Publications by authors named "Uwe Platzbecker"

262 Publications

Nutritional Status at Diagnosis and Pre-transplant Weight Loss Impact Outcomes of Acute Myeloid Leukemia Patients Following Allogeneic Stem Cell Transplantation.

Hemasphere 2021 Mar 10;5(3):e532. Epub 2021 Feb 10.

Medical Clinic and Policlinic 1, Hematology, Cellular Therapy and Hemostaseology, Leipzig University Hospital, Leipzig, Germany.

The nutritional status at diagnosis, as well as weight loss during chemotherapy, are important factors for morbidity and mortality in cancer patients. They might also influence outcomes in patients with acute myeloid leukemia (AML) receiving allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the body mass index (BMI) at diagnosis, prior to HSCT, and the BMI difference (ΔBMI = BMI-BMI) in 662 AML patients undergoing allogeneic HSCT. Patients being obese at AML diagnosis had significantly higher nonrelapse mortality (NRM) and shorter overall survival (OS) after HSCT, but no distinct cumulative incidence of relapse than nonobese patients. Weight loss during chemotherapy (ΔBMI > -2) was a strong predictor for higher NRM and shorter OS in univariate and multivariate analyses. These results were observed across all European LeukemiaNet (ELN) 2017 risk groups but especially in patients with favorable or intermediate ELN2017 risk and patients transplanted in morphologic complete remission. Only in patients being obese at AML diagnosis, weight loss did not result in adverse outcomes. ΔBMI > -2 represents a strong, independent, and modifiable risk factor for AML patients treated with HSCT. Nutritional monitoring and supplementation during disease course might improve patients' outcomes.
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http://dx.doi.org/10.1097/HS9.0000000000000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886498PMC
March 2021

The Genomic Landscape of Myeloid Malignancies: Options for Pan-myeloid Therapies?

Hemasphere 2021 Mar 10;5(3):e537. Epub 2021 Feb 10.

Universitätsklinikum Leipzig, Medizinische Klinik und Poliklinik für Hämatologie und Zelltherapie, Hämostaseologie, Leipzig, Germany.

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http://dx.doi.org/10.1097/HS9.0000000000000537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886402PMC
March 2021

Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial.

Leukemia 2021 Feb 18. Epub 2021 Feb 18.

Medizinische Klinik und Poliklinik I, Universitätsklinikum der Technischen Universität Dresden, Dresden, Germany.

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.
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http://dx.doi.org/10.1038/s41375-021-01148-xDOI Listing
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

Author Correction: Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Nat Med 2021 Feb 9. Epub 2021 Feb 9.

Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1038/s41591-021-01253-5DOI Listing
February 2021

Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes.

J Clin Oncol 2021 Feb 4:JCO2001659. Epub 2021 Feb 4.

Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy.

Purpose: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication.

Methods: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed.

Results: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (, , and ) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within - and -related MDS. MDS with complex karyotype and/or gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features.

Conclusion: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.
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http://dx.doi.org/10.1200/JCO.20.01659DOI Listing
February 2021

Characteristics and outcome of patients with acute myeloid leukaemia and t(8;16)(p11;p13): results from an International Collaborative Study.

Br J Haematol 2021 Mar 2;192(5):832-842. Epub 2021 Feb 2.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

In acute myeloid leukaemia (AML) t(8;16)(p11;p13)/MYST3-CREBBP is a very rare abnormality. Previous small series suggested poor outcome. We report on 59 patients with t(8;16) within an international, collaborative study. Median age was 52 (range: 16-75) years. AML was de novo in 58%, therapy-related (t-AML) in 37% and secondary after myelodysplastic syndrome (s-AML) in 5%. Cytogenetics revealed a complex karyotype in 43%. Besides MYST3-CREBBP, whole-genome sequencing on a subset of 10 patients revealed recurrent mutations in ASXL1, BRD3, FLT3, MLH1, POLG, TP53, SAMD4B (n = 3, each), EYS, KRTAP9-1 SPTBN5 (n = 4, each), RUNX1 and TET2 (n = 2, each). Complete remission after intensive chemotherapy was achieved in 84%. Median follow-up was 5·48 years; five-year survival rate was 17%. Patients with s-/t-AML (P = 0·01) and those with complex karyotype (P = 0·04) had an inferior prognosis. Allogeneic haematopoietic cell transplantation (allo-HCT) was performed in 21 (36%) patients, including 15 in first complete remission (CR1). Allo-HCT in CR1 significantly improved survival (P = 0·04); multivariable analysis revealed that allo-HCT in CR1 was effective in de novo AML but not in patients with s-AML/t-AML and less in patients exhibiting a complex karyotype. In summary, outcomes of patients with t(8;16) are dismal with chemotherapy, and may be substantially improved with allo-HCT performed in CR1.
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http://dx.doi.org/10.1111/bjh.17336DOI Listing
March 2021

Prognostic impact of rapid reduction of involved free light chains in multiple myeloma patients under first-line treatment with Bendamustine, Prednisone, and Bortezomib (BPV).

J Cancer Res Clin Oncol 2021 Jan 12. Epub 2021 Jan 12.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Härtelstraße 16-18, 04107, Leipzig, Germany.

Introduction: Light chain involvement is observed in almost every patient (pt) with newly diagnosed multiple myeloma (MM). Owing to a relatively short half-life, rapid reduction in the involved free light chain (iFLC) is of potential prognostic value.

Methods: This retrospective analysis included 92 pts with newly diagnosed MM treated with bendamustine, prednisone, and bortezomib (BPV).

Results: After a median number of two (range 1-5) BPV cycles, the majority of pts (n = 86; 93%) responded with either sCR (n = 21), CR (n = 1), nCR (n = 25), VGPR (n = 20), or PR (n = 19). PFS and OS at 48 months were 39% and 67%, respectively. At baseline, 79 out of 92 pts (86%) had iFLC levels above the upper standard level and an abnormal ratio of involved to uninvolved free light chain ≥ 8. In a subgroup analysis of these pts, we evaluated the prognostic importance of an early reduction of the iFLC during the first two BPV cycles. A reduction ≥ 50% of the iFLC on day 8 of the first cycle was observed in 31 of 69 pts. These pts had a significantly better median PFS of 49 months as compared to 20 months in 38 pts with a lower iFLC reduction (p = 0.002). In contrast, OS did not differ significantly with a 48 months survival of 77% vs 69% (p > 0.05).

Conclusion: These results indicate that a rapid decrease in the iFLC on day 8 is an early prognostic marker for newly diagnosed MM pts undergoing BPV treatment.
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http://dx.doi.org/10.1007/s00432-020-03504-3DOI Listing
January 2021

MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic.

Future Oncol 2021 Jan 11. Epub 2021 Jan 11.

Mays Cancer Center, UT Health San Antonio Cancer Center, San Antonio, TX 78229, USA.

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.
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http://dx.doi.org/10.2217/fon-2020-1048DOI Listing
January 2021

Decitabine treatment in 311 patients with acute myeloid leukemia: outcome and impact of mutations - a registry based analysis.

Leuk Lymphoma 2021 Jan 5:1-15. Epub 2021 Jan 5.

Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany.

We performed a registry-based analysis of 311 AML patients treated with decitabine in a standard of care setting to assess response and survival data with a distinct focus on the impact of the mutation status. Median age was 73 years. 172 patients received decitabine first-line and 139 in r/r disease. The ORR (whole cohort) was 30% with a median overall survival of 4.7 months. First-line patients achieved better responses than r/r-patients (ORR: 38% vs. 21%) resulting in a median OS of 5.8 months vs. 3.9 months. NGS based mutation analysis was performed in 180 patients. 20 patients (11%) harbored a mutation. Response rates and survival did not differ significantly between mutated patients and wild-type patients. This analysis of a large cohort of AML patients provides response rates and OS data after decitabine treatment. Interestingly, outcome was not negatively influenced by a mutation.
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http://dx.doi.org/10.1080/10428194.2020.1864354DOI Listing
January 2021

Natural born survivors: the inglorious TP53.

Blood 2020 Dec;136(24):2727-2728

Leipzig University Hospital.

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http://dx.doi.org/10.1182/blood.2020008212DOI Listing
December 2020

Patient stratification in myelodysplastic syndromes: how a puzzle may become a map.

Hematology Am Soc Hematol Educ Program 2020 12;2020(1):418-425

Department of Hematology, Cellular Therapy and Hemostaseology, Leipzig University Hospital, Leipzig, Germany; German MDS Study Group (D-MDS), Leipzig, Germany; and European Myelodysplastic Syndromes Cooperative Group (EMSCO), Leipzig, Germany.

Heterogeneity is the disease-defining epithet of myelodysplastic syndromes (MDS), a clonal disorder of hematopoietic stem and progenitor cells. During the last decade, significant progress has been made to better understand the diversity of clinical, molecular, cellular, and immunological factors that are bound to the prognosis and outcomes of patients with MDS. Despite the rapid generation of all of this biological information, how to implement it has fallen short. Redefining clinical tools to use this new information remains a challenge. The holistic integration of novel, high-impact individual risk parameters such as patient-reported outcomes or mutational and immunological data into conventional risk stratification systems may further refine patient subgroups, improve predictive power for survival, and provide a next-generation classification and prognosis system for patients with MDS. Dichotomic treatment strategies in patients with MDS according to their patient and disease profiles highlight the importance of precise risk stratification, which may be complemented by the definition of granular cohorts of patients with myeloid neoplasms and a druggable target (ie, IDH1/2 mutations) across conventional blast thresholds.
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http://dx.doi.org/10.1182/hematology.2020000126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727505PMC
December 2020

ELN risk stratification and outcomes in secondary and therapy-related AML patients consolidated with allogeneic stem cell transplantation.

Bone Marrow Transplant 2020 Nov 19. Epub 2020 Nov 19.

Medical Clinic and Policlinic 1, Hematology, Cellular Therapy and Hemostaseology, Leipzig University Hospital, Leipzig, Germany.

Secondary or therapy-related acute myeloid leukemia (s/tAML) differs biologically from de novo disease. In general s/tAML patients have inferior outcomes after chemotherapy, compared to de novo cases and often receive allogeneic stem cell transplantation (HSCT) for consolidation. The European LeukemiaNet (ELN) risk stratification system is commonly applied in AML but the clinical significance is unknown in s/tAML. We analyzed 644 s/tAML or de novo AML patients receiving HSCT. s/tAML associated with older age and adverse risk, including higher ELN risk. Overall, s/tAML patients had similar cumulative incidence of relapse (CIR), but higher non-relapse mortality (NRM) and shorter overall survival (OS). In multivariate analyses, after adjustment for ELN risk and pre-HSCT measurable residual disease status, disease origin did not impact outcomes. Within the ELN favorable risk group, CIR was higher in s/tAML compared to de novo AML patients likely due to a different distribution of genetic aberrations, which did not translate into shorter OS. Within the ELN intermediate and adverse group outcomes were similar in de novo and s/tAML patients. Thus, not all s/tAML have a dismal prognosis and outcomes of s/tAML after allogeneic HSCT in remission are comparable to de novo patients when considering ELN risk.
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http://dx.doi.org/10.1038/s41409-020-01129-1DOI Listing
November 2020

Allogeneic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes and Prevention of Relapse.

Clin Lymphoma Myeloma Leuk 2021 Jan 16;21(1):1-7. Epub 2020 Oct 16.

Medical Department I, Hematology and Cell Therapy, Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany.

Myelodysplastic syndromes (MDS) mainly affect the elderly population, which implies that the majority of patients cannot tolerate intensive therapeutic approaches, including allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The underlying impaired stem-cell function leads to peripheral cytopenia, including a propensity to progress to acute myeloid leukemia. Allo-HSCT is considered the only potentially curable therapy. Reduced-intensity conditioning regimens have shown to improve early tolerability of the procedure, but late effects like graft-versus-host disease and relapse remain major challenges in the care of these patients. Therefore, special attention should be paid to posttransplantation care in terms of graft-versus-host disease management, measurable residual disease monitoring, and prevention of relapse. In fact, recent advances in the field have shown that minimal residual disease measurement and preemptive therapies may be a promising approach to prevent or at least delay relapse. This review briefly discusses indication and selection of patients for allo-HSCT in MDS, pretransplantation evaluation and choice of conditioning regimens, and prophylactic and preemptive approaches to prevent relapse after allo-HSCT.
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http://dx.doi.org/10.1016/j.clml.2020.10.008DOI Listing
January 2021

Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study.

J Clin Oncol 2021 Jan 27;39(1):48-56. Epub 2020 Oct 27.

Department of Hematology and Cell Therapy, University Clinic Leipzig, Leipzig, Germany.

Purpose: Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs.

Patients And Methods: In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid.

Results: Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks.

Conclusion: Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.
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http://dx.doi.org/10.1200/JCO.20.01895DOI Listing
January 2021

Case Report: Allogeneic Stem Cell Transplantation Following Induction With CPX-351 in Patients With Acute Myeloid Leukemia Is Feasible.

Front Oncol 2020 16;10:1746. Epub 2020 Sep 16.

University of Leipzig Medical Center, Clinic and Policlinic for Hematology and Celltherapy, Leipzig, Germany.

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) and treatment-related acute myeloid leukemia (tAML) after chemotherapy or radiation therapy for other neoplasms are associated with poor outcomes. CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, has been shown to improve outcomes in AML-MRC and tAML compared with standard 7+3 regimens. Here we report the cases of four consecutive patients with AML-MRC or tAML who received CPX-351 as outpatient induction therapy immediately followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Two patients received allo-HSCT in remission (one in complete remission and one in partial remission) and two patients received allo-HSCT in aplasia (one at 11 days and one at 52 days after the start of induction therapy with CPX-351). With a median follow-up of 188 days after allo-HSCT, all but one patient are alive and two are in remission. Further studies will help define and expand the role of CPX-351 in the treatment of AML-MRC and tAML, especially in patients expected to undergo allo-HSCT.
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http://dx.doi.org/10.3389/fonc.2020.01746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526474PMC
September 2020

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

Interactions of Anemia, FGF-23, and Bone in Healthy Adults-Results From the Study of Health in Pomerania (SHIP).

J Clin Endocrinol Metab 2021 Jan;106(1):e288-e299

Department of Medicine III and Center for Healthy Aging, Dresden Technical University Medical Center, Dresden, Germany.

Context: Osteoporosis and anemia are among the most common diseases in the aging population with an increasing prevalence worldwide.

Objective: As the bone-derived hormone fibroblast growth factor 23 (FGF-23) was recently reported to regulate erythropoiesis, we examined age-related associations between hemoglobin levels and bone quality, bone turnover, and FGF-23 concentrations.

Design: We used data from more than 5000 adult subjects who participated in the population-based cohorts of the Study of Health in Pomerania (SHIP and SHIP-Trend). Bone quality was assessed by quantitative ultrasound at the heel, bone turnover by measurement of carboxy-terminal telopeptide of type I collagen (CTX), and intact amino-terminal propeptide of type I procollagen (P1NP) serum concentrations, respectively. Anemia was defined as hemoglobin <13 g/dL in men and <12 g/dL in women. Carboxy-terminal FGF-23 levels were measured in plasma in a subset of 852 subjects.

Results: Anemic subjects had poorer bone quality, higher fracture risk, and lower serum levels of P1NP than nonanemic individuals. Linear regression models revealed positive associations between hemoglobin and bone quality in subjects aged 40 or above and inverse associations with CTX in subjects aged 60 or above. Hemoglobin and FGF-23 concentrations were inversely associated, while FGF-23 was not related to bone quality or turnover.

Conclusion: Our data corroborate a close link between FGF-23 and anemia, which is related to poor bone quality in elderly people. We observed no direct association of FGF-23 with bone parameters. Further studies are needed clarifying the role of FGF-23 on bone and red blood cell production.
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http://dx.doi.org/10.1210/clinem/dgaa716DOI Listing
January 2021

New Approaches for Anemia in MDS.

Authors:
Uwe Platzbecker

Clin Lymphoma Myeloma Leuk 2020 Sep;20 Suppl 1:S59-S60

University of Leipzig, Medical Clinic I, Hematology and Cellular Therapy, Liebigstr. 22, 04103 Leipzig, Germany. Electronic address:

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http://dx.doi.org/10.1016/S2152-2650(20)30463-8DOI Listing
September 2020

Pitfalls in Assessing Response to Treatment in MDS.

Authors:
Uwe Platzbecker

Clin Lymphoma Myeloma Leuk 2020 Sep;20 Suppl 1:S20-S21

University of Leipzig, Medical Clinic I, Hematology and Cellular Therapy, Liebigstr. 22, 04103 Leipzig, Germany. Electronic address:

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http://dx.doi.org/10.1016/S2152-2650(20)30448-1DOI Listing
September 2020

Allogeneic stem cell transplantation mitigates the adverse prognostic impact of high diagnostic BAALC and MN1 expression in AML.

Ann Hematol 2020 Oct 29;99(10):2417-2427. Epub 2020 Aug 29.

Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Liebigstraße 22, Haus 7, 04103, Leipzig, Germany.

For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, high expression of the AML-associated genes BAALC (brain and acute leukemia, cytoplasmic) and MN1 (meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic BAALC/ABL1 and MN1/ABL1 copy numbers in 302 AML patients. High BAALC/ABL1 and MN1/ABL1 copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high BAALC and MN1 expression are mitigated by allogeneic HSCT. But preHSCT BAALC/ABL1 and MN1/ABL1 assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic BAALC or MN1 expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.
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http://dx.doi.org/10.1007/s00277-020-04235-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481166PMC
October 2020

Guideline-based indicators for adult patients with myelodysplastic syndromes.

Blood Adv 2020 08;4(16):4029-4044

Department of Hematology and Central Hematology Laboratory, Inselspital/Bern University Hospital, and.

Myelodysplastic syndromes (MDSs) represent a heterogeneous group of hematological stem cell disorders with an increasing burden on health care systems. Evidence-based MDS guidelines and recommendations (G/Rs) are published but do not necessarily translate into better quality of care if adherence is not maintained in daily clinical practice. Guideline-based indicators (GBIs) are measurable elements for the standardized assessment of quality of care and, thus far, have not been developed for adult MDS patients. To this end, we screened relevant G/Rs published between 1999 and 2018 and aggregated all available information as candidate GBIs into a formalized handbook as the basis for the subsequent consensus rating procedure. An international multidisciplinary expert panel group (EPG) of acknowledged MDS experts (n = 17), health professionals (n = 7), and patient advocates (n = 5) was appointed. The EPG feedback rates for the first and second round were 82% (23 of 28) and 96% (26 of 27), respectively. A final set of 29 GBIs for the 3 domains of diagnosis (n = 14), therapy (n = 8), and provider/infrastructural characteristics (n = 7) achieved the predefined agreement score for selection (>70%). We identified shortcomings in standardization of patient-reported outcomes, toxicity, and geriatric assessments that need to be optimized in the future. Our GBIs represent the first comprehensive consensus on measurable elements addressing best practice performance, outcomes, and structural resources. They can be used as a standardized instrument with the goal of assessing, comparing, and fostering good quality of care within clinical development cycles in the daily care of adult MDS patients.
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http://dx.doi.org/10.1182/bloodadvances.2020002314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448599PMC
August 2020

Prognostic impact of the ELN2017 risk classification in patients with AML receiving allogeneic transplantation.

Blood Adv 2020 08;4(16):3864-3874

Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Leipzig, Germany.

In 2017, an updated European LeukemiaNet (ELN) risk classification was published allocating patients with acute myeloid leukemia (AML) to 3 risk groups on the basis of certain cytogenetic and molecular aberrations. To date, studies of the prognostic significance of the ELN2017 risk classification in the context of an allogeneic hematopoietic stem cell transplantation (HSCT) are lacking. We performed risk stratification according to the ELN2017 classification in 234 patients with AML who underwent allogeneic HSCT as a consolidation therapy. In our cohort, the risk of 39.7% of the patients was classified as favorable, that of 12.8% as intermediate, and that of 47.4% as adverse. In the context of allogeneic HSCT, the assignment to the 3 ELN2017 risk groups retained its prognostic significance, with patients with favorable risk having the best prognosis and those with adverse risk having the worst one. Subgroup analyses showed that patients with a monosomal karyotype or TP53 mutation had considerably increased relapse rates, even in the adverse-risk group. When we analyzed the impact of digital droplet PCR-based measurable residual disease (MRD) before allogeneic HSCT, MRD+ patients had impaired prognoses, with cumulative incidence of relapse and overall survival comparable to those of patients classified as having an ELN2017 adverse genetic risk. This study is the first to demonstrate that the ELN2017 classification distinguishes the 3 risk groups with significantly distinct prognoses, even after allogeneic HSCT, and emphasizes the dismal prognosis of patients with AML with TP53 mutations, monosomal karyotype, or MRD positivity after allogeneic HSCT.
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http://dx.doi.org/10.1182/bloodadvances.2020001904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448597PMC
August 2020

Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Bone Lab Dresden, Department of Medicine III & Center for Healthy Aging, and.

Myelodysplastic syndromes (MDS) are clonal malignant hematopoietic disorders in the elderly characterized by ineffective hematopoiesis. This is accompanied by an altered bone microenvironment, which contributes to MDS progression and higher bone fragility. The underlying mechanisms remain largely unexplored. Here, we show that myelodysplastic NUP98‑HOXD13 (NHD13) transgenic mice display an abnormally high number of osteoblasts, yet a higher fraction of nonmineralized bone, indicating delayed bone mineralization. This was accompanied by high fibroblast growth factor-23 (FGF-23) serum levels, a phosphaturic hormone that inhibits bone mineralization and erythropoiesis. While Fgf23 mRNA expression was low in bone, brain, and kidney of NHD13 mice, its expression was increased in erythroid precursors. Coculturing these precursors with WT osteoblasts induced osteoblast marker gene expression, which was inhibited by blocking FGF-23. Finally, antibody-based neutralization of FGF-23 in myelodysplastic NHD13 mice improved bone mineralization and bone microarchitecture, and it ameliorated anemia. Importantly, higher serum levels of FGF‑23 and an elevated amount of nonmineralized bone in patients with MDS validated the findings. C‑terminal FGF‑23 correlated negatively with hemoglobin levels and positively with the amount of nonmineralized bone. Thus, our study identifies FGF-23 as a link between altered bone structure and ineffective erythropoiesis in MDS with the prospects of a targeted therapeutic intervention.
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http://dx.doi.org/10.1172/jci.insight.137062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455070PMC
August 2020

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Nat Med 2020 10 3;26(10):1549-1556. Epub 2020 Aug 3.

Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease, rapid transformation to acute myeloid leukemia (AML), resistance to conventional therapies and dismal outcomes. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R). Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.
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http://dx.doi.org/10.1038/s41591-020-1008-zDOI Listing
October 2020

RNA-sequencing of acute promyelocytic leukemia primary blasts reveals novel molecular biomarkers of early death events.

Leuk Lymphoma 2020 12 29;61(13):3066-3077. Epub 2020 Jul 29.

Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Although acute promyelocytic leukemia (APL) has evolved to the AML entity with the best prognosis, typical 'early death' (ED) events still account for mortality rates of ∼20% in population-based studies. To investigate this poorly understood issue we performed whole transcriptome analysis of  = 7 APL ED cases compared to  = 7 APL cases with long term remission. We discovered the proteins S100A8/S100A9 and EFEMP1 as the most differentially expressed factors. In an independent cohort of  = 58 APL patients EFEMP1 over-expression was associated with a worse overall survival. Furthermore, a subgroup analysis of ED caused by hemorrhagic complications revealed an association of metallothioneins (MT1G/MT1E) with higher bleeding rates, ED events and negative prognostic effects on overall survival. Finally, we identified a novel TPM4-KLF2 fusion transcripts in 44/64 APL samples. In summary, we report a comprehensive transcriptomic analysis and novel potential biomarkers of ED biology, which highlight novel pathways in ED events in APL.
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http://dx.doi.org/10.1080/10428194.2020.1797006DOI Listing
December 2020

Disease management of patients with immune thrombocytopenia-results of a representative retrospective survey in Germany.

Ann Hematol 2020 Sep 25;99(9):2085-2093. Epub 2020 Jul 25.

Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital Leipzig, Leipzig, Germany.

Clinical research has resulted in an improvement of treatment options for patients with immune thrombocytopenia (ITP) over the last years. However, only few data exist on the real-life management of patients with ITP. To expand the knowledge, a multicenter, national survey was undertaken in 26 hematology practices distributed all over Germany. All patients with a diagnosis of ITP were documented using questionnaires, irrespective of the diagnosis date over a period of 2 years. Overall, data of 1023 patients were evaluated with 56% of patients being older than 60 years. Seventy-nine percent of the patients had chronic (> 12 months), 16% persistent (> 3-12 months), and 5% newly diagnosed (0-3 months) ITP. In 61% of cases, the disease lasted 3 or more years before survey documentation started. Main strategies applied as first-line therapy consisted of steroids in 45% and a "watch and wait" approach in 41% of patients. During second- and third-line strategies, treatment with steroids decreased (36% and 28%, respectively), while treatment modalities such as TPO-RAs increased (19% and 26%, respectively). As expected, patients with a low platelet count and thus a higher risk for bleeding and mortality received treatment (esp. steroids) more frequently during first line than those with a higher platelet count. Up to a third of patients were treated with steroids for more than a year. Overall, our study provides a cross-section overview about the current therapeutic treatment landscape in German ITP patients. The results will help to improve therapeutic management of ITP patients.
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http://dx.doi.org/10.1007/s00277-020-04173-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419449PMC
September 2020