1year is the first validated predictor of late overall and non-relapse mortality. High-risk patients as defined by EASIX-1year might be considered for intensified surveillance and prophylactic measures.
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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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10.
Hematopoietic stem cell boost for persistent neutropenia after CAR-T cell therapy: a GLA/DRST study
Gagelmann, N., Wulf, G. G., Duell, J., Glass, B., Heteren, P. V., von Tresckow, B., Fischer, M., Penack, O., Ayuk, F. A., Einsele, H., et al
Blood advances. 2022
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Editor's Choice
Abstract
Hematotoxicity after chimeric antigen receptor (CAR)-T cell therapy is associated with infection and death but management remains unclear. We report results of 31 patients receiving hematopoietic stem cell boost (HSCB; 30 autologous, 1 allogeneic) for either sustained severe neutropenia of grade 4 (<0.5 x109/l), sustained moderate neutropenia (less than or equal to 1.5 x109/l) and high risk of infection, or neutrophil count less than or equal to 2.0 x109/l and active infection. Median time from CAR-T cell therapy to HSCB was 43 days and median absolute neutrophil count at time of HSCB was 0.2. Median duration of neutropenia prior to HSCB was 38 days (range, 7-151). Overall neutrophil response rate (recovery or improvement) was observed in 26 patients (84%) within a median of 9 days (95% confidence interval, 7-14). Time to response was significantly associated with the duration of prior neutropenia (p=0.007). All non-responders died within the first year after HSCB. One-year overall survival for all patients was 59% and significantly different for neutropenia ≤38 days (85%) versus neutropenia >38 days prior to HSCB (44%; p=0.029). In conclusion, early or prophylactic HSCB showed quick response and improved outcomes for sustained moderate to severe neutropenia after CAR-T.
PICO Summary
Population
Adults with persistent neutropenia after CAR-T cell therapy (n=31)
Intervention
Hematopoietic stem cell boost (HSCB; 30 autologous, 1 allogeneic)
Comparison
None
Outcome
Median time from CAR-T cell therapy to HSCB was 43 days and median absolute neutrophil count at time of HSCB was 0.2. Median duration of neutropenia prior to HSCB was 38 days (range, 7-151). Overall neutrophil response rate (recovery or improvement) was observed in 26 patients (84%) within a median of 9 days (95% confidence interval, 7-14). Time to response was significantly associated with the duration of prior neutropenia. All non-responders died within the first year after HSCB. One-year overall survival for all patients was 59% and significantly different for neutropenia ≤38 days (85%) versus neutropenia >38 days prior to HSCB (44%).