Publications by authors named "Christoph Schmid"

266 Publications

Development and validation of a disease risk stratification system for patients with haematological malignancies: a retrospective cohort study of the European Society for Blood and Marrow Transplantation registry.

Lancet Haematol 2021 Mar;8(3):e205-e215

Hematology Division, Chaim Sheba Medical Center, Tel Aviv University, Ramat Gan, Israel.

Background: Diagnosis and remission status at the time of allogeneic haematopoietic stem-cell transplantation (HSCT) are the principal determinants of overall survival following transplantation. We sought to develop a contemporary disease-risk stratification system (DRSS) that accounts for heterogeneous transplantation indications.

Methods: In this retrospective cohort study we included 55 histology and remission status combinations across haematological malignancies, including acute leukaemia, lymphoma, multiple myeloma, and myeloproliferative and myelodysplastic disorders. A total of 47 265 adult patients (aged ≥18 years) who received an allogeneic HSCT between Jan 1, 2012, and Dec 31, 2016, and were reported to the European Society for Blood and Marrow Transplantation registry were included. We divided EBMT patients into derivation (n=25 534), tuning (n=18 365), and geographical validation (n=3366) cohorts. Disease combinations were ranked in a multivariable Cox regression for overall survival in the derivation cohort, cutoff for risk groups were evaluated for the tuning cohort, and the selected system was tested on the geographical validation cohort. An independent single-centre US cohort of 660 patients transplanted between Jan 1, 2010, and Dec 31, 2015 was used to externally validate the results.

Findings: The DRSS model stratified patients in the derivation cohort (median follow-up was 2·1 years [IQR 1·0-3·2]) into five risk groups with increasing mortality risk: low risk (reference group), intermediate-1 (hazard ratio for overall survival 1·26 [95% CI 1·17-1·36], p<0·0001), intermediate-2 (1·53 [1·42-1·66], p<0·0001), high (2·03 [1·86-2·22], p<0·0001), and very high (2·87 [2·63-3·13], p<0·0001). DRSS levels were also associated with a stepwise increase in risk across the tuning and geographical validation cohort. In the external validation cohort (median follow-up was 5·7 years [IQR 4·5-7·1]), the DRSS scheme separated patients into 4 risk groups associated with increasing risk of mortality: intermediate-2 risk (hazard ratio [HR] 1·34 [95% CI 1·04-1·74], p=0·025), high risk (HR 2·03 [95% CI 1·39-2·95], p=0·00023) and very-high risk (HR 2·26 [95% CI 1·62-3·15], p<0·0001) patients compared with the low risk and intermediate-1 risk group (reference group). Across all cohorts, between 64% and 65% of patients were categorised as having intermediate-risk disease by a previous prognostic system (ie, the disease-risk index [DRI]). The DRSS reclassified these intermediate-risk DRI patients, with 855 (6%) low risk, 7111 (51%) intermediate-1 risk, 5700 (41%) intermediate-2 risk, and 375 (3%) high risk or very high risk of 14 041 patients in a subanalysis combining the tuning and internal geographic validation cohorts. The DRI projected 2-year overall survival was 62·1% (95% CI 61·2-62·9) for these 14 041 patients, while the DRSS reclassified them into finer prognostic groups with overall survival ranging from 45·7% (37·4-54·0; very high risk patients) to 73·1% (70·1-76·2; low risk patients).

Interpretation: The DRSS is a novel risk stratification tool including disease features related to histology, genetic profile, and treatment response. The model should serve as a benchmark for future studies. This system facilitates the interpretation and analysis of studies with heterogeneous cohorts, promoting trial-design with more inclusive populations.

Funding: The Varda and Boaz Dotan Research Center for Hemato-Oncology Research, Tel Aviv University.
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http://dx.doi.org/10.1016/S2352-3026(20)30394-XDOI Listing
March 2021

Using a cochlear implant processor as contralateral routing of signals device in unilateral cochlear implant recipients.

Eur Arch Otorhinolaryngol 2021 Feb 22. Epub 2021 Feb 22.

Department of ENT, Head and Neck Surgery, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland.

Purpose: In unilateral cochlear implant (CI) recipients, a contralateral routing of signals (CROS) device enables to receive auditory information from the unaided side. This study investigates the feasibility as well as subjective and objective benefits of using a CI processor as a CROS device in unilateral CI recipients.

Methods: This is a single-center, prospective cohort study. First, we tested the directionality of the CROS processor in an acoustic chamber. Second, we examined the difference of speech perception in quiet and in noise in ten unilateral CI recipients with and without the CROS processor. Third, subjective ratings with the CROS processor were evaluated according to the Client Oriented Scale of Improvement Questionnaire.

Results: There was a time delay between the two devices of 3 ms. Connection of the CROS processor led to a summation effect of 3 dB as well as a more constant amplification along all azimuths. Speech perception in quiet showed an increased word recognition score at 50 dB (mean improvement 7%). In noise, the head shadow effect could be mitigated with significant gain in speech perception (mean improvement 8.4 dB). This advantage was reversed in unfavorable listening situations, where the CROS device considerably amplified the noise (mean:  - 4.8 dB). Subjectively, patients who did not normally wear a hearing aid on the non-CI side were satisfied with the CROS device.

Conclusions: The connection and synchronization of a CI processor as a CROS device is technically feasible and the signal processing strategies of the device can be exploited. In contra-laterally unaided patients, a subjective benefit can be achieved when wearing the CROS processor.
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http://dx.doi.org/10.1007/s00405-021-06684-xDOI Listing
February 2021

Post-reclamation microbial diversity and functions in hexachlorocyclohexane (HCH) contaminated soil in relation to spontaneous HCH tolerant vegetation.

Sci Total Environ 2021 May 19;767:144653. Epub 2021 Jan 19.

Helmholtz Zentrum München GmbH, Research Unit for Comparative Microbiome Analysis, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany. Electronic address:

The toxicity, volatility and persistence of the obsolete organochlorine pesticide hexachlorocyclohexane (HCH), makes reclamation of contaminated areas a priority for the health and welfare of neighboring human communities. Microbial diversity and functions and their relation to spontaneous vegetation in post-excavation situations, are essential indicators to consider in bioaugmentation or microbe-assisted phytoremediation strategies at field scale. Our study aimed to evaluate the effects of long-term HCH contamination on soil and plant-associated microbial communities, and whether contaminated soil has the potential to act as a bacterial inoculum in post-excavation bioremediation strategies. To scrutinize the role of vegetation, the potential nitrogen fixation of free-living and symbiotic diazotrophs of the legume Lotus tenuis was assessed as a measure of nutrient cycling functions in soil under HCH contamination. Potential nitrogen fixation was generally not affected by HCH, with the exception of lower nifH gene counts in excavated contaminated rhizospheres, most probably a short-term HCH effect on early bacterial succession in this compartment. HCH shaped microbial communities in long-term contaminated bulk soil, where we identified possible HCH tolerants such as Sphingomonas and Altererythrobacter. In L. tenuis rhizosphere, microbial community composition was additionally influenced by plant growth stage. Sphingobium and Massilia were the bacterial genera characteristic for HCH contaminated rhizospheres. Long-term HCH contamination negatively affected L. tenuis growth and development. However, root-associated bacterial community composition was driven solely by plant age, with negligible HCH effect. Results showed that L. tenuis acquired possible HCH tolerant bacteria such as the Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium clade, Sphingomonas, Massilia or Pantoea which could simultaneously offer plant growth promoting (PGP) benefits for the host. Finally, we identified an inoculum with possibly HCH tolerant, PGP bacteria transferred from the contaminated bulk soil to L. tenuis roots through the rhizosphere compartment, consisting of Mesorhizobium loti, Neorhizobium galegae, Novosphingobium lindaniclasticum, Pantoea agglomerans and Lysobacter bugurensis.
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http://dx.doi.org/10.1016/j.scitotenv.2020.144653DOI Listing
May 2021

Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT.

Leukemia 2021 Feb 4. Epub 2021 Feb 4.

EBMT Paris Study Office, Department of Hematology and Cell Therapy, Hôpital Saint-Antoine, Paris, France.

Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.
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http://dx.doi.org/10.1038/s41375-021-01135-2DOI Listing
February 2021

Damage-induced chromatome dynamics link Ubiquitin ligase and proteasome recruitment to histone loss and efficient DNA repair.

Mol Cell 2021 02 1;81(4):811-829.e6. Epub 2021 Feb 1.

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland; Faculty of Natural Sciences, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. Electronic address:

Eukaryotic cells package their genomes around histone octamers. In response to DNA damage, checkpoint activation in yeast induces core histone degradation resulting in 20%-40% reduction in nucleosome occupancy. To gain insight into this process, we developed a new approach to analyze the chromatin-associated proteome comprehensively before and after damage. This revealed extensive changes in protein composition after Zeocin-induced damage. First, core histones and the H1 homolog Hho1 were partially lost from chromatin along with replication, transcription, and chromatin remodeling machineries, while ubiquitin ligases and the proteasome were recruited. We found that the checkpoint- and INO80C-dependent recruitment of five ubiquitin-conjugating factors (Rad6, Bre1, Pep5, Ufd4, and Rsp5) contributes to core and linker histone depletion, reducing chromatin compaction and enhancing DNA locus mobility. Importantly, loss of Rad6/Bre1, Ufd4/TRIP12, and Pep5/VPS11 compromise DNA strand invasion kinetics during homology-driven repair. Thus we provide a comprehensive overview of a functionally relevant genome-wide chromatin response to DNA damage.
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http://dx.doi.org/10.1016/j.molcel.2020.12.021DOI Listing
February 2021

Sustained cellular immunity in adults recovered from mild COVID-19.

Cytometry A 2021 Jan 31. Epub 2021 Jan 31.

Hematology and Oncology, Medical Faculty, University of Augsburg, Augsburg, Germany.

Transient lymphocytopenia is frequently observed in acute phase of coronavirus disease 2019 (COVID-19). It remains a concern whether impairment of cellular immunity may be retained after COVID-19. Here, we demonstrate by extensive lymphocyte profiling in 44 adults after mild COVID-19 that cellular immunity is not fundamentally altered in convalescent patients. Except for increased activated CD8+ lymphocytes, total counts of B, T, and NK cells and their subsets did not differ significantly between patients after COVID-19 and healthy controls after a median of 27 days (range 13-45) suggesting no residual cellular immune deficiency after recovery from mild COVID-19.
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http://dx.doi.org/10.1002/cyto.a.24309DOI Listing
January 2021

Defining the Role of Donor Lymphocyte Infusion in High-Risk Hematologic Malignancies.

J Clin Oncol 2021 Feb 12;39(5):397-418. Epub 2021 Jan 12.

Department of Medicine 2, Goethe University, Frankfurt am Main, Germany.

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http://dx.doi.org/10.1200/JCO.20.01719DOI Listing
February 2021

Second- and third-generation tyrosine kinase inhibitors for Philadelphia-positive adult acute lymphoblastic leukemia relapsing post allogeneic stem cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party.

Bone Marrow Transplant 2020 Dec 9. Epub 2020 Dec 9.

Service d'Hématologie et de Thérapie cellulaire, Hôpital Saint Antoine, ALWP Office (EBMT), Paris, France.

Second- and third-generation tyrosine kinase inhibitors (TKI) play an important role in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, data on feasibility and efficacy of using these drugs for persisting or relapsed Ph + ALL after allogeneic stem cell transplantation (alloSCT) are scarce. Based on the EBMT Acute Leukemia Working Party registry, we evaluated the use of second-/third-generation TKI in 140 patients with Ph + ALL, suffering from measurable residual disease (MRD, n = 6), molecular relapse (MRel, n = 23), or hematological relapse (HRel, n = 111) following alloSCT. Treatment included dasatinib in 104, nilotinib in 18, or ponatinib in 18 patients. Forty-nine patients received TKI monotherapy, while 91 received additional treatment. Toxicity of second-/third-generation TKI post alloSCT was comparable to pretransplant use and could be managed with dose reduction or temporary discontinuation. Response rates were 71% (overall) and 61% (following TKI monotherapy). For the entire cohort, 2- and 5-year overall survival (OS) was 49% and 33%, respectively. OS was comparable among patients treated for persisting MRD/MRel and HRel. Among patients treated with TKI monotherapy, 2- and 5-year OS was 38% and 33%, respectively. The data underscore that second-/third-generation TKI are important compounds for the management of active Ph + ALL post alloSCT.
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http://dx.doi.org/10.1038/s41409-020-01173-xDOI Listing
December 2020

Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group.

Ann Hematol 2020 Nov 16. Epub 2020 Nov 16.

Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University, Moorenstr. 5, 40225, Düsseldorf, Germany.

Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1-19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRD, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.
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http://dx.doi.org/10.1007/s00277-020-04321-xDOI Listing
November 2020

A multicenter prospective, randomized, placebo-controlled phase II/III trial for preemptive acute graft-versus-host disease therapy.

Leukemia 2020 Oct 20. Epub 2020 Oct 20.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Acute graft-versus-host disease (aGvHD) contributes to about 50% of transplant-related mortality (non-relapse mortality) after allogeneic hematopoietic stem cell transplantation (HSCT). Here the predictive value of a urinary proteomic profile (aGvHD_MS17) was tested together with preemptive prednisolone therapy. Two-hundred and fifty-nine of 267 patients were eligible for analysis. Ninety-two patients were randomized upon aGvHD_MS17 classification factor above 0.1 to receive either prednisolone (2-2.5 mg/kg, N = 44) or placebo (N = 47; N = 1 randomization failure) for 5 days followed by tapering. The remaining 167 patients formed the observation group. The primary endpoint of the randomized trial was incidence of aGvHD grade II between randomization and day +100 post HSCT. Analysis of the short-term preemptive prednisolone therapy in the randomized patients showed no significant difference in incidence or severity of acute GvHD (HR: 1.69, 95% CI: 0.66-4.32, P = 0.27). Prednisolone as preemptive treatment did not lead to an increase in relapse (20.2% in the placebo and 14.0% in the prednisolone group (P = 0.46)). The frequency of adverse events was slightly higher in the placebo group (64.4% versus 50%, respectively). Taken together, the results of the Pre-GvHD trial demonstrated the feasibility and safety of preemptive prednisolone treatment in the randomized patients.
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http://dx.doi.org/10.1038/s41375-020-01059-3DOI Listing
October 2020

Intraoperative endoluminal pyloromyotomy as a novel approach to reduce delayed gastric emptying after pylorus-preserving pancreaticoduodenectomy-a retrospective study.

Langenbecks Arch Surg 2020 Oct 14. Epub 2020 Oct 14.

Department of General, Visceral and Transplant Surgery, University Hospital Augsburg, Stenglinstrasse 2, Augsburg, 86156, Germany.

Background: Delayed gastric emptying (DGE) is one of the most common complications after pylorus-preserving partial pancreaticoduodenectomy (ppPD). The aim of this retrospective study was to assess whether an intraoperative pyloromyotomy during ppPD prior to the creation of duodenojejunostomy reduces DGE.

Methods: Patients who underwent pylorus-preserving pancreaticoduodenectomy between January 2015 and December 2017 were divided into two groups on the basis of whether an intraoperative pyloromyotomy was performed (pyloromyotomy (PM) group) or not (no pyloromyotomy (NP) group). The primary endpoint was DGE according to the ISGPS definition. The confirmatory analysis of the primary endpoint was performed with multivariate analysis.

Results: One hundred and ten patients were included in the statistical analysis. Pyloromyotomy was performed in 44 of 110 (40%) cases. DGE of any grade was present in 62 patients (56.4%). The DGE rate was lower in the PM group (40.9%) compared with the NP group (66.7%), and pyloromyotomy was associated with a reduced risk for DGE in univariate (OR 0.35, 95% CI 0.16-0.76; P = 0.008) and multivariate analyses (OR 0.32, 95% CI 0.13-0.77; P = 0.011). The presence of an intra-abdominal complication was an independent risk factor for DGE in the multivariate analysis (OR 5.54, 95% CI 2.00-15.36; P = 0.001).

Conclusion: Intraoperative endoluminal pyloromyotomy during ppPD was associated with a reduced risk for DGE in this retrospective study. Pyloromyotomy should be considered a simple technique that can potentially reduce DGE rates after ppPD.
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http://dx.doi.org/10.1007/s00423-020-02008-5DOI Listing
October 2020

Evaluation of Trends and Prognosis Over Time in Patients with AML Relapsing After Allogeneic Hematopoietic Cell Transplant Reveals Improved Survival for Young Patients in Recent Years.

Clin Cancer Res 2020 Dec 28;26(24):6475-6482. Epub 2020 Sep 28.

Department of Clinical Hematology and Cellular Therapy, Saint-Antoine Hospital, INSERM UMR 938 and Sorbonne University, Paris, France.

Purpose: Relapsed acute myeloid leukemia (AML) post allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis.

Experimental Design: To assess prognosis of patients with recurrent AML post allo-HCT over time, we analyzed European Society for Blood and Marrow Transplantation registry data of 8,162 adult patients with AML who relapsed between 2000 and 2018 after allo-HCT performed in first complete remission from matched sibling, unrelated, or haploidentical donors.

Results: The 2-year overall survival (OS) rate from relapse was 17%. For 3,630 patients, <50 years of age, the 2-year OS continuously increased from 16% between 2000 and 2004 to 18% for 2005-2009, to 21% for 2010-2014, and to 26% for 2015-2018 ( = 0.001). Improvement over time was noted both after relapse within and beyond 6 months from allo-HCT. On multivariate analysis among patients <50 years of age, OS was positively affected by a later year of relapse (baseline: 2000-2004; HR, 0.82; < 0.02 for 2010-2014 and HR, 0.72; = 0.0002 for 2015-2018), good performance status, favorable cytogenetics, and longer time from transplant to relapse, but negatively affected by increasing age. In contrast, among 4,532 patients, >50 years of age, the year of relapse had no influence on OS (16% for 2000-2004 and 14% for 2015-2018; = 0.56). Regarding treatment, encouraging results were observed after second allo-HCT, which was performed within 2 years after relapse in 17% of the entire cohort, resulting in a 2-year OS of 30.7%.

Conclusions: Outcome after posttransplant relapse among younger patients has improved significantly in recent years, likely reflecting, among other factors, the efficacy of posttransplant salvage including second allo-HCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3134DOI Listing
December 2020

Measurable residual disease (MRD) testing for acute leukemia in EBMT transplant centers: a survey on behalf of the ALWP of the EBMT.

Bone Marrow Transplant 2021 Jan 28;56(1):218-224. Epub 2020 Jul 28.

EBMT Paris Study Office/CEREST-TC, Paris, France.

Detectable measurable residual disease (MRD) is a key prognostic factor in both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients. Thus, we conducted a survey in EBMT transplant centers focusing on pre- and post-allo-HCT MRD. One hundred and six centers from 29 countries responded. One hundred had a formal strategy for routine MRD assessment, 91 for both ALL and AML. For ALL (n = 95), assessing MRD has been routine practice starting from 2010 (range, 1990-2019). Techniques used for MRD assessment consisted of PCR techniques alone (n = 27), multiparameter flow cytometry (MFC, n = 16), both techniques (n = 43), next-generation sequencing (NGS) + PCR (n = 2), or PCR + MFC + NGS (n = 7). The majority of centers assessed MRD every 2-3 months for 2 (range, 1-until relapse) years. For AML, assessing MRD was routine in 92 centers starting in 2010 (range 1990-2019). Assessment of MRD was by PCR (n = 23), MFC (n = 13), both PCR and MFC (n = 39), both PCR and NGS (n = 3), and by all three techniques (n = 14). The majority assesses MRD for AML every 2-3 months for 2 (range, 1-until relapse) years. This survey is the first step in the aim to include MRD status as a routine registry capture parameter in acute leukemia.
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http://dx.doi.org/10.1038/s41409-020-01005-yDOI Listing
January 2021

52 years of ecological restoration following a major disturbance by opencast lignite mining does not reassemble microbiome structures of the original arable soils.

Sci Total Environ 2020 Nov 20;745:140955. Epub 2020 Jul 20.

Helmholtz Zentrum München GmbH, Research Unit for Comparative Microbiome Analysis, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Technical University of Munich, Chair of Soil Science, Emil-Ramann-Straße 2, 85354 Freising, Germany. Electronic address:

Opencast mining for lignite continuously creates areas of land that require restoration. Here we applied a chronosequence approach to investigate the development of soil bacterial communities during 52 years as influenced by the restoration process and subsequent changes in soil physico-chemical conditions starting from the initial reclamation of the sites. By comparison with the unaffected soils near the mine, we were able to address the question if soil bacterial communities have reached a steady state within 52 years, which is comparable to the original soil. Our study revealed three distinct phases of the restoration process, each with a specific bacterial community composition. The effect size of these changes was similar to the one observed for seasonal dynamics at our sites. At the beginning of the restoration process Flavobacteriaceae, Cytophagaceae and Sphingobacteriaceae were found as typical members of the bacterial community as well as Rhizobiales as a result of the cultivation of alfalfa on the restored plots. At later stage the families Peptostreptococcaceae, Desulfurellaceae as well as Streptomycetaceae increased in relative abundance and became dominant members of the bacterial community. Even though overall bacterial abundance and richness exhibited values comparable to the original soil already 5 years after the start of the restoration process, main responder analyses reveal differences in the bacterial community structure even 52 years after the start of the restoration process. Mostly Nitrospirae were reduced in abundance in the soils restored for 52 years compared to the original soils. To broaden the significance of our study, we compared our data bioinformatically with published results from other restored areas, which were previously affected by opencast mining. Despite different durations of the different restoration phase, we could observe a large degree of conformity when bacterial patterns of succession were compared indicating common modes of action of ecological restoration tools for bacterial communities.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140955DOI Listing
November 2020

Pinna-Imitating Microphone Directionality Improves Sound Localization and Discrimination in Bilateral Cochlear Implant Users.

Ear Hear 2020 07 16;42(1):214-222. Epub 2020 Jul 16.

Department of ENT, Head and Neck Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

Objectives: To compare the sound-source localization, discrimination, and tracking performance of bilateral cochlear implant users with omnidirectional (OMNI) and pinna-imitating (PI) microphone directionality modes.

Design: Twelve experienced bilateral cochlear implant users participated in the study. Their audio processors were fitted with two different programs featuring either the OMNI or PI mode. Each subject performed static and dynamic sound field spatial hearing tests in the horizontal plane. The static tests consisted of an absolute sound localization test and a minimum audible angle test, which was measured at eight azimuth directions. Dynamic sound tracking ability was evaluated by the subject correctly indicating the direction of a moving stimulus along two circular paths around the subject.

Results: PI mode led to statistically significant sound localization and discrimination improvements. For static sound localization, the greatest benefit was a reduction in the number of front-back confusions. The front-back confusion rate was reduced from 47% with OMNI mode to 35% with PI mode (p = 0.03). The ability to discriminate sound sources straight to the sides (90° and 270° angle) was only possible with PI mode. The averaged minimum audible angle value for the 90° and 270° angle positions decreased from a 75.5° to a 37.7° angle when PI mode was used (p < 0.001). Furthermore, a non-significant trend towards an improvement in the ability to track moving sound sources was observed for both trajectories tested (p = 0.34 and p = 0.27).

Conclusions: Our results demonstrate that PI mode can lead to improved spatial hearing performance in bilateral cochlear implant users, mainly as a consequence of improved front-back discrimination with PI mode.
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http://dx.doi.org/10.1097/AUD.0000000000000912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757747PMC
July 2020

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With -Internal Tandem Duplication Mutation (SORMAIN).

J Clin Oncol 2020 09 16;38(26):2993-3002. Epub 2020 Jul 16.

Department of Internal Medicine, Hematology, Oncology and Immunology, Philipps University Marburg and University Hospital Gießen and Marburg, Campus Marburg, Marburg, Germany.

Purpose: Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the like tyrosine kinase 3 gene (ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT.

Patients And Methods: In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first.

Results: With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib.

Conclusion: Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for ITD-positive AML.
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http://dx.doi.org/10.1200/JCO.19.03345DOI Listing
September 2020

Impact of total body irradiation- vs chemotherapy-based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia.

Am J Hematol 2020 Jul 13. Epub 2020 Jul 13.

Saint Antoine Hospital, INSERM UMR 938, Université Pierre et Marie Curie, Paris, France and EBMT Paris study office / CEREST-TC, Paris, France.

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI) vs chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo-HCT with post-transplant cyclophosphamide, following TBI (N = 89, 9%) or CT (n = 919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs 47 years, P < .01) and more likely to receive BM graft (57% vs 43%, P = .01). Two-year overall chronic GVHD (cGVHD) incidence was 42% vs 27% (P < .01) and extensive cGVHD incidence was 9% vs 12% (P = .33) in TBI and CT cohorts, respectively. Graft failure was reported in two (2%) TBI- and 65 (7%) CT-MAC recipients (P = .08). Death from veno-occlusive disease was reported in one (3%) TBI and 11 (3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio = 1.95, 95% confidence interval:1.2-3.1, P < .01) compared to CT-based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia-free survival, non-relapse mortality, overall survival or GVHD-relapse-free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI-based MAC and CT-based MAC in patients with AML after haplo-HCT/PTCy.
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http://dx.doi.org/10.1002/ajh.25934DOI Listing
July 2020

The FLAMSA concept-past and future.

Ann Hematol 2020 Sep 27;99(9):1979-1988. Epub 2020 Jun 27.

Medizinische Klinik Universitätsklinikum Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany.

The FLAMSA reduced intensity (RIC) concept, also known as "sequential therapy", is a conceptual platform for the treatment of leukemia separated in several parts: induction therapy, a sequence of antileukemic and immunosuppressive conditioning for allogeneic stem cell transplantation, and immune restitution supported by donor lymphocyte transfusions. The antileukemic part consists of fludarabine, cytosine arabinoside, and amsacrine (FLAMSA); non-cross reactive agents like fludarabine and amsacrine have been successfully used in cases of refractoriness and relapse. Immunosuppressive conditioning and transplantation follow after only 3 days of rest. This way, the toxicity of allogeneic transplantation could be reduced and the anti-leukemia effects by using allogeneic immune cells could be optimized. This review summarizes available data on efficacy and toxicity of this approach. Further, possible strategies for improvements are discussed in order to provide better chances for elderly and frail patients and patients with advanced and high-risk disease. Among others, several new agents are available that target molecular changes of leukemia for induction of remission and allow for bridging the time after transplantation until adoptive immunotherapy becomes safe and effective.
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http://dx.doi.org/10.1007/s00277-020-04131-1DOI Listing
September 2020

Clonal diversity and genetic variation of the sedge in an alpine fen depend on soil nutrients.

PeerJ 2020 3;8:e8887. Epub 2020 Jun 3.

Institute for Evolution and Biodiversity, Faculty of Biology, University of Münster, Münster, Germany.

In this study we analysed the impact of water regime and soil nutrients on the clonal diversity and genetic variation of the sedge in a central alpine fen. For our analysis, we established 16 study plots randomly distributed over the fen. We determined the exact elevation of each plot as an indicator for the water regime and measured the content of phosphorous and potassium in the soil of each plot. Clonal diversity and genetic variation of were assessed with nuclear microsatellites using leaf material collected in 20 subplots along a diagonal cross within each study plot. The influence of water regime and soil mineral nutrients on clonal diversity and genetic variation was estimated by Bayesian multiple regression. Our study revealed a clear impact of soil nutrient conditions on clonal diversity and genetic variation of , which increased with the concentration of phosphorous and decreased with the concentration of potassium. Key background to these findings seems to be the relative offspring success from generative as compared to clonal propagation. Phosphorous acquisition is essential during seedling establishment. Clonal diversity and genetic variation increase, therefore, at sites with higher phosphorous contents due to more successful recruitment. High levels of clonal diversity and genetic variation at sites of low potassium availability may in contrast be mainly caused by increased plant susceptibility to abiotic stress under conditions of potassium deficiency, which brings about more gaps in stands and favors the ingrowth from other clones or recruitment from seeds.
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http://dx.doi.org/10.7717/peerj.8887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275680PMC
June 2020

Assessing the surgical outcome of the "chopsticks" technique in endoscopic transsphenoidal adenoma surgery.

Neurosurg Focus 2020 06;48(6):E15

1Department of Neurosurgery, Clinical Neuroscience Center.

Objective: The "chopsticks" technique is a 3-instrument, 2-hand mononostril technique that has been recently introduced in endoscopic neurosurgery. It allows a dynamic surgical view controlled by one surgeon only while keeping bimanual dissection. Being a mononostril approach, it requires manipulation of the mucosa of one nasal cavity only. The rationale of the technique is to reduce nasal morbidity without compromising surgical results and complication rates. There are, however, no data available on its results in endoscopic surgery (transsphenoidal surgery [TSS]) for pituitary adenoma.

Methods: The authors performed a cohort analysis of prospectively collected data on 144 patients (156 operations) undergoing TSS using the chopsticks technique with 3T intraoperative MRI. All patients had at least 3 months of postoperative neurosurgical, endocrinological, and rhinological follow-up (Sino-Nasal Outcome Test-20 [SNOT-20] and Sniffin' Sticks). The surgical technique is described, and the achieved gross-total resection (GTR) and extent of resection (EOR) together with patients' clinical outcomes and complications are descriptively reported.

Results: On 3-month postoperative MRI, GTR was achieved in 71.2% of patients with a mean EOR of 96.7%. GTR was the surgical goal in 122 of 156 cases and was achieved in 106 of 122 (86.9%), with a mean EOR of 98.7% (median 100%, range 49%-100%). There was no surgical mortality. At a median follow-up of 15 months (range 3-70 months), there was 1 permanent neurological deficit. As of the last available follow-up, 11.5% of patients had a new pituitary single-axis deficit, whereas 26.3% had improvement in endocrinological function. Three patients had new postoperative hyposmia. One patient had severe impairment of sinonasal function (SNOT-20 score > 40). The operation resulted in endocrine remission in 81.1% of patients with secreting adenomas.

Conclusions: This study shows that the chopsticks technique confers resection and morbidity results that compare favorably with literature reports of TSS. This technique permits a single surgeon to perform effective endoscopic bimanual dissection through a single nostril, reducing manipulation of healthy tissue and thereby possibly minimizing surgical morbidity.
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http://dx.doi.org/10.3171/2020.3.FOCUS2065DOI Listing
June 2020

Large Vessel Vasculitis as a Possible Mechanism of Vascular Side Effects of Ponatinib: A Case Report.

J Hematol 2019 Jun 30;8(2):83-85. Epub 2019 Jun 30.

Department of Hematology and Oncology, Universitaetsklinikum Augsburg, Stenglinstrasse 2, 86156 Augsburg, Germany.

Arterial occlusive events (AOEs) such as cerebrovascular, cardiovascular and peripheral arterial events are known side effects of ponatinib, assumed due to the rapid development and increase of arteriosclerosis, while the definitive pathomechanisms therefore are still unclear. We present a case of clinically apparent large vessel vasculitis and discuss this phenomenon as a possible mechanism of AOEs beside arteriosclerosis.
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http://dx.doi.org/10.14740/jh519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153681PMC
June 2019

LSM2-8 and XRN-2 contribute to the silencing of H3K27me3-marked genes through targeted RNA decay.

Nat Cell Biol 2020 05 6;22(5):579-590. Epub 2020 Apr 6.

Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.

In fission yeast and plants, RNA processing and degradation contribute to heterochromatin silencing, alongside conserved pathways of transcriptional repression. It has not been known whether similar pathways exist in metazoans. Here, we describe a pathway of silencing in Caenorhabditis elegans somatic cells, in which the highly conserved RNA-binding complex LSM2-8 contributes selectively to the repression of heterochromatic reporters and endogenous genes bearing the Polycomb mark, histone H3K27me3. This acts by degrading selected transcripts through the XRN-2 exoribonuclease. Disruption of the LSM2-8 pathway leads to mRNA stabilization. Unlike previously described pathways of heterochromatic RNA degradation, LSM2-8-mediated RNA degradation does not target nor require H3K9 methylation. Intriguingly, loss of this pathway coincides with a localized reduction in H3K27me3 at lsm-8-sensitive loci. We have thus uncovered a mechanism of RNA degradation that selectively contributes to the silencing of a subset of H3K27me3-marked genes, revealing a previously unrecognized layer of post-transcriptional control in metazoan heterochromatin.
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http://dx.doi.org/10.1038/s41556-020-0504-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212045PMC
May 2020

Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with -internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Haematologica 2020 Jun 2;105(6):1507-1516. Epub 2020 Apr 2.

Sorbonne Universités, UPMC University of Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Hematology Department, AP-HP, Saint Antoine Hospital, Paris, France.

The () gene is mutated in 25-30% of patients with acute myeloid leukemia (AML). Because of the poor prognosis associated with -internal tandem duplication mutated AML, allogeneic hematopoietic stem-cell transplantation (SCT) was commonly performed in first complete remission. Remarkable progress has been made in frontline treatments with the incorporation of FLT3 inhibitors and the development of highly sensitive minimal/measurable residual disease assays. Similarly, recent progress in allogeneic hematopoietic SCT includes improvement of transplant techniques, the use of haploidentical donors in patients lacking an HLA matched donor, and the introduction of FLT3 inhibitors as post-transplant maintenance therapy. Nevertheless, current transplant strategies vary between centers and differ in terms of transplant indications based on the internal tandem duplication allelic ratio and concomitant nucleophos-min-1 mutation, as well as in terms of post-transplant maintenance/consolidation. This review generated by international leukemia or transplant experts, mostly from the European Society for Blood and Marrow Transplantation, attempts to develop a position statement on best approaches for allogeneic hematopoietic SCT for AML with -internal tandem duplication including indications for and modalities of such transplants and on the potential optimization of post-transplant maintenance with FLT inhibitors.
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http://dx.doi.org/10.3324/haematol.2019.243410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271578PMC
June 2020

Alternative donors provide comparable results to matched unrelated donors in patients with acute lymphoblastic leukemia undergoing allogeneic stem cell transplantation in second complete remission: a report from the EBMT Acute Leukemia Working Party.

Bone Marrow Transplant 2020 09 17;55(9):1763-1772. Epub 2020 Mar 17.

Acute Leukemia Working Party office, Hôpital Saint Antoine, APHP, Paris, France.

Relapse of acute lymphoblastic leukemia (ALL) remains a major therapeutic challenge. Despite the consensus for proceeding to allogeneic stem cell transplantation (HSCT) in relapsing patients with ALL who achieve second complete remission (CR2) with salvage therapy, most patients lack a suitable matched-related histocompatible donor. The present multicenter retrospective study compared, for ALL patients in CR2, the HSCT outcome from all four possible alternative hematopoietic stem cell sources, namely matched unrelated 10/10 (n = 281), mismatched unrelated 9/10 (n = 125), haploidentical (n = 105), and cord blood (n = 104) donors. The 2-year outcomes were not statistically different between the four donor sources with respect to overall survival (38.3-47.2%), leukemia-free survival (30.5-39.6%), relapse incidence (32.6-37.6%), nonrelapse mortality (27.5-34.6%), and graft-versus-host disease-free relapse survival (21.4-33.1%). Donor choices for ALL patients achieving CR2 post first relapse are broad, ensuring that most patient in need secures a graft. Therefore, in practice, the donor choice should depend on timely availability and policy center.
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http://dx.doi.org/10.1038/s41409-020-0849-xDOI Listing
September 2020

Loss of an H3K9me anchor rescues laminopathy-linked changes in nuclear organization and muscle function in an Emery-Dreifuss muscular dystrophy model.

Genes Dev 2020 04 5;34(7-8):560-579. Epub 2020 Mar 5.

Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.

Mutations in the nuclear structural protein lamin A produce rare, tissue-specific diseases called laminopathies. The introduction of a human Emery-Dreifuss muscular dystrophy (EDMD)-inducing mutation into the lamin (LMN-Y59C), recapitulates many muscular dystrophy phenotypes, and correlates with hyper-sequestration of a heterochromatic array at the nuclear periphery in muscle cells. Using muscle-specific emerin Dam-ID in worms, we monitored the effects of the mutation on endogenous chromatin. An increased contact with the nuclear periphery along chromosome arms, and an enhanced release of chromosomal centers, coincided with the disease phenotypes of reduced locomotion and compromised sarcomere integrity. The coupling of the LMN-Y59C mutation with the ablation of CEC-4, a chromodomain protein that anchors H3K9-methylated chromatin at the nuclear envelope (NE), suppressed the muscle-associated disease phenotypes. Deletion of also rescued LMN-Y59C-linked alterations in chromatin organization and some changes in transcription. Sequences that changed position in the LMN-Y59C mutant, are enriched for E2F (EFL-2)-binding sites, consistent with previous studies suggesting that altered Rb-E2F interaction with lamin A may contribute to muscle dysfunction. In summary, we were able to counteract the dominant muscle-specific defects provoked by LMNA mutation by the ablation of a lamin-associated H3K9me anchor, suggesting a novel therapeutic pathway for EDMD.
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http://dx.doi.org/10.1101/gad.332213.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111258PMC
April 2020

Inferior outcome of allogeneic stem cell transplantation for secondary acute myeloid leukemia in first complete remission as compared to de novo acute myeloid leukemia.

Blood Cancer J 2020 03 3;10(3):26. Epub 2020 Mar 3.

Department of Haematology, Saint Antoine Hospital, Université Pierre et Marie Curie, INSERM UMR 938, Paris, France.

Following chemotherapy, secondary acute myeloid leukemia (sAML), occurring after antecedent hematologic diseases, previous chemotherapy or radiation, has an inferior prognosis compared with de novo AML. To define the outcome of sAML in the context of allogeneic stem cell transplantation (alloSCT), a retrospective, registry-based comparison was performed, including 11,439 patients with de novo and 1325 with sAML. Among transplants in first complete remission (CR1) (n = 8,600), the 3-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) was 28.5% and 16.4% for de novo, and 35% and 23.4% for sAML. Three-year overall survival (OS), leukemia-free survival (LFS) and Graft-versus-Host Disease/relapse-free survival (GRFS) was 60.8%, 55.1%, and 38.6% for de novo, and 46.7%, 41.6%, and 28.4% for sAML, respectively. In multivariate analysis, sAML was associated with a lower OS (HR = 1.33 [95% CI = 1.21-1.48]; p < 10), LFS (HR = 1.32 [95% CI = 1.19-1.45]; p < 10) and GRFS (HR = 1.2 [95% CI = 1.1-1.31]; p < 10) and higher NRM (HR = 1.37 [95% CI = 1.17-1.59]; p < 10) and RI (HR = 1.27 [95% CI = 1.12-1.44]; p < 10). Results of the Cox model were confirmed in a matched-pair analysis. In contrast, results did not differ between de novo and sAML after alloSCT in induction failure or relapse. Hence, this analysis identified sAML as an independent risk factor for outcome after alloSCT in CR1.
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http://dx.doi.org/10.1038/s41408-020-0296-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054545PMC
March 2020

Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients.

Bone Marrow Transplant 2020 06 29;55(6):1114-1125. Epub 2020 Jan 29.

Service d' Hématologie Clinique et Thérapie Cellulaire, Hospital Saint-Antoine, Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Paris, France.

To address limitations of the currently used reduced-intensity/myeloablative conditioning (RIC/MAC) classification scheme we aimed to develop a tool that can capture more standardized the conditioning intensity of allogeneic hematopoietic cell transplantation (HCT). We assigned intensity weight scores for frequently used conditioning regimen components and used their sum to generate the transplant conditioning intensity (TCI) score. We retrospectively tested the impact of TCI on 8255 adult (45-65 years) acute myeloid leukemia patients who underwent HCT in first complete remission. A Cox model for early nonrelapse mortality (NRM) yielded a 3-group TCI risk scheme (low, intermediate, high) with respective TCI scores of [1-2], [2.5-3.5] and [4-6]. On multivariate modeling, TCI grouping was highly and better predictive for early (day 100 and 180) NRM, 2-year NRM and relapse (REL) as compared with the RIC/MAC classification. Validation was done on 200 bootstrap samples. Moreover, TCI scoring enabled the identification of a distinct subgroup of RIC and MAC conditioning regimens with an intermediate TCI [2.5-3.5] score that had identical outcomes and which are frequently referred as "reduced toxicity conditioning". TCI scheme provides an improvement of the RIC/MAC classification. We propose TCI as a new tool to define and measure the conditioning regimen intensity.
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http://dx.doi.org/10.1038/s41409-020-0803-yDOI Listing
June 2020