Publications by authors named "Jan M Middeke"

15 Publications

  • Page 1 of 1

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

Five-year survival follow-up of a phase III randomised trial comparing ofatumumab versus physicians' choice for bulky fludarabine-refractory chronic lymphocytic leukaemia: a short report.

Br J Haematol 2020 05 28;189(4):689-693. Epub 2020 Jan 28.

Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.

In 2014, an interim analysis of a phase 3 study was performed to evaluate the effectiveness of ofatumumab in patients with bulky fludarabine-refractory chronic lymphocytic leukaemia (BFR CLL) as compared to physician's choice. The five-year follow-up of this phase 3 trial showed that ofatumumab therapy resulted in a numerically but not significantly longer overall survival. As only few patients had the chance to receive a kinase inhibitor later, the study displays the survival of BFR CLL patients in the period prior to receiving small-molecule inhibitors. Ofatumumab is a well-tolerable treatment option in multiresistant advanced CLL.
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http://dx.doi.org/10.1111/bjh.16429DOI Listing
May 2020

Clostridium Difficile infections in patients with AML or MDS undergoing allogeneic hematopoietic stem cell transplantation identify high risk for adverse outcome.

Bone Marrow Transplant 2020 02 18;55(2):367-375. Epub 2019 Sep 18.

Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden University of Technology Dresden, Dresden, Germany.

Clostridium difficile (CD) infection is the main cause of nosocomial enterocolitis in western countries and in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT). Recipients of alloHCT are at high risk for CD infection but large studies in this population are rare and conflicting results have been reported. We analyzed 727 patients with AML or MDS undergoing alloHCT in our center from 2004 to 2015. Ninety-six patients (13%) had CD infection and 103 patients (14%) were identified as asymptomatic carriers by screening at admission and once a week during aplasia. Patients with CD infection had a shorter median overall survival of 8 months (95% CI, 6-36 months) compared with 25 months (95% CI, 17-35 months) for patients without CD infection, (HR 1.4, p = 0.04). CD positive patients were less likely to develop acute graft-versus-host disease (aGvHD; HR 0.6, p = 0.004) compared with CD-negative patients, but did not show differences in gastrointestinal aGvHD (HR 0.9, p = 0.5). Symptomatic patients developed gastrointestinal aGvHD (HR 2.5, p = 0.02) more often compared with asymptomatic CD positive patients. This analysis demonstrates a high prevalence for CD infection in patients undergoing alloHCT. A significant lower overall survival for patients with CD infection could be demonstrated.
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http://dx.doi.org/10.1038/s41409-019-0678-yDOI Listing
February 2020

The prevalence of extramedullary acute myeloid leukemia detected by FDG-PET/CT: final results from the prospective PETAML trial.

Haematologica 2020 Jun 29;105(6):1552-1558. Epub 2019 Aug 29.

Department of Nuclear Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Extramedullary (EM) disease in patients with acute myeloid leukemia (AML) is a known phenomenon. Since the prevalence of EM AML has so far only been clinically determined on examination, we performed a prospective study in patients with AML. The aim of the study was to determine the prevalence of metabolically active EM AML using total body Fluorodesoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) imaging at diagnosis prior to initiation of therapy. In order to define the dynamics of EM AML throughout treatment, PET-positive patients underwent a second FDG-PET/CT imaging series during follow up by the time of remission assessment. A total of 93 patients with AML underwent FDG-PET/CT scans at diagnosis. The prevalence of PET-positive EM AML was 19% with a total of 65 EM AML manifestations and a median number of two EM manifestations per patient (range, 1-12), with a median maximum standardized uptake value of 6.1 (range, 2-51.4). When adding those three patients with histologically confirmed EM AML who were FDG-PET/CT negative in the FDG-PET/CT at diagnosis, the combined prevalence for EM AML was 22%, resulting in 77% sensitivity and 97% specificity. Importantly, 60% (6 of 10) patients with histologically confirmed EM AML still had active EM disease in their follow up FDG-PET/CT. FDG-PET/CT reveals a high prevalence of metabolically active EM disease in AML patients. Metabolic activity in EM AML may persist even beyond the time point of hematologic remission, a finding that merits further prospective investigation to explore its prognostic relevance. (Trial registered ).
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http://dx.doi.org/10.3324/haematol.2019.223032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271590PMC
June 2020

Validation of the Revised Pretransplant Assessment of Mortality Score in Patients with Acute Myelogenous Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2018 09 21;24(9):1947-1951. Epub 2018 May 21.

Universitätsklinikum Carl Gustav Carus der TU Dresden, Medizinische Klinik und Poliklinik I, Dresden, Germany; Deutsche Knochenmarkspenderdatei Clinical Trials Unit, Dresden, Germany.

Despite recent advances, allogeneic hematopoietic stem cell transplantation (allo-HSCT) continues to be accompanied by a high rate of morbidity and mortality. Several scores have been developed to predict outcome after allo-HSCT. The recently revised Pretransplant Assessment of Mortality (PAM) score is based on patient age, donor type, disease risk, cytomegalovirus (CMV) serostatus of patient and donor, and forced expiratory volume in 1 second (FEV). The aim of this study was to analyze the predictive power of the PAM score in an independent large cohort of patients with acute myelogenous leukemia (AML). We selected adult patients with AML who underwent a first allo-HSCT at the University Hospital of Dresden, a tertiary care hospital with a large transplantation program. All adult patients treated between January 1, 2003, and July 1, 2015, were included. The PAM score was calculated as described previously. Overall survival (OS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) after allo-HSCT were analyzed. Age, AML type, sex match, CMV match, donor type, European Leukemia Net risk classification, type of conditioning, disease stage, and PAM score as a continuous variable were selected a priori for multivariate Cox regression analyses. A total of 544 patients met the inclusion criteria. The median patient age was 57 years. With a median follow-up of 47 months (range, 1 to 161 months), the estimated OS for the whole cohort at 4 years was 43%, with a CIR of 30% and an NRM of 31%. The probability of OS at 4 years was 65% for patients with a PAM score of 0, 52% in those with a PAM score of 1, 33% in those with a PAM score of 2, and 22% in those with a PAM score of 3 (P < .001, log-rank test). Both the CIR and NRM increased with higher PAM scores (P = .005 and P < .001, respectively, Gray test). In multivariate analysis, age (hazard ratio [HR], 1.02 per year; P = .004), disease stage (primary induction failure versus first complete remission (CR1); HR, 1.5; P = .03), and the PAM score (HR 1.04; P = .03) had a significant impact on OS. This is the first independent validation of the revised PAM score allowing for simple and valid estimation of transplantation outcomes. It can serve as an important tool in counseling patients with AML, as well as in designing future trials.
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http://dx.doi.org/10.1016/j.bbmt.2018.05.021DOI Listing
September 2018

Pilot Study on Mass Spectrometry-Based Analysis of the Proteome of CD34⁺CD123⁺ Progenitor Cells for the Identification of Potential Targets for Immunotherapy in Acute Myeloid Leukemia.

Proteomes 2018 Feb 12;6(1). Epub 2018 Feb 12.

Department of Medicine I, University Hospital of Dresden, 01307 Dresden, Germany.

Targeting of leukemic stem cells with specific immunotherapy would be an ideal approach for the treatment of myeloid malignancies, but suitable epitopes are unknown. The comparative proteome-level characterization of hematopoietic stem and progenitor cells from healthy stem cell donors and patients with acute myeloid leukemia has the potential to reveal differentially expressed proteins which can be used as surface-markers or as proxies for affected molecular pathways. We employed mass spectrometry methods to analyze the proteome of the cytosolic and the membrane fraction of CD34 and CD123 co-expressing FACS-sorted leukemic progenitors from five patients with acute myeloid leukemia. As a reference, CD34⁺CD123⁺ normal hematopoietic progenitor cells from five healthy, granulocyte-colony stimulating factor (G-CSF) mobilized stem cell donors were analyzed. In this Tandem Mass Tag (TMT) 10-plex labelling-based approach, 2070 proteins were identified with 171 proteins differentially abundant in one or both cellular compartments. This proof-of-principle-study demonstrates the potential of mass spectrometry to detect differentially expressed proteins in two compartment fractions of the entire proteome of leukemic stem cells, compared to their non-malignant counterparts. This may contribute to future immunotherapeutic target discoveries and individualized AML patient characterization.
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http://dx.doi.org/10.3390/proteomes6010011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874770PMC
February 2018

The TP53 Pro72Arg SNP in de novo acute myeloid leukaemia - results of two cohort studies involving 215 patients and 3759 controls.

Br J Haematol 2018 04 20;181(1):148-151. Epub 2017 Jan 20.

Division of Haematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

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http://dx.doi.org/10.1111/bjh.14527DOI Listing
April 2018

TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.

Br J Haematol 2016 Mar 13;172(6):914-22. Epub 2016 Jan 13.

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

Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.
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http://dx.doi.org/10.1111/bjh.13912DOI Listing
March 2016

Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.

Blood 2014 May 20;123(19):2960-7. Epub 2014 Mar 20.

Universitätsklinikum Carl Gustav Carus der Technische Universität Dresden, Medizinische Klinik und Poliklinik I, Dresden, Germany;

Patients with acute myeloid leukemia (AML) and abnormalities of chromosome 17p (abnl(17p)) are at high-risk of treatment failure. Poor outcomes have been reported with conventional chemotherapy. To accurately define the outcome after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with abnl(17p) AML, we analyzed the results of patients with this abnormality who received an allogeneic HSCT between January 2000 and December 2010 in 1 of 4 well-defined cohorts (Fred Hutchinson Cancer Research Center, Haemato Oncology Foundation for Adults in the Netherlands, Study Alliance Leukemia, German Cooperative Transplant Study Group). Data of 201 patients with a median age of 54 years were evaluable. At the time of analysis, 30 patients were alive with a median follow-up of 30 months. The 3-year probability of overall survival (OS) was 15% (95% confidence interval [CI], 10-20). The cumulative incidence of relapse at 3 years was 49% (95% CI, 42-56). Notably, almost 70% of all relapses occurred within the first 6 months after HSCT. Patients who were transplanted in first complete remission (CR1) had superior OS compared with those with advanced disease (22% vs 9%, P < .001). Our findings confirm the high-risk of treatment failure in abnl(17p) AML even after allogeneic HSCT in CR1. Although allogeneic HSCT remains a valid option in CR1, alternative treatment strategies are needed for the remaining patients.
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http://dx.doi.org/10.1182/blood-2013-12-544957DOI Listing
May 2014

Impact of allogeneic haematopoietic stem cell transplantation in patients with abnl(17p) acute myeloid leukaemia.

Br J Haematol 2013 Apr 21;161(2):237-44. Epub 2013 Feb 21.

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

The role of allogeneic stem cell transplantation (HSCT) as compared to chemotherapy in acute myeloid leukaemia (AML) patients with abnormalities of chromosome 17p [abnl(17p)] has not yet been defined. Therefore, we analysed 3530 AML patients treated in three randomized, prospective, controlled clinical trials and compared post-remission therapies using a multivariate Cox regression analysis to determine whether allogeneic HSCT is superior than chemotherapy in overcoming the detrimental impact of patients with abnl(17p) AML. One hundred and forty-three patients (4%) were identified with abnl(17p) AML. All patients had received intensive induction chemotherapy. Forty-seven patients with a median age of 54 years (18-69 years) proceeded to allogeneic HSCT in first or second remission. The 3-year overall survival (OS) rate for the entire cohort of patients was 4% [95% confidence interval (CI), 1-7%]. OS and event-free survival at 3 years, calculated from the day of HSCT, was 11% (95% CI, 2-20%) and 6% (95% CI, 0-13%), respectively. Multivariate Cox regression analysis showed no benefit of allogeneic HSCT compared to chemotherapy (Hazard Ratio 0·97, 95% CI 0·56-1·67, P = 0·9). In conclusion, allogeneic HSCT does not improve survival in patients with abnl(17p) AML as compared to other adverse cytogenetic risk abnormalities.
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http://dx.doi.org/10.1111/bjh.12253DOI Listing
April 2013

Outcome of high-risk acute myeloid leukemia after allogeneic hematopoietic cell transplantation: negative impact of abnl(17p) and -5/5q-.

Blood 2012 Sep 31;120(12):2521-8. Epub 2012 Jul 31.

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

The European LeukemiaNet classification combines a heterogeneous group of aberrations as adverse-risk abnormalities. Our goal was to investigate the outcomes associated with distinct high-risk chromosomal abnormalities in acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). We performed a retrospective cohort analysis in patients with high-risk AML who received first, HLA-compatible, allogeneic HSCT between January 2005 and December 2008. Data from 236 patients with a median age of 55 years were included. Because complex karyotype (CK), -5/5q-, and abnl(17p) are overlapping categories, a hierarchical classification system based on the presence or absence of abnl(17p) and -5/5q- was developed. Patients with abnl(17p) had a 2-year event-free survival (EFS) of 11% (95% confidence interval [CI], 0%-25%), patients with -5/5q- but no abnl(17p) a 2-year EFS of 29% (95% CI, 14%-44%), and patients with adverse-risk AML but neither of the 2 marker lesions a 2-year EFS of 49% (95% CI, 39%-59%). Notably, complex and monosomal karyotypes lost their prognostic value when these marker lesions were excluded. In conclusion, hierarchical classification of adverse-risk karyotypes by 2 marker lesions, abnl(17p) and -5/5q-, is effective in prognostication of the outcome of allogeneic HSCT in AML.
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http://dx.doi.org/10.1182/blood-2012-03-417972DOI Listing
September 2012