Publications by authors named "Edgar Jost"

68 Publications

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

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

Pulmonary infections in patients with and without hematological malignancies: diagnostic yield and safety of flexible bronchoscopy-a retrospective analysis.

J Thorac Dis 2020 Sep;12(9):4860-4867

Department of Pneumology and Intensive Care Medicine, University Hospital RWTH Aachen, Aachen, Germany.

Background: Fiberoptic bronchoscopy (FOB) with broncho-alveolar lavage (BAL) is frequently performed in patients with hematological malignancies and pulmonary opacities. While the safety of the procedure in this patient population has been shown, data about the diagnostic yield widely differ between studies. Furthermore, data comparing diagnostic yield and safety of flexible bronchoscopy to narrow sources of pulmonary infections in patients with and without underlying hematological malignancy are lacking.

Methods: We carried out a retrospective analysis of bronchoscopies done for the diagnostic work-up of pulmonary infections. Diagnostic yield and the occurrence of complications in patients with and without hematological disease were compared.

Results: In total n=268 bronchoscopies were done in patients suffering from a hematological malignancy (HM) compared to n=408 bronchoscopies in patients without hematological malignancy (NHM). The overall diagnostic yield was similar and did not differ between the groups (HM: 67.2% NHM: 64.7%; P=0.5622). However, when cultures positive for Candida were not considered as clinically relevant diagnostic yield was higher in the HM group (HM: 62.7% NHM: 53.9%; P=0.0261) due to a higher detection rate of fungi and viruses (both P<0.001). Interestingly, the diagnostic yield for bacteria was not decreased by pre-treatment with antibiotics in either group (both P>0.05). There was no difference in the complication rate between the groups and most complications were considered as minor.

Conclusions: In summary, our data demonstrate similar diagnostic yield and safety of flexible bronchoscopy for diagnosing pulmonary infection in patients with and without underlying hematological malignancy.
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http://dx.doi.org/10.21037/jtd-20-835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578490PMC
September 2020

Role of Inflammatory Factors during Disease Pathogenesis and Stem Cell Transplantation in Myeloproliferative Neoplasms.

Cancers (Basel) 2020 Aug 12;12(8). Epub 2020 Aug 12.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany.

Hematopoiesis is a highly regulated and complex process involving hematopoietic stem cells (HSCs), cell surface adhesion molecules, and cytokines as well as cells of the hematopoietic niche in the bone marrow (BM). Myeloproliferative neoplasms (MPNs) are characterized by clonal expansion of HSCs involving one or more blood cell lineages. Philadelphia-negative MPNs (Ph-neg MPNs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In nearly all patients with Ph-neg MPN, mutations in the genes encoding janus kinase 2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL) can be detected and, together with additional mutations in epigenetic modifier genes, these genetic aberrations contribute to the clonal expansion of the cells. In addition to these intracellular changes in the malignant clone, inflammatory processes involving both the clonal and the non-clonal cells contribute to the signs and symptoms of the patients, as well as to progression of the disease to myelofibrosis (MF) or acute leukemia, and to thrombotic complications. This contribution has been corroborated in preclinical studies including mouse models and patient-derived iPS cells, and in clinical trials, using anti-inflammatory drugs such as JAK inhibitors and steroids, or immunomodulatory drugs such as IMiDs and interferon-alpha (IFNa), all of which change the (im)balance of circulating inflammatory factors (e.g., TNFa, IL-1b, and TGFβ) in MPN. Currently, allogeneic hematopoietic (stem) cell transplantation (allo-HCT) remains the only curative treatment for Ph-neg MPN and is the treatment of choice in intermediate-2 and high-risk MF. HCT can reverse inflammatory changes induced by MPN as well as fibrosis in a large proportion of patients, but it also induces itself profound changes in inflammatory cells and cytokines in the patient, which may help to eradicate the disease but also in part cause significant morbidity (e.g., by graft-versus-host disease). In this review, we focus on the contribution of aberrant inflammation to disease pathogenesis in Ph-neg MPN as well as the current understanding of its alterations after allogeneic HCT.
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http://dx.doi.org/10.3390/cancers12082250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463735PMC
August 2020

Favorable COVID-19 course despite significant comorbidities in a ruxolitinib-treated patient with primary myelofibrosis.

Eur J Haematol 2020 Nov 16;105(5):655-658. Epub 2020 Jul 16.

Department of Pneumology and Intensive Care Medicine, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.

COVID-19 carries a high risk of severe disease course, particularly in patients with comorbidities. Therapy of severe COVID-19 infection has relied on supportive intensive care measures. More specific approaches including drugs that limit the detrimental "cytokine storm", such as Janus-activated kinase (JAK) inhibitors, are being discussed. Here, we report a compelling case of a 55-yo patient with proven COVID-19 pneumonia, who was taking the JAK1/2 inhibitor ruxolitinib in-label for co-existing primary myelofibrosis for 15 months prior to coronavirus infection. The patient had significant comorbidities, including chronic kidney disease, arterial hypertension, and obesity, and our previous cohort suggested that he was thus at high risk for acute respiratory distress syndrome (ARDS) and death from COVID-19. Since abrupt discontinuation of ruxolitinib may cause fatal cytokine storm and ARDS, ruxolitinib treatment was continued and was well tolerated, and the patient´s condition remained stable, without the need for mechanical ventilation or vasopressors. The patient became negative for SARS-CoV-2 and was discharged home after 15 days. In conclusion, our report provides clinical evidence that ruxolitinib treatment is feasible and can be beneficial in patients with COVID-19 pneumonia, preventing cytokine storm and ARDS.
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http://dx.doi.org/10.1111/ejh.13480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361537PMC
November 2020

Does time from diagnosis to treatment affect the prognosis of patients with newly diagnosed acute myeloid leukemia?

Blood 2020 Aug;136(7):823-830

Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany.

In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. All registered non-acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.
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http://dx.doi.org/10.1182/blood.2019004583DOI Listing
August 2020

Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial.

J Clin Oncol 2020 01 3;38(3):257-270. Epub 2019 Dec 3.

University Hospital of Ulm, Ulm, Germany.

Purpose: DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all- retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML).

Patients And Methods: Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety.

Results: The addition of ATRA resulted in a higher remission rate (21.9% with ATRA 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided = .06). For valproate, no effect was observed (17.8% with valproate 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided = .44). Median overall survival was 8.2 months with ATRA 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms.

Conclusion: The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.
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http://dx.doi.org/10.1200/JCO.19.01053DOI Listing
January 2020

Tracking myeloid malignancies by targeted analysis of successive DNA methylation at neighboring CG dinucleotides.

Haematologica 2019 08 31;104(8):e349-e351. Epub 2019 Jan 31.

Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University, Aachen

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http://dx.doi.org/10.3324/haematol.2018.209734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669165PMC
August 2019

Variants of cause transcript-specific DNA methylation patterns and affect hematopoiesis.

Life Sci Alliance 2018 Dec 13;1(6):e201800153. Epub 2018 Dec 13.

Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, RWTH Aachen University Medical School, Aachen, Germany.

De novo DNA methyltransferase 3A (DNMT3A) plays pivotal roles in hematopoietic differentiation. In this study, we followed the hypothesis that alternative splicing of has characteristic epigenetic and functional sequels. Specific transcripts were either down-regulated or overexpressed in human hematopoietic stem and progenitor cells, and this resulted in complementary and transcript-specific DNA methylation and gene expression changes. Functional analysis indicated that, particularly, transcript 2 (coding for DNMT3A2) activates proliferation and induces loss of a primitive immunophenotype, whereas transcript 4 interferes with colony formation of the erythroid lineage. Notably, in acute myeloid leukemia expression of transcript 2 correlates with its in vitro DNA methylation and gene expression signatures and is associated with overall survival, indicating that variants also affect malignancies. Our results demonstrate that specific variants have a distinct epigenetic and functional impact. Particularly, DNMT3A2 triggers hematopoietic differentiation and the corresponding signatures are reflected in acute myeloid leukemia.
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http://dx.doi.org/10.26508/lsa.201800153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293073PMC
December 2018

[Stem cell transplantation unit: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)].

Bull Cancer 2019 Jan 21;106(1S):S1-S9. Epub 2018 Dec 21.

University Hospital RWTH Aachen, medical faculty, department of hematology, oncology, hemostaseology and stem cell transplantation, Pauwelsstraße 30, 52074 Aachen, Allemagne. Electronic address:

Allogeneic hematopoietic cell transplantation (HCT) is part of the standard of care for many hematological diseases. Over the last decades, significant advances in patient and donor selection, conditioning regimens as well as supportive care of patients undergoing allogeneic HCT leading to improved overall survival have been made. In view of many new treatment options in cellular and molecular targeted therapies, the place of allogeneic transplantation in therapy concepts must be reviewed. Most aspects of HCT are well standardized by national guidelines or laws as well as by certification labels such as FACT-JACIE. However, the requirements for human resources, construction and layout of a unit treating patients during the transplantation procedure and for different complications are not well defined. Here, we describe the process of planning a transplant unit in order to open a discussion that could lead to more precise guidelines in the field of personnel and infrastructural requirements for hospitals caring for people with severe immunosuppression.
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http://dx.doi.org/10.1016/j.bulcan.2018.11.005DOI Listing
January 2019

Characterization of acute myeloid leukemia with del(9q) - Impact of the genes in the minimally deleted region.

Leuk Res 2019 01 17;76:15-23. Epub 2018 Nov 17.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, University Hospital RWTH Aachen University, Aachen, Germany. Electronic address:

Acute myeloid leukemia is an aggressive disease that arises from clonal expansion of malignant hematopoietic precursor cells of the bone marrow. Deletions on the long arm of chromosome 9 (del(9q)) are observed in 2% of acute myeloid leukemia patients. Our deletion analysis in a cohort of 31 del(9q) acute myeloid leukemia patients further supports the importance of a minimally deleted region composed of seven genes potentially involved in leukemogenesis: GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2. Importantly, among them HNRNPK, encoding heterogeneous nuclear ribonucleoprotein K is proposed to function in leukemogenesis. We show that expression of HNRNPK and the other genes of the minimally deleted region is significantly reduced in patients with del(9q) compared with normal karyotype acute myeloid leukemia. Also, two mRNAs interacting with heterogeneous nuclear ribonucleoprotein K, namely CDKN1A and CEBPA are significantly downregulated. While the deletion size is not correlated with outcome, associated genetic aberrations are important. Patients with an additional t(8;21) show a good prognosis. RUNX1-RUNX1T1, which emerges from the t(8;21) leads to transcriptional down-regulation of CEBPA. Acute myeloid leukemia patients with mutations in CEBPA have a good prognosis as well. Interestingly, in del(9q) patients with CEBPA mutation mRNA levels of HNRNPK and the other genes located in the minimally deleted region is restored to normal karyotype level. Our data indicate that a link between CEBPA and the genes of the minimally deleted region, among them HNRNPK contributes to leukemogenesis in acute myeloid leukemia with del(9q).
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http://dx.doi.org/10.1016/j.leukres.2018.11.007DOI Listing
January 2019

Germ line predisposition to myeloid malignancies appearing in adulthood.

Expert Rev Hematol 2018 08 23;11(8):625-636. Epub 2018 Jul 23.

a Medical Faculty, Dept. of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation , University Hospital RWTH Aachen , Aachen , Germany.

Introduction: Germ line predisposition to myeloid neoplasms has been incorporated in the WHO 2016 classification of myeloid neoplasms and acute leukemia. The new category of disease is named hereditary myeloid disorder (HMD). Although most myeloid neoplasms are sporadic, germ line mutations and familial predisposition can contribute to development of chronic myeloid diseases and acute myeloid leukemia. This finding and upcoming frequent use of genome wide detection of molecular aberrations will lead to a higher detection rate of a genetic predisposition and influence treatment decisions. Hereditary predisposition is responsible for 5-10% of myeloid malignancies. Management of affected patients begins by the awareness of treating physicians of the problem and a precise work up of the patient and family members. Areas covered: This review focuses on current knowledge about germ line predisposition for myeloid neoplasms including diagnostic, prognostic, and therapeutic aspects in adult patients. Essential information for clinical routine is provided. Expert commentary: Compared to a patient without predisposition, adaptation of treatment strategy for patients with an HMD is often necessary, especially to avoid higher risk of relapse or higher toxicity during chemotherapy or transplantation. Mistakes in choice of a related donor can be omitted. Relatives at risk of developing a HMD need specific surveillance.
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http://dx.doi.org/10.1080/17474086.2018.1494566DOI Listing
August 2018

Presence of TERT Promoter Mutations is a Secondary Event and Associates with Elongated Telomere Length in Myxoid Liposarcomas.

Int J Mol Sci 2018 Feb 18;19(2). Epub 2018 Feb 18.

Department of Hematology, Oncology, Haemostaseology and Stem Cell Transplantation, RWTH Aachen University Medical Faculty, 52074 Aachen, Germany.

The occurrence of promoter mutations has been well described in soft tissue sarcomas (STS). However, the biological role of these mutations as well as their impact on telomere length in STS is still unclear. We analyzed 116 patient samples diagnosed with 22 distinct histological subtypes of bone and STS for the occurrence of promoter mutations by Sanger sequencing. We observed promoter mutations at an overall frequency of 9.5% distributed over 7 different sarcoma subtypes. Except for one chondrosarcoma case harboring a C250T mutation, all other mutations were detected at location C228T. By far the far highest frequency of promoter mutations was found in myxoid liposarcoma (MLS) (4 out of 9 cases studied, i.e., 44%). Assessment of telomere length from tumor biopsies revealed that promoter-mutated MLSs had significantly fewer shortened telomeres in comparison to wildtype MLSs. Based on the frequency of promoter mutations and the elongated telomere length in mutated compared to wildtype MLS, we hypothesize that occurrence of promoter mutations has a pivotal role in the disease progression as a secondary genetic event at a time when tumor cells face the need for telomere elongation to allow further proliferation.
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http://dx.doi.org/10.3390/ijms19020608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855830PMC
February 2018

[Allogeneic haematopoietic cell transplantation for diffuse large B cell lymphoma: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

Bull Cancer 2017 Dec 22;104(12S):S131-S135. Epub 2017 Nov 22.

Universitätsklinikum Aachen, Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Aachen, Allemagne; Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, Saint-Priest-en-Jarez, France. Electronic address:

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly in the case of after autologous stem cell transplantation if remission can be achieved. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This section specifically reports on our conclusions regarding diffuse large B cell lymphoma.
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http://dx.doi.org/10.1016/j.bulcan.2017.10.018DOI Listing
December 2017

[Allogeneic hematopoietic cell transplantation for Hodgkin's disease, mantle cell lymphoma and other rare entities: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

Bull Cancer 2017 Dec 23;104(12S):S112-S120. Epub 2017 Nov 23.

Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, Saint-Priest-en-Jarez, France. Electronic address:

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic haematopoietic cell transplantation is a potentially curative option, in particular in the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic haematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This manuscript specifically reports on our conclusions regarding Hodgkin's lymphoma as well as rarer entities, such as T cell lymphomas.
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http://dx.doi.org/10.1016/j.bulcan.2017.06.020DOI Listing
December 2017

[Allogeneic haematopoietic cell transplantation for indolent lymphomas: Guidelines from the Francophone Society Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

Bull Cancer 2017 Dec 22;104(12S):S121-S130. Epub 2017 Nov 22.

Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, 42271 Saint-Priest-en-Jarez, France. Electronic address:

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This paper specifically reports on our conclusions regarding indolent lymphomas, mainly follicular lymphoma and chronic lymphocytic leukemia.
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http://dx.doi.org/10.1016/j.bulcan.2017.05.010DOI Listing
December 2017

[Use of alternative donors for allogeneic haematopoietic cell transplantation in lymphoid neoplasms: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)].

Bull Cancer 2017 Dec 21;104(12S):S106-S111. Epub 2017 Nov 21.

Institut de cancérologie Lucien-Neuwirth, département d'hématologie clinique, 42, rue St-Étienne, Saint-Priest-en-Jarez, France. Electronic address:

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic haematopoietic cell transplantation (allo-HCT) is a potentially curative option, in particular in the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allo-HCT for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This manuscript reports on general considerations regarding allo-HCT for lymphoma and elaborates on the use of alternative donors in this setting.
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http://dx.doi.org/10.1016/j.bulcan.2017.08.008DOI Listing
December 2017

Elimination of different leukaemia subtypes using novel CD89-specific human cytolytic fusion proteins.

Br J Haematol 2018 10 19;183(2):313-317. Epub 2017 Oct 19.

Department of Immunotherapy, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Aachen, Germany.

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http://dx.doi.org/10.1111/bjh.14971DOI Listing
October 2018

Evidence for a pre-existing telomere deficit in non-clonal hematopoietic stem cells in patients with acute myeloid leukemia.

Ann Hematol 2017 Sep 3;96(9):1457-1461. Epub 2017 Jul 3.

Department of Hematology, Oncology, Haemostaseology and Stem Cell Transplantation, RWTH Aachen University Medical Faculty, Aachen, Germany.

Telomere shortening represents an established mechanism connecting aging and cancer development. We sequentially analyzed telomere length (TL) of 49 acute myeloid leukemia (AML) patients at diagnosis (n = 24), once they achieved complete cytological remission (CCR) and/or during refractory disease or relapse and after 1-year follow-up, with all patients having at least two sequential samples. TL was analyzed by monochrome multiplex quantitative polymerase chain reaction. We have observed substantially shortened TL in the cells of patients at diagnosis compared to age-adjusted controls. In patients reaching CCR after chemotherapy, telomere shortening was less pronounced than in persistence or relapse but still significantly shortened compared to controls. We estimate patients harboring approximately 20 years of premature telomere loss compared to healthy aged-matched subjects at the time of AML onset. Our data indicate a pre-existing telomere deficit in non-clonal hematopoiesis of AML patients providing a link between age and AML development.
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http://dx.doi.org/10.1007/s00277-017-3049-zDOI Listing
September 2017

Perioperative intravenous immunoglobulin treatment in a patient with severe acquired von Willebrand syndrome: case report and review of the literature.

Clin Case Rep 2017 05 30;5(5):664-670. Epub 2017 Mar 30.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation Medical Faculty RWTH Aachen University Aachen Germany.

Acquired von Willebrand syndrome may be related to plasma cell dyscrasia and can cause severe bleeding complications. Treatment, for example, with intravenous immunoglobulins may be indicated in selected cases. Physicians treating plasma cell dyscrasia have to be aware of bleeding complications in these patients, and clarification is necessary.
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http://dx.doi.org/10.1002/ccr3.890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412814PMC
May 2017

[Transfer of allogeneic stem cell transplant recipients to the intensive care unit: Guidelines from the Francophone society of marrow transplantation and cellular therapy (SFGM-TC)].

Bull Cancer 2016 Nov 2;103(11S):S220-S228. Epub 2016 Nov 2.

CHU de Lille, LIRIC Inserm U995, université Lille 2, 59000 Lille, France. Electronic address:

Transferring a patient undergoing an allogeneic stem cell transplantation to the intensive care unit (ICU) is always a challenging situation on a medical and psychological point of view for the patient and his relatives as well as for the medical staff. Despite the progress in hematology and intensive care during the last decade, the prognosis of these patients admitted to the ICU remains poor and mortality is around 50 %. The harmonization working party of the SFGM-TC assembled hematologists and intensive care specialist in order to improve conditions and modalities of the transfer of a patient after allogeneic stem cell transplantation to the ICU. We propose a structured medical form comprising all essential information necessary for optimal medical care on ICU.
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http://dx.doi.org/10.1016/j.bulcan.2016.09.008DOI Listing
November 2016

A three-gene expression-based risk score can refine the European LeukemiaNet AML classification.

J Hematol Oncol 2016 09 1;9(1):78. Epub 2016 Sep 1.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Background: Risk stratification based on cytogenetics of acute myeloid leukemia (AML) remains imprecise. The introduction of novel genetic and epigenetic markers has helped to close this gap and increased the specificity of risk stratification, although most studies have been conducted in specific AML subpopulations. In order to overcome this limitation, we used a genome-wide approach in multiple AML populations to develop a robust prediction model for AML survival.

Methods: We conducted a genome-wide expression analysis of two data sets from AML patients enrolled into the AMLCG-1999 trial and from the Tumor Cancer Genome Atlas (TCGA) to develop a prognostic score to refine current risk classification and performed a validation on two data sets of the National Taiwan University Hospital (NTUH) and an independent AMLCG cohort.

Results: In our training set, using a stringent multi-step approach, we identified a small three-gene prognostic scoring system, named Tri-AML score (TriAS) which highly correlated with overall survival (OS). Multivariate analysis revealed TriAS to be an independent prognostic factor in all tested training and additional validation sets, even including age, current cytogenetic-based risk stratification, and three other recently developed expression-based scoring models for AML.

Conclusions: The Tri-AML score allows robust and clinically practical risk stratification for the outcome of AML patients. TriAS substantially refined current ELN risk stratification assigning 44.5 % of the patients into a different risk category.
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http://dx.doi.org/10.1186/s13045-016-0308-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009640PMC
September 2016

CD64-directed microtubule associated protein tau kills leukemic blasts ex vivo.

Oncotarget 2016 Oct;7(41):67166-67174

Fraunhofer Institute for Molecular Biology and Applied Ecology, Aachen, Germany.

Fc gamma receptor I (FcγRI, CD64) is a well-known target antigen for passive immunotherapy against acute myeloid leukemia and chronic myelomonocytic leukemia. We recently reported the preclinical immunotherapeutic potential of microtubule associated protein tau (MAP) against a variety of cancer types including breast carcinoma and Hodgkin's lymphoma. Here we demonstrate that the CD64-directed human cytolytic fusion protein H22(scFv)-MAP kills ex vivo 15-50% of CD64+ leukemic blasts derived from seven myeloid leukemia patients. Furthermore, in contrast to the nonspecific cytostatic agent paclitaxel, H22(scFv)-MAP showed no cytotoxicity towards healthy CD64+ PBMC-derived cells and macrophages. The targeted delivery of this microtubule stabilizing agent therefore offers a promising new strategy for specific treatment of CD64+ leukemia.
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http://dx.doi.org/10.18632/oncotarget.11568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341865PMC
October 2016

MicroRNA expression profiles of serum from patients before and after chemotherapy.

Genom Data 2015 Dec 2;6:125-7. Epub 2015 Sep 2.

Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.

Recovery of the blood and immune system after chemotherapy requires proliferation of hematopoietic stem and progenitor cells (HPSCs). It has been shown that systemically released factors in serum after chemotherapy stimulate HSPC expansion in vitro. We wondered if microRNAs (miRNAs) circulating in serum could account for this effect. Therefore, we compared the miRNA expression profiles of serum from patients with hematologic malignancies before and after chemotherapy. In addition to a general decrease in miRNA expression after chemotherapy, we found 23 miRNAs to be significantly differentially expressed in serum before versus after chemotherapy. The miRNA microarray data are available at NCBI's Gene Expression Omnibus (GEO) Series accession number GSE57570. Here, we provide a detailed protocol of the miRNA microarray and data analysis.
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http://dx.doi.org/10.1016/j.gdata.2015.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664708PMC
December 2015

DNA-methylation in C1R is a prognostic biomarker for acute myeloid leukemia.

Clin Epigenetics 2015 4;7:116. Epub 2015 Nov 4.

Helmholtz-Institute for Biomedical Engineering, Stem Cell Biology and Cellular Engineering, University Hospital of the RWTH Aachen, Pauwelsstrasse 20, 52074 Aachen, Germany.

Background: Epigenetic aberrations play a central role in the pathophysiology of acute myeloid leukemia (AML). It has been shown that molecular signatures based on DNA-methylation (DNAm) patterns can be used for classification of the disease. In this study, we followed the hypothesis that DNAm at a single CpG site might support risk stratification in AML.

Findings: Using DNAm profiles of 194 patients from The Cancer Genome Atlas (TCGA), we identified a CpG site in complement component 1 subcomponent R (C1R) as best suited biomarker: patients with higher methylation at this CpG site (>27 % DNAm) reveal significantly longer overall survival (53 versus 11 months; P < 0.0001). This finding was validated in an independent set of 62 DNAm profiles of cytogenetically normal AML patients (P = 0.009) and with a region-specific pyrosequencing assay in 84 AML samples (P = 0.012). DNAm of C1R correlated with genomic DNAm and gene expression patterns, whereas there was only moderate association with gene expression levels of C1R. These results indicate that DNAm of C1R is a biomarker reflecting chromatin reorganization rather than being of pathophysiological relevance per se. Notably, DNAm of C1R was associated with occurrence of specific genomic mutations that are traditionally used for risk stratification in AML. Furthermore, DNAm of C1R correlates also with overall survival in several other types of cancer, but the prognostic relevance was less pronounced than in AML.

Conclusions: Analysis of DNAm at C1R provides a simple, robust, and cost-effective biomarker to further complement risk assessment in AML.
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http://dx.doi.org/10.1186/s13148-015-0153-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632269PMC
November 2015

Telomere shortening in enterocytes of patients with uncontrolled acute intestinal graft-versus-host disease.

Blood 2015 Nov 20;126(22):2518-21. Epub 2015 Oct 20.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany;

Acute intestinal graft-versus-host disease (aGVHD) refractory to immunosuppressive treatment is a serious complication after allogenic hematopoietic stem cell transplantation (HSCT). The underlying mechanisms of refractory aGVHD of the gut are not fully understood. Although telomere length (TL) reflects the replicative history of a cell, critically short telomeres have been associated with replicative exhaustion and tissue failure. In this study, we demonstrate that enterocytes of patients with refractory intestinal aGVHD show significantly increased proliferation, which translates into significant and critical telomere attrition following HSCT as compared with unaffected patients undergoing HSCT. Calculated telomere loss in aGVHD patients is 190 bp/wk, thereby massively exceeding physiological steady-state TL shortening rates such as in lymphocytes (∼50 bp/y). Our data support the hypothesis that increased compensatory proliferation following continued tissue damage can result in massive telomere loss in enterocytes of aGVHD patients. The present study introduces aGVHD-triggered increased cellular turnover and telomere loss with subsequent replicative exhaustion as a mechanism for refractory gut GVHD that is compatible with the long-term clinical aspect of the disease and provides a basis for stem cell protective therapies in the treatment of aGVHD.
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http://dx.doi.org/10.1182/blood-2015-03-633289DOI Listing
November 2015

Novel angiogenin mutants with increased cytotoxicity enhance the depletion of pro-inflammatory macrophages and leukemia cells ex vivo.

Cancer Immunol Immunother 2015 Dec 15;64(12):1575-86. Epub 2015 Oct 15.

Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, University Hospital RWTH Aachen, Pauwelsstr. 20, 52074, Aachen, Germany.

Immunotoxins are fusion proteins that combine a targeting component such as an antibody fragment or ligand with a cytotoxic effector component that induces apoptosis in specific cell populations displaying the corresponding antigen or receptor. Human cytolytic fusion proteins (hCFPs) are less immunogenic than conventional immunotoxins because they contain human pro-apoptotic enzymes as effectors. However, one drawback of hCFPs is that target cells can protect themselves by expressing endogenous inhibitor proteins. Inhibitor-resistant enzyme mutants that maintain their cytotoxic activity are therefore promising effector domain candidates. We recently developed potent variants of the human ribonuclease angiogenin (Ang) that were either more active than the wild-type enzyme or less susceptible to inhibition because of their lower affinity for the ribonuclease inhibitor RNH1. However, combining the mutations was unsuccessful because although the enzyme retained its higher activity, its susceptibility to RNH1 reverted to wild-type levels. We therefore used molecular dynamic simulations to determine, at the atomic level, why the affinity for RNH1 reverted, and we developed strategies based on the introduction of further mutations to once again reduce the affinity of Ang for RNH1 while retaining its enhanced activity. We were able to generate a novel Ang variant with remarkable in vitro cytotoxicity against HL-60 cells and pro-inflammatory macrophages. We also demonstrated the pro-apoptotic potential of Ang-based hCFPs on cells freshly isolated from leukemia patients.
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http://dx.doi.org/10.1007/s00262-015-1763-8DOI Listing
December 2015

A high BMI is a risk factor in younger patients with de novo acute myelogenous leukemia.

Eur J Haematol 2016 Jul 17;97(1):17-24. Epub 2015 Sep 17.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Overweight and obese patients have an increased risk to develop several malignancies and, additionally, body mass index (BMI) impacts on outcome in several solid tumors. However, little is known for AML. We analyzed a cohort of 3526 patients with AML treated in three prospective multicenter trials within the German Study Alliance Leukemia. In multivariate analyses, we identified BMI as an independent risk factor for both DFS (HR 1.014, P = 0.0217) and OS (HR 1.015, P < 0.0036). Interestingly, overweight and obesity seemed to be a risk factor predominantly in patients with de novo AML younger than 65 yr with intermediate risk and adverse cytogenetics. Overweight with a BMI ≥25 kg/m² best discriminated the worse outcome and led to an absolute reduction in long-term survival of 5-7% in the group of all younger patients (3-yr OS 39.9% vs. 47.3%; 10-yr OS 28.7% vs. 33.8%, P = 0.0002). Additionally, response to induction therapy was significantly reduced in these patients (76.9% vs. 82.8%, P < 0.0001). Thus, in younger patients with de novo AML, overweight and obesity are risk factors for impaired response to induction therapy, DFS and OS. This effect is, in part but not fully, explained by dose reduction such as dose-capping at a body surface area of 2 m².
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http://dx.doi.org/10.1111/ejh.12675DOI Listing
July 2016

Drugging the unfolded protein response in acute leukemias.

J Hematol Oncol 2015 Jul 16;8:87. Epub 2015 Jul 16.

Apoptosis Research Centre (ARC), National University of Ireland, Galway, Ireland.

The unfolded protein response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, is mediated by three major stress sensors IRE-1α, PERK, and ATF6α. Studies described the UPR as a critical network in selection, adaptation, and survival of cancer cells. While previous reviews focused mainly on solid cancer cells, in this review, we summarize the recent findings focusing on acute leukemias. We take into account the impact of the underlying genetic alterations of acute leukemia cells, the leukemia stem cell pool, and provide an outline on the current genetic, clinical, and therapeutic findings. Furthermore, we shed light on the important oncogene-specific regulation of individual UPR signaling branches and the therapeutic relevance of this information to answer the question if the UPR could be an attractive novel target in acute leukemias.
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http://dx.doi.org/10.1186/s13045-015-0184-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504168PMC
July 2015

The Fc-alpha receptor is a new target antigen for immunotherapy of myeloid leukemia.

Int J Cancer 2015 Dec 12;137(11):2729-38. Epub 2015 Jun 12.

Department of Experimental Medicine and Immunotherapy, Institute for Applied Medical Engineering, RWTH Aachen University Clinic, Aachen, Germany.

Antibody-based immunotherapy of leukemia requires the targeting of specific antigens on the surface of blasts. The Fc gamma receptor (CD64) has been investigated in detail, and CD64-targeting immunotherapy has shown promising efficacy in the targeted ablation of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML) and chronic myeloid leukemia cells (CML). Here we investigate for the first time the potential of FcαRI (CD89) as a new target antigen expressed by different myeloid leukemic cell populations. For specific targeting and killing, we generated a recombinant fusion protein comprising an anti-human CD89 single-chain Fragment variable and the well-characterized truncated version of the potent Pseudomonas aeruginosa exotoxin A (ETA'). Our novel therapeutic approach achieved in vitro EC50 values in range 0.2-3 nM depending on the applied stimuli, that is, interferon gamma or tumor necrosis factor alpha. We also observed a dose-dependent apoptosis-mediated cytotoxicity, which resulted in the elimination of up to 90% of the target cells within 72 hr. These findings were also confirmed ex vivo using leukemic primary cells from peripheral blood samples of three previously untreated patients. We conclude that CD89-specific targeting of leukemia cell lines can be achieved in vitro and that the efficient elimination of leukemic primary cells supports the potential of CD89-ETA' as a potent, novel immunotherapeutic agent.
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http://dx.doi.org/10.1002/ijc.29628DOI Listing
December 2015