Publications by authors named "Nicolaus Kroger"

425 Publications

Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years.

Bone Marrow Transplant 2021 Feb 23. Epub 2021 Feb 23.

Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany.

Numbers of Hematopoietic cell transplantation (HCT) in Europe and collaborating countries continues to rise with 48,512 HCT in 43,581 patients, comprising of 19,798 (41%) allogeneic and 28,714 (59%) autologous, reported by 700 centers in 51 countries during 2019. Main indications were myeloid malignancies 10,764 (25%), lymphoid malignancies 27,895 (64%), and nonmalignant disorders 3173 (7%). A marked growth in CAR-T cellular therapies from 151 in 2017 to 1134 patients in 2019 is observed. This year's analyses focus on changes over 30 years. Since the first survey in 1990 where 143 centers reported 4234 HCT, the number has increased to 700 centers and 48,512 HCT. Transplants were reported in 20 countries in 1990, and 51, 30 years later. More than 800,000 HCT in 715,000 patients were reported overall. Next to the massive expansion of HCT technology, most notable developments include the success of unrelated donor and haploidentical HCT, an increase followed by decrease in the number of cord blood transplants, use of reduced intensity HCT in older patients, and the phenomenal rise in cellular therapy. This annual report of the European Society for Blood and Marrow Transplantation (EBMT) reflects current activity and highlights important trends vital for health care planning.
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http://dx.doi.org/10.1038/s41409-021-01227-8DOI Listing
February 2021

Conditioning intensity before allogeneic haematopoietic stem cell transplantation: a quality control audit.

Br J Haematol 2021 Feb 22. Epub 2021 Feb 22.

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

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http://dx.doi.org/10.1111/bjh.17369DOI Listing
February 2021

Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies.

Front Immunol 2020 2;11:613954. Epub 2021 Feb 2.

Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.
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http://dx.doi.org/10.3389/fimmu.2020.613954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884746PMC
February 2021

The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis.

Front Immunol 2020 25;11:614976. Epub 2021 Jan 25.

Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, Baden Wuerttemberg-Hessen, and University Hospital Ulm, Ulm, Germany.

T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided.
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http://dx.doi.org/10.3389/fimmu.2020.614976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868530PMC
January 2021

Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia.

Front Immunol 2020 19;11:584520. Epub 2021 Jan 19.

Hopital Saint-Louis, APHP, Université de Paris, Paris, France.

Results from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Several competing models have been developed to classify donors as KIR-advantageous or disadvantageous. Basically, these models differ by grouping donors based on distinct KIR-KIR-ligand combinations or by haplotype motif assignment. This study aimed to validate different models for unrelated donor selection for patients with Myelodysplatic Syndromes (MDS) or secondary Acute Myeloid Leukemia (sAML). In a joint retrospective study of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) registry data from 1704 patients with secondary AML or MDS were analysed. The cohort consisted mainly of older patients (median age 61 years) with high risk disease who had received chemotherapy-based reduced intensity conditioning and anti-thymocyte globulin prior to allogeneic HCT from well-matched unrelated stem cell donors. The impact of the predictors on Overall Survival (OS) and relapse incidence was tested in Cox regression models adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type. genes were typed using high-resolution amplicon-based next generation sequencing. In univariable and multivariable analyses none of the models predicted OS and the risk of relapse consistently. Our results do not support the hypothesis that optimizing NK-mediated alloreactivity is possible by KIR-genotype informed selection of HLA-matched unrelated donors. However, in the context of allogeneic transplantation, NK-cell biology is complex and only partly understood. KIR-genes are highly diverse and current assignment of haplotype motifs based on the presence or absence of selected KIR genes is over-simplistic. As a consequence, further research is highly warranted and should integrate cutting edge knowledge on KIR genetics, and NK-cell biology into future studies focused on homogeneous groups of patients and treatment modalities.
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http://dx.doi.org/10.3389/fimmu.2020.584520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851088PMC
January 2021

Thiotepa-busulfan-fludarabine (TBF) conditioning regimen in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis: an outcome analysis from the Chronic Malignancies Working Party of the EBMT.

Bone Marrow Transplant 2021 Feb 1. Epub 2021 Feb 1.

CHU de Lille, univ Lille, INSERM U1286, Infinite, 59000, Lille, France.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option in MF. There is no consensus on the optimal conditioning regimen. We report outcomes of 187 patients with MF transplanted between 2010 and 2017 conditioned with TBF. Median age was 58 years. Median interval from diagnosis to allo-HCT was 44 months. Donors were haploidentical (41%), unrelated (36%) or HLA-identical siblings (23%). Stem cell source was PB in 60%. Conditioning was myeloablative in 48% of cases. Antithymocyte globulin (ATG) was used in 41% of patients. At 100 days, neutrophil and platelet engraftment were 91% and 63% after a median of 21 and 34 days, respectively. Grade II-IV and III-IV acute GVHD occurred in 24% and 12%, while at 3 years, all grade chronic GVHD and chronic extensive GVHD had been diagnosed in 38% and 11%. At 3 years, OS, RFS and GRFS were 55%, 49% and 43%, respectively. RI and NRM were 17% and 33%. On multivariate analysis, poor KPS and the use of unrelated donors were associated with worse GRFS and a higher grade II-IV acute GVHD, respectively. Neither donor type nor intensity of the conditioning regimen influenced survival outcomes. TBF is a feasible conditioning regimen in allo-HCT for MF in all donor settings although longer term outcomes are required.
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http://dx.doi.org/10.1038/s41409-021-01222-zDOI Listing
February 2021

How much has allogeneic stem cell transplant-related mortality improved since the 1980s? A retrospective analysis from the EBMT.

Blood Adv 2020 Dec;4(24):6283-6290

European Society for Blood and Marrow Transplantation (EBMT) Transplant Complications Working Party, Paris, France.

We performed a study to find out how advances in modern medicine have improved the mortality risk of allogeneic stem cell transplantation. We analyzed major transplantation outcome parameters in adult patients on the European Society for Blood and Marrow Transplantation (EBMT) registry who had hematologic malignancies and had received transplants from matched sibling donors. We performed multivariate analyses using the Cox proportional-hazards model including known risk factors for nonrelapse mortality and a matched-pairs analysis. We identified 38 800 patients who fulfilled the inclusion criteria. Considerable changes in patient characteristics have occurred in the past decades, such as older age, different underlying diseases, and a higher proportion of patients with advanced disease. Major reasons for transplantation-related death in the 1980s were infectious complications and graft-versus-host disease. Nonrelapse mortality, measured at 1 year after transplantation, has decreased over time: 29.7% from 1980 through 1989, 24.4% from 1990 through 1999, 14.8% from 2000 through 2009, and 12.2% from 2010 through 2016. On multivariate analysis, the year of transplantation was associated with reduced nonrelapse mortality (P < .0001; hazard ratio [HR] [95% confidence interval (CI)], 0.8 [0.79-0.82], for 5-year intervals) and decreased overall mortality (P < .0001; HR [95% CI], 0.87 [0.86-0.88]. In the matched-pairs analysis of 3718 patients in each group, nonrelapse mortality at 1 year was 24.4% in the 1990s and 9.5% from 2013 through 2016 (P < .0001; HR [95% CI], 0.39 [0.34-0.43]). Transplantation-related mortality has decreased significantly in the past 40 years. These favorable data facilitate evidence-based treatment decisions on transplantation indications in the context of the availability of novel immunotherapies.
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http://dx.doi.org/10.1182/bloodadvances.2020003418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756984PMC
December 2020

Hematopoietic Stem Cell Transplantation for Hepatitis-associated Aplastic Anemia Following Liver Transplantation for Nonviral Hepatitis: A Retrospective Analysis and a Review of the Literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT).

J Pediatr Hematol Oncol 2020 Dec 2. Epub 2020 Dec 2.

Hopital St. Louis, Paris.

Hepatitis-associated aplastic anemia (HAAA) has been reported in 23% to 33% of patients who received orthotopic liver transplantation (LT) for acute liver disease of unknown origin (nonviral hepatitis). In this situation, hematopoietic stem cell transplantation (HSCT) might be a curative option. Here the authors report on 6 patients who received HSCT after LT for nonviral HAAA hepatitis. The outcomes were interpreted in the context of recently reported immune suppressive therapy (IST) outcomes in 8 patients with HAAA and to HSCT outcomes in patients with HAAA who recovered from hepatitis without undergoing LT. All patients transplanted by using HLA-identical sibling donors (3 out of 6) were alive and had normal liver function and hematopoiesis without graft versus host disease. Both patients receiving bone marrow from a matched unrelated donor (MUD) experienced extensive graft versus host disease that was fatal for one patient. Thereby, the authors conclude that HSCT can be considered as a first-choice treatment for this category of patients when HLA-identical donors are available. When no HLA-identical donor is available, IST should be applied as HSCT with other donor sources might be reserved for IST nonresponders or poor responders.
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http://dx.doi.org/10.1097/MPH.0000000000001991DOI Listing
December 2020

Role of pre-transplant MRD level detected by flow cytometry in recipients of allogeneic stem cell transplantation with AML.

Eur J Haematol 2020 Nov 29. Epub 2020 Nov 29.

Department of Stem Cell Transplantation, University Medical Center Eppendorf, University of Hamburg, Hamburg, Germany.

Objectives And Methods: We analyzed the impact of pretransplant MRD level in bone marrow measured by flow cytometry using "different from normal" method on outcomes for 189 AML patients (108 males; median age, 58 (21-80) years). All patients were subdivided into negative (n = 96), "low" (0.1%-0.5%, n = 32), and "high" MRD (>0.5%, n = 61) groups.

Results: In multivariate analysis, the hazard ratios for "high" and "low" MRD levels related to MRD negativity were 7.9 (95% CI 3.5-18.1, P < .001) and 5.4 (95% CI 2.1-14, P = .0058) for relapse; 2.3 (95% CI 1.3-4.1, P = .006) and 1.6 (95% CI 0.82-3.3, P = .16) for OS; and 2.8 (95% CI 1.7-4.7, P < .001) and 2.2 (95% CI 1.1-4.2, P = .02) for LFS, respectively. We found no significant impact of "low" MRD level on relapses (0.68, 95% CI 0.33-1.4, P = .30), OS (0.72, 95% CI: 0.36-1.5, P = .36) and LFS (0.79, 95% CI: 0.42-1.5, P = .46) related to "high" MRD group.

Conclusions: Presence of detectable MRD was indicative for a high relapse risk, low LFS and OS. "Low" MRD level showed no significant impact on relapse, LFS and OS related to "high" MRD group.
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http://dx.doi.org/10.1111/ejh.13557DOI Listing
November 2020

Allogeneic stem cell transplant in patients with acute myeloid leukemia and karnofsky performance status score less than or equal to 80%: A study from the acute leukemia working party of the European Society for Blood and Marrow Transplantation (EBMT).

Cancer Med 2021 Jan 26;10(1):23-33. Epub 2020 Nov 26.

EBMT Paris Study Office, Saint Antoine Hospital, Paris, France.

Limited data are currently available on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) with a reduced performance status. We herein present the results of a registry study on 2,936 AML patients undergoing allo-SCT in first remission (CR1) with a Karnofsky Performance Status (KPS) score less than or equal to 80%. Two-year leukemia-free survival (LFS), overall survival (OS) and graft-versus-host disease (GVHD)-free, and relapse-free survival (GRFS) rates were 54%, 59%, and 41%, respectively. In multivariable analysis, patients with a KPS score = 80% had lower non-relapse mortality (NRM) and superior OS in comparison to patients with a KPS score <80% (p < 0.001). In the subgroup of patients with a KPS score =80%, a reduced-intensity conditioning (RIC) regimen was associated with an increased risk of relapse (p = 0.002) and lower GRFS (p < 0.001) compared to myeloablative conditioning (MAC). Differently, in patients with a KPS score <80%, a RIC regimen resulted in lower NRM (p < 0.001), whereas relapse incidence did not differ, thus leading to an improved GRFS (p = 0.008) as compared to MAC. A transplant from a matched sibling donor (MSD) was associated with a reduced incidence of grade III-IV acute GVHD (p < 0.01) and NRM (p < 0.01) in comparison to other donor types. In conclusion, allo-SCT appears feasible in AML patients with a jeopardized KPS score. Survival is significantly affected by the conditioning intensity, which should be adjusted according to the severity of KPS impairment.
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http://dx.doi.org/10.1002/cam4.3593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826477PMC
January 2021

Comparison of Haploidentical Bone Marrow versus Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Posttransplant Cyclophosphamide in Patients with Acute Leukemia.

Clin Cancer Res 2021 Feb 4;27(3):843-851. Epub 2020 Nov 4.

Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorbonne University, and INSERM UMRs 938, Paris, France.

Purpose: Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option in the absence of a matched related donor.

Experimental Design: We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, = 401) versus UD mobilized peripheral blood stem cells (UD-PB, = 192) transplantation in the setting of PTCy.

Results: The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively ( < 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively ( < 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively ( = 0.21). In the multivariate analysis, the risk of grade 2-4 acute GvHD (HR = 0.53, = 0.01) and chronic GvHD (HR = 0.50, = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival.

Conclusions: The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2809DOI Listing
February 2021

The role of novel agents for consolidation after autologous transplantation in newly diagnosed multiple myeloma: a systematic review.

Ann Hematol 2021 Feb 29;100(2):405-419. Epub 2020 Oct 29.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Despite the increasing inclusion of novel agents within the multiple myeloma (MM) treatment sequence, their role for posttransplant consolidation therapy remains unclear. We systematically reviewed studies evaluating the efficacy of novel agent consolidation. We identified 11 citations on 12 prospective comparative studies, and 5 citations were single-arm or comparative studies with preliminary results. Nine different regimens were evaluated in 5905 patients. Risk assessment yielded serious risk of bias and heterogeneity across study designs was high. Irrespective of the regimen, deepened responses after consolidation were seen and improvements were more pronounced with multi-agent consolidation. Bortezomib, thalidomide, and dexamethasone improved long-term survival versus duplet consolidation, including in patients with high-risk cytogenetics. The addition of daratumumab to triplet regimens yielded modestly improved responses with significantly increased rates of minimal residual disease negativity but survival results were limited by short follow-up. In high-risk MM, responses were not different, whereas progression-free survival appeared to be improved with consolidation therapy, challenging the association of response and overall outcome in this subgroup. Our findings highlight the necessity of longer follow-up and consistent reporting to ensure comparability of studies to enable better evidence assessment and to identify patients benefitting from consolidation therapy.
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http://dx.doi.org/10.1007/s00277-020-04316-8DOI Listing
February 2021

Treosulfan-Based Conditioning Regimen for Second Allograft in Patients with Myelofibrosis.

Cancers (Basel) 2020 Oct 23;12(11). Epub 2020 Oct 23.

Hematology Department, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Relapse after allogeneic hematopoietic stem cell transplantation (AHSCT) in myelofibrosis (MF) patients remains as a significant issue despite advances in transplantation procedures and significant prolongation in survival. Second AHSCT is a potential treatment option but associated with high treatment-related mortality and novel less toxic conditioning regimens are needed. In 33 MF patients with relapse after AHSCT and failure to donor lymphocyte infusion (DLI) we investigated treosulfan (36-42 g/m) in combination with fludarabine and anti-thymocyte globulin (ATG) as conditioning regimen for a second AHSCT with matched related ( = 2), unrelated ( = 23), or mismatched unrelated ( = 8) donors. All patients achieved leukocyte engraftment after a median of 11 days, and 56 ± 13% experienced acute GVHD grade II-IV at day 100. The therapy-related mortality at day 100 and at 3 years was 16% and 31%, respectively. The cumulative incidence of relapse at 5 years was 16%, resulting in a 5-year disease-free and overall survival of 45% and 47%, respectively. Treosulfan-based conditioning for second allograft in relapsed MF patients resulted in about 50% of the patients in long-term freedom from disease.
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http://dx.doi.org/10.3390/cancers12113098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690833PMC
October 2020

Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European society for blood and marrow transplantation (EBMT).

Am J Hematol 2021 01 27;96(1):69-79. Epub 2020 Oct 27.

CHU de Lille, Université de Lille, Lille, France.

The role of spleen size and splenectomy for the prediction of post-allogeneic hematopoietic stem cell transplant (allo-HCT) outcome in myelofibrosis remains under debate. In EBMT registry, we identified a cohort of 1195 myelofibrosis patients transplanted between 2000-2017 after either fludarabine-busulfan or fludarabine-melphalan regimens. Overall, splenectomy was performed in 202 (16.9%) patients and its use decreased over time (28.3% in 2000-2009 vs 14.1% in 2010-2017 period). By multivariate analysis, splenectomy was associated with less NRM (HR 0.64, 95% CI 0.44-0.93, P = .018) but increased risk of relapse (HR 1.43, 95% CI 1.01-2.02, P = .042), with no significant impact on OS (HR 0.86, 95% CI 0.67-1.12, P = .274). However, in subset analysis comparing the impact of splenectomy vs specific spleen sizes, for patients with progressive disease, an improved survival was seen in splenectomised subjects compared to those patients with a palpable spleen length ≥ 15 cm (HR 0.44, 95% CI 0.28-0.69, P < .001), caused by a significant reduction in NRM (HR 0.26, 95% CI 0.14-0.49, P < .001), without significantly increased relapse risk (HR 1.47, 95% CI 0.87-2.49, P = .147). Overall, despite the possible biases typical of retrospective cohorts, this study highlights the potential detrimental effect of massive splenomegaly in transplant outcome and supports the role of splenectomy for myelofibrosis patients with progressive disease and large splenomegaly.
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http://dx.doi.org/10.1002/ajh.26020DOI Listing
January 2021

Evaluation of six different types of sequential conditioning regimens for allogeneic stem cell transplantation in relapsed/refractory acute myelogenous leukemia - a study of the Acute Leukemia Working Party of the EBMT.

Leuk Lymphoma 2021 Feb 11;62(2):399-409. Epub 2020 Oct 11.

Department of Hematology and Cell Therapy, Hopital Saint-Antoine, Paris, France.

The Acute Leukemia Working Party (ALWP) of the EBMT assessed the outcome of allogeneic stem cell transplantation (alloSCT) in patients with relapsed/refractory AML (r/rAML) evaluating six sequential conditioning regimens (SR) groups. A total of 2132 patients were included. LFS at 2 years was 28.9%, 33.6%, 35.3%, 20.6%, 24.4%, and 27% for the FLAMSA-TBI4, FLAMSA-Chemo, Mel-Flu-TBI8, Mel-Treo-Flu, Thio-ETO-Cy-Bu2-Flu, and Clo-ARAC-(Bu2/TBI4)-Cy groups, respectively. In patients <55 years of age Mel-Flu-TBI8 had the best LFS, which was statistically significant only in comparison to the Mel-Treo-Flu group, while in patients ≥55 years LFS was best with FLAMSA-Chemo without significant differences compared to FLAMSA-TBI4 and Mel-Flu-TBI8. Furthermore, best NRM rates were obtained with the two FLAMSA regimens groups. Our study suggests that in younger (<55 years) patients a more intense regimen might be used whereas in older (≥55 years) patients the focus might be more on tolerability.
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http://dx.doi.org/10.1080/10428194.2020.1827248DOI Listing
February 2021

Long-Term Survival Benefit after Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia.

Biol Blood Marrow Transplant 2020 Oct 9. Epub 2020 Oct 9.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients age ≤70 years at diagnosis who underwent allo-HCT (n = 119) compared with those who did not (n = 142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower risk (CPSS low/intermediate-1) or higher risk (intermediate-2/high) showed significantly improved outcomes after transplantation in higher-risk patients, with a 37% reduced hazard for death. However, although higher CPSS was associated with worse outcomes in the nontransplantation group, the score was of limited utility for post-transplantation risk stratification. This study may provide further support for the potentially beneficial role of allo-HCT in terms of long-term survival in higher-risk patients but also underscores the need for transplantation-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of patients with CMML. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.007DOI Listing
October 2020

Comparable outcomes of haploidentical transplant with TBF conditioning versus matched unrelated donor with fludarabine/busulfan conditioning for acute myeloid leukemia.

Bone Marrow Transplant 2020 Oct 6. Epub 2020 Oct 6.

Department of Haematology and EBMT Paris Study Office/CEREST-TC, Saint Antoine Hospital, INSERM UMR 938, Université Pierre et Marie Curie, Paris, France.

We compared transplant outcomes of 708 acute myeloid leukemia (AML) patients receiving haploidentical allogeneic hematopoietic-cell transplantation using thiotepa/busulfan/fludarabine (TBF) conditioning with posttransplant cyclophosphamide (ptCy), to 2083 patients receiving matched unrelated donor (MUD) transplantation using fludarabine/busulfan (FB) conditioning and in vivo T-cell depletion. For intermediate cytogenetic risk AML transplanted in first complete remission (CR1), multivariate analysis revealed that haplo-TBF significantly increased nonrelapse mortality (NRM) (HR 2.1; p = 0.0006) but did not affect relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), or graft-versus-host disease-free, relapse-free survival (GRFS). For high cytogenetic risk AML transplanted in CR1, haplo-TBF significantly increased NRM (HR = 2.7; p = 0.02), decreased RI (HR = 0.45; p = 0.03) but had no influence on LFS, OS, or GRFS. For AML transplanted in CR2, haplo-TBF significantly increased NRM (HR = 2.36; p = 0.008), decreased RI (HR = 0.38; p = 0.005), but had no influence on LFS, OS, or GRFS. Finally, for AML patients transplanted with active disease, haplo-TBF had no influence on transplant outcomes. In conclusion, compared to MUD-FB, haplo-TBF increased NRM, reduced RI in high-risk AML in CR, resulting in similar LFS, OS, and GRFS. These results comparing two different approaches support the use of a haploidentical family donor for high-risk AML patients lacking a matched sibling donor.
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http://dx.doi.org/10.1038/s41409-020-01074-zDOI Listing
October 2020

Idelalisib treatment prior to allogeneic stem cell transplantation for patients with chronic lymphocytic leukemia: a report from the EBMT chronic malignancies working party.

Bone Marrow Transplant 2020 Oct 2. Epub 2020 Oct 2.

University of Heidelberg, Heidelberg, Germany.

No studies have been reported so far on bridging treatment with idelalisib for patients with chronic lymphocytic leukemia (CLL) prior to allogeneic hematopoietic cell transplantation (alloHCT). To study potential carry-over effects of idelalisib and to assess the impact of pathway-inhibitor (PI) failure we performed a retrospective EBMT registry-based study. Patients with CLL who had a history of idelalisib treatment and received a first alloHCT between 2015 and 2017 were eligible. Data on 72 patients (median age 58 years) were analyzed. Forty percent of patients had TP53 CLL and 64% had failed on at least one PI. No primary graft failure occurred. Cumulative incidences of acute GVHD °II-IV and chronic GVHD were 51% and 39%, respectively. Estimates for 2-year overall survival (OS), progression-free survival (PFS), and cumulative incidences of relapse/progression (CIR) and non-relapse mortality NRM were 59%, 44%, 25%, and 31%. In univariate analysis, drug sensitivity was a strong risk factor. For patients who had failed neither PI treatment nor chemoimmunotherapy (CIT) the corresponding 2-year estimates were 73%, 65%, 15%, and 20%, respectively. In conclusion, idelalisib may be considered as an option for bridging therapy prior to alloHCT. Owing to the high risk for acute GVHD intensified clinical monitoring is warranted.
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http://dx.doi.org/10.1038/s41409-020-01069-wDOI Listing
October 2020

Incidence and Outcome of Late Relapse after Allogeneic Stem Cell Transplantation for Myelofibrosis.

Biol Blood Marrow Transplant 2020 12 17;26(12):2279-2284. Epub 2020 Sep 17.

University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

In this cross-sectional study, we retrospectively evaluated the files of 227 patients with myelofibrosis who underwent transplantation between 1994 and 2015 for relapse later than 5 years after allogeneic stem cell transplantation (SCT). A total of 94 patients who were alive and in remission at 5 years were identified with follow-up of at least 5 years (median, 9.15 years) after SCT. Thirteen patients (14%) experienced late molecular (n = 6) or hematologic (n = 7) relapse at a median of 7.1 years while 81 patients did not experience relapse. Relapse patients received either donor lymphocyte infusion (DLI) (n = 7) and/or second transplantation (n = 4). Of those, 72.7% achieved again full donor cell chimerism and molecular remission, and after a median follow-up of 45 months, the 3-year overall survival rates for patients with or without relapse were 90.9% (95% confidence interval [CI], 77% to 100%) and 98.8% (95% CI, 96% to 100%), respectively (P = .13). We conclude that late relapse occurs in about 14% of the patients and the majority can be successfully salvaged with DLI and/or second allograft. All patients with molecular relapse are alive and support the long-time molecular monitoring in myelofibrosis patients after allogeneic SCT.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.006DOI Listing
December 2020

1,25-dihydroxyvitamin-D3 but not the clinically applied marker 25-hydroxyvitamin-D3 predicts survival after stem cell transplantation.

Bone Marrow Transplant 2021 Feb 27;56(2):419-433. Epub 2020 Aug 27.

Department of Internal Medicine III, Hematology and Medical Oncology, University Medical Center of Regensburg, Regensburg, Germany.

The serum level of 25-hydroxyvitamin-D3 is accepted as marker for a person's vitamin D status but its role for the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is controversially discussed. The impact of 1,25-dihydroxyvitamin-D3 on HSCT outcome, however, has never been studied. In a discovery cohort of 143 HSCT patients we repeatedly (day -16 to 100) measured 1,25-dihydroxyvitamin-D3 and in comparison the well-established marker for serum vitamin D status 25-hydroxyvitamin-D3. Only lower 1,25-dihydroxyvitamin-D3 levels around HSCT (day -2 to 7, peritransplant) were significantly associated with higher 1-year treatment-related mortality (TRM) risk (Mann-Whitney U test, P = 0.001). This was confirmed by Cox-model regression without and with adjustment for baseline risk factors and severe acute Graft-versus-Host disease (aGvHD; unadjusted P = 0.001, adjusted P = 0.005). The optimal threshold for 1,25-dihydroxyvitamin-D3 to identify patients at high risk was 139.5 pM. Also in three replication cohorts consisting of altogether 365 patients 1,25-dihydroxyvitamin-D3 levels below 139.5 pM had a 3.3-fold increased risk of TRM independent of severe aGvHD compared to patients above 139.5 pM (Cox-model unadjusted P < 0.0005, adjusted P = 0.001). Our data highlight peritransplant 1,25-dihydroxyvitamin-D3 levels but not the commonly monitored 25-hydroxyvitamin-D3 levels as potent predictor of 1-year TRM and suggest to monitor both vitamin D metabolites in HSCT patients.
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http://dx.doi.org/10.1038/s41409-020-01031-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870805PMC
February 2021

Efficacy and Tolerability of High- versus Low-dose Lenalidomide Maintenance Therapy of Multiple Myeloma after Autologous Blood Stem Cell Transplantation.

Clin Cancer Res 2020 Nov 17;26(22):5879-5886. Epub 2020 Aug 17.

University Hospital Düsseldorf, Düsseldorf, Germany.

Purpose: For multiple myeloma, high-dose chemotherapy and autologous blood stem-cell transplantation (ASCT) followed by lenalidomide maintenance (LenMT) at 10-15 mg/day is considered standard of care. However, dose reductions due to side effects are common and median LenMT doses achieved over time may remain lower. Dose response during LenMT has never been investigated.

Patients And Methods: In a multicenter, randomized, open-label trial, patients with multiple myeloma after ASCT and high-dose lenalidomide consolidation therapy (CT) at 25 mg/day were randomized to receive LenMT at either 25 or 5 mg/day. Primary endpoint was progression-free survival (PFS).

Results: Ninety-four patients (median age, 58 years) were randomized to either arm, with 22% having International Staging System (ISS) stage 3 and 22% being in complete remission (CR). After median follow-up of 46.7 months, median doses of 14.5 and 5 mg/day were achieved in the two arms; 53% of dose reductions occurring during CT. In the high- and the low-dose arm, median PFS was 44.8 and 33.0 months (HR, 0.65; 95% CI, 0.44-0.97; = 0.032), 36% and 23% of patients had stringent CR as best response ( = 0.08), and 4-year OS was 79% and 67% ( = 0.16), respectively. Hematologic toxicity, grade ≥3 neutropenia, and infections were initially more common with LenMT 25 mg, but decreased after dose adjustments. SPM incidence and quality-of-life (QoL) scores in both arms were similar.

Conclusions: LenMT dose correlated with efficacy and toxicity. High rates of dose reductions during CT argue against a high starting dose. However, continuous up- and down-titration for each patient to the current maximum tolerated dose is prudent.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0841DOI Listing
November 2020

Association of Country-Specific Socioeconomic Factors With Survival of Patients Who Experience Severe Classic Acute Graft-vs.-Host Disease After Allogeneic Hematopoietic Cell Transplantation. An Analysis From the Transplant Complications Working Party of the EBMT.

Front Immunol 2020 23;11:1537. Epub 2020 Jul 23.

Department of Haematology, Oncology and Internal Medicine, Medical Uniwersity of Warsaw, Warsaw, Poland.

Acute graft-vs.-host disease (aGvHD) is one of the most frequent causes of transplant-related mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). Its treatment is complex and costly. The aim of this study was to retrospectively analyze the impact of country-specific socioeconomic factors on outcome of patients who experience severe aGvHD. Adults with hematological malignancies receiving alloHCT from either HLA-matched siblings ( = 1,328) or unrelated donors ( = 2,824) developing grade 3 or 4 aGvHD were included. In univariate analysis, the probability of TRM at 2 years was increased for countries with lower current Health Care Expenditure (HCE, = 0.04), lower HCE as % of Gross Domestic Product per capita ( = 0.003) and lower values of the Human Development Index ( = 0.02). In a multivariate model, the risk of TRM was most strongly predicted by current HCE (HR = 0.76, = 0.006). HCE >median was also associated with reduced risk of the overall mortality (HR 0.73, = 0.0006) and reduced risk of treatment failure (either relapse or TRM; HR 0.77, = 0.004). We conclude that country-specific socioeconomic factors, in particular current HCE, are strongly associated with survival of patients who experience severe aGvHD.
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http://dx.doi.org/10.3389/fimmu.2020.01537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390847PMC
July 2020

Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN.

Blood 2020 Oct;136(18):2051-2064

Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) that leads to progressive bone marrow (BM) fibrosis. Although the cellular mutations involved in the pathogenesis of PMF have been extensively investigated, the sequential events that drive stromal activation and fibrosis by hematopoietic-stromal cross-talk remain elusive. Using an unbiased approach and validation in patients with MPN, we determined that the differential spatial expression of the chemokine CXCL4/platelet factor-4 marks the progression of fibrosis. We show that the absence of hematopoietic CXCL4 ameliorates the MPN phenotype, reduces stromal cell activation and BM fibrosis, and decreases the activation of profibrotic pathways in megakaryocytes, inflammation in fibrosis-driving cells, and JAK/STAT activation in both megakaryocytes and stromal cells in 3 murine PMF models. Our data indicate that higher CXCL4 expression in MPN has profibrotic effects and is a mediator of the characteristic inflammation. Therefore, targeting CXCL4 might be a promising strategy to reduce inflammation in PMF.
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http://dx.doi.org/10.1182/blood.2019004095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678060PMC
October 2020

Development of a Short Instrument for Measuring Health-Related Quality of Life in Oncological Patients for Clinical Use: Protocol for an Observational Study.

JMIR Res Protoc 2020 Jul 29;9(7):e17854. Epub 2020 Jul 29.

Department of Medical Psychology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Background: Cancer patients often suffer from the physical and psychological burden of their disease and its treatment. This is frequently insufficiently identified and addressed in clinical practice. In the context of improving patient-centered care in oncological patients, patient-reported outcomes (PROs) represent an important addition to current routine care. So far, available PRO questionnaires for cancer patients are unsuitable for routine procedures due to their length and complexity.

Objective: This study aimed to develop and psychometrically test a short questionnaire to measure health-related quality of life (HrQoL) in cancer patients for use in routine care.

Methods: This observational study consists of two parts: (1) a qualitative study to develop a short questionnaire measuring HrQoL and (2) a quantitative study to psychometrically test this questionnaire in five oncological departments of a comprehensive cancer center. In part 1 of the study, semistructured interviews with 28 cancer patients, as well as five focus groups with 22 clinicians and nurses, were conducted to identify clinically relevant dimensions of HrQoL. The identified dimensions were complemented with related dimensions from empirical studies and reviewed via expert discussion. Based on this, a short instrument was developed. In part 2 of the study, the developed questionnaire was tested in cancer in- and outpatients at five participating oncological clinics using additional standardized questionnaires assessing HrQoL and other important PROs. The questionnaire was presented to more than 770 patients twice during treatment.

Results: The project started in May 2017 with recruitment for study phase I beginning in December 2017. Recruitment for study phases I and II ended in April 2018 and February 2019, respectively. After study phase II and psychometrical analyses, the newly developed questionnaire measuring the HrQoL of all cancer entities in routine care was finalized.

Conclusions: With five to six dimensions and one item per dimension, the developed questionnaire is short enough to not disrupt routine procedures during treatment and is profound enough to inform clinicians about the patient's HrQoL impairments and status.

Trial Registration: Open Science Framework Registries 10.17605/OSF.IO/Y7XCE; https://osf.io/y7xce/.

International Registered Report Identifier (irrid): RR1-10.2196/17854.
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http://dx.doi.org/10.2196/17854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424483PMC
July 2020

FLAMSA-Based Reduced-Intensity Conditioning versus Myeloablative Conditioning in Younger Patients with Relapsed/Refractory Acute Myeloid Leukemia with Active Disease at the Time of Allogeneic Stem Cell Transplantation: An Analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2020 11 24;26(11):2165-2173. Epub 2020 Jul 24.

Department of Clinical Hematology and Cell Therapy, Hôpital Saint-Antoine, AP-HP, Sorbonne University, INSERM UMR 938, Paris, France.

The use of myeloablative conditioning (MAC) in the setting of active relapsed/refractory (R/R) acute myeloid leukemia (AML) has been hindered by high historical rates of nonrelapse mortality (NRM). FLAMSA (fludarabine, Ara-C, and amsacrine) chemotherapy (CT) followed by reduced-intensity conditioning (RIC) has been proposed as an effective and potentially safer alternative in this scenario. As improvements in supportive care have contributed to decreasing NRM rates after MAC, a comparative reassessment of these two strategies was performed. This was a registry-based analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Eligibility criteria included age 18 to 50 years, primary refractory, first or second relapsed active AML, first allogeneic stem cell transplantation from a matched sibling donor (MSD) or an unrelated donor (UD) performed between 2005 and 2018, MAC or FLAMSA-RIC. A total of 1018 patients were included. The median patient age was 39 years (range, 18 to 50). Two hundred and fifty-eight patients received busulfan (Bu)/cyclophosphamide (Cy), 314 received Cy/total body irradiation (TBI), 318 received FLAMSA-TBI, and 128 received FLAMSA-CT. The median duration of follow-up was 50 months. In univariate analysis, the 2-year relapse incidence (RI) (54%; 95% confidence interval (CI), 50%-57%), leukemia-free survival (LFS) (30%; 95% CI, 27%-33%), and refined graft-versus-host disease-free, relapse-free survival (GRFS) (21%; 95% CI, 18%-24%) were not significantly different between cohorts. Lower 2-year NRM was observed in the FLAMSA-CT group (7% versus 16% in Bu/Cy, 19% in Cy/TBI, and 18% in FLAMSA-TBI; P = .04), as well as increased 2-year overall survival (OS) (50% versus 33% in Bu/Cy, 34% in Cy/TBI, and 36% in FLAMSA-TBI; P = .03). These results were maintained in the multivariate analysis (hazard ratio [HR] for NRM: .40, P = .01; HR for OS: .65, P = .01; Bu/Cy as reference). These data suggest that FLAMSA-CT may be a preferred conditioning regimen in patients with active R/R AML due to lower NRM. Yet, the high relapse rates observed in our analyses emphasize the need for novel therapeutic strategies in this clinical setting.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.020DOI Listing
November 2020

Allogeneic Stem Cell Transplantation for Patients with Lower-Risk Myelodysplastic Syndrome.

Biol Blood Marrow Transplant 2020 11 24;26(11):2047-2052. Epub 2020 Jul 24.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The indication for allogeneic stem cell transplantation (SCT) in patients with lower-risk myelodysplastic syndrome (MDS) is controversial. Here we report 60 patients with a low risk (n = 32) or intermediate risk (n = 28) classification according to the revised International Prognostic Scoring System (IPSS-R) who underwent allogeneic SCT with a reduced-intensity conditioning (n = 45) or myeloablative conditioning (n = 15) regimen from an HLA-identical sibling (n = 9), a matched unrelated donor (n = 36), or a mismatched unrelated donor (n = 15). The rates of grade II-IV and grade III-IV acute graft-versus-host disease were 32% and 7%, respectively, resulting in a transplantation-related mortality (TRM) of 17% at 3 years. The cumulative incidence of relapse at 5 years was only 7%, resulting in a 5-year disease-free survival of 72% and overall survival (OS) of 79%. Transplantation from a fully matched donor resulted in significantly improved OS at 5 years (91% versus 70%). Allogeneic SCT in lower-risk MDS (IPSS-R low or intermediate risk) from an HLA-matched donor resulted in excellent OS with a low risk of relapse.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.018DOI Listing
November 2020