Publications by authors named "Michael Lübbert"

190 Publications

Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin.

Blood 2021 Feb 17. Epub 2021 Feb 17.

Berlin Institute of Health (BIH), Berlin, Germany, Germany.

In the international randomized phase III RATIFY trial, the multi-kinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18-59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients on the midostaurin arm achieved protocol-specified complete remission (CR) and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD) positive AML who were entered on the RATIFY or the AMLSG 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD as well as whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative, but acquired mutations in signaling pathways (e.g. MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD-clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed suggesting either resistance mechanisms bypassing FLT3-inhibition or loss of midostaurin inhibitory activity due to inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD mutated AML under treatment with midostaurin in combination with intensive chemotherapy.
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http://dx.doi.org/10.1182/blood.2020007626DOI Listing
February 2021

Bisulfite-free epigenomics and genomics of single cells through methylation-sensitive restriction.

Commun Biol 2021 Feb 1;4(1):153. Epub 2021 Feb 1.

Department of Medicine I, Medical Center - University of Freiburg, Freiburg, Germany.

Single-cell multi-omics are powerful means to study cell-to-cell heterogeneity. Here, we present a single-tube, bisulfite-free method for the simultaneous, genome-wide analysis of DNA methylation and genetic variants in single cells: epigenomics and genomics of single cells analyzed by restriction (epi-gSCAR). By applying this method, we obtained DNA methylation measurements of up to 506,063 CpGs and up to 1,244,188 single-nucleotide variants from single acute myeloid leukemia-derived cells. We demonstrate that epi-gSCAR generates accurate and reproducible measurements of DNA methylation and allows to differentiate between cell lines based on the DNA methylation and genetic profiles.
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http://dx.doi.org/10.1038/s42003-021-01661-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851132PMC
February 2021

Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial.

Blood 2020 Dec;136(26):3041-3050

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.
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http://dx.doi.org/10.1182/blood.2020005998DOI Listing
December 2020

Genomic heterogeneity in core-binding factor acute myeloid leukemia and its clinical implication.

Blood Adv 2020 Dec;4(24):6342-6352

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact.
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http://dx.doi.org/10.1182/bloodadvances.2020002673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757000PMC
December 2020

Decitabine induces gene derepression on monosomic chromosomes: in vitro and in vivo effects in adverse-risk cytogenetics AML.

Cancer Res 2020 Nov 17. Epub 2020 Nov 17.

Department of Medicine I, Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany

Hypomethylating agents (HMA) have become the backbone of non-intensive AML/MDS treatment, primarily by virtue of their activity in patients with adverse genetics, e.g., monosomal karyotypes, often with losses on chromosome 7, 5 or 17. However, no comparable activity is observed with cytarabine (AraC), a cytidine analogue without DNA-hypomethylating properties. As evidence exists for compounding hypermethylation and gene silencing of hemizygous tumor suppressor genes (TSG), we thus hypothesized that this effect may preferentially be reversed by the HMA decitabine (DAC) and azacitidine (AZA). An unbiased RNA-seq approach was developed to interrogate DAC-induced transcriptome changes in AML cell lines with or without a deletion of chromosomes 7q, 5q or 17p. HMA treatment (DAC or AZA) preferentially upregulated several hemizygous TSG in this genomic region, significantly derepressing endogenous retrovirus (ERV)3-1 with promoter demethylation, enhanced chromatin accessibility, and increased H3K4me3 levels. DAC globally reactivated multiple transposable elements, with activation of the dsRNA sensor RIG-I and interferon regulatory factor (IRF)7. Induction of ERV3-1 and RIG-I mRNA was also observed during DAC treatment in vivo in serially sorted peripheral blood AML blasts. In patient-derived murine monosomal karyotype AML xenografts, DAC treatment resulted in superior survival rates compared to AraC. Collectively, these data demonstrate preferential gene derepression and ERV reactivation in AML with chromosomal deletions, providing a mechanistic explanation that supports the clinical observation of superiority of HMA over AraC in this difficult-to-treat patient group.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1430DOI Listing
November 2020

Survival Improvement over Time of 960 s-AML Patients Included in 13 EORTC-GIMEMA-HOVON Trials.

Cancers (Basel) 2020 Nov 11;12(11). Epub 2020 Nov 11.

GIGA-I3, Hematology, University of Liège, 4000 Liège, Belgium.

We report the outcomes of secondary acute myeloid leukemia (s-AML) patients included in one of 13 European Organisation for Research and Treatment of Cancer (EORTC) collaborative AML trials using intensive remission-induction chemotherapy. Among 8858 patients treated between May 1986 and January 2008, 960 were identified as having s-AML, either after MDS (cohort A; = 508), occurring after primary solid tumors or hematologic malignancies other than MDS (cohort B; = 361), or after non-malignant conditions or with a history of toxic exposure (cohort C; = 91). Median age was 64 years, 60 years and 61 years in cohort A, B and C, respectively. Among patients ≤60 years and classified in the cohorts A or B ( = 367), the 5-year overall survival (OS) rate was 28%. There was a systematic improvement in the 5-year OS rate over three time periods ( < 0.001): 7.7% (95% CI: 1.3-21.7%) for patients treated before 1990 (period 1: = 26), 23.3% (95% CI: 17.1-30.0%) for those treated between 1990 and 2000 (period 2: = 188) and 36.5% (95% CI: 28.7-44.3%) for those treated in 2000 or later (period 3: n = 153). In multivariate analysis, male gender (HR = 1.39; = 0.01), WBC ≥ 25 × 10/L (HR = 2.00; < 0.0001), age 46-60 years (HR = 1.65; < 0.001) and poor-risk cytogenetics (HR = 2.17; < 0.0001) were independently associated with shorter OS, while being treated during period 2 (HR = 0.50, = 0.003) or period 3 (HR = 0.43; = 0.0008). Having received high-dose cytarabine (HD-AraC) ( = 48) in the induction chemotherapy (HR = 0.54, = 0.012) was associated with a longer OS. In contrast, among patients >60 years of age ( = 502), the OS was dismal, and there was no improvement over time.
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http://dx.doi.org/10.3390/cancers12113334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697114PMC
November 2020

Hemolytic crisis in a patient treated with eculizumab for paroxysmal nocturnal hemoglobinuria possibly triggered by SARS-CoV-2 (COVID-19): a case report.

Ann Hematol 2021 Mar 10;100(3):841-842. Epub 2020 Nov 10.

Department of Nephrology, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1007/s00277-020-04318-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652905PMC
March 2021

Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans.

Sci Transl Med 2020 10;12(567)

Department of Internal Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany.

Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis. We found that T cells of patients relapsing with AML after allo-HCT exhibited reduced glycolysis and interferon-γ production. Functional studies in multiple mouse models of leukemia showed that leukemia-derived lactic acid (LA) interfered with T cell glycolysis and proliferation. Mechanistically, LA reduced intracellular pH in T cells, led to lower transcription of glycolysis-related enzymes, and decreased activity of essential metabolic pathways. Metabolic reprogramming by sodium bicarbonate (NaBi) reversed the LA-induced low intracellular pH, restored metabolite concentrations, led to incorporation of LA into the tricarboxylic acid cycle as an additional energy source, and enhanced graft-versus-leukemia activity of murine and human T cells. NaBi treatment of post-allo-HCT patients with relapsed AML improved metabolic fitness and interferon-γ production in T cells. Overall, we show that metabolic reprogramming of donor T cells is a pharmacological strategy for patients with relapsed AML after allo-HCT.
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http://dx.doi.org/10.1126/scitranslmed.abb8969DOI Listing
October 2020

Characterization of myelodysplastic syndromes progressing to acute lymphoblastic leukemia.

Ann Hematol 2021 Jan 16;100(1):63-78. Epub 2020 Jun 16.

Service and Central Laboratory of Hematology, Department of Oncology and Department of Laboratory Medicine and Pathology, Lausanne University Hospital (CHUV), Rue du Bugnon 46, Lausanne, CH-1011, Switzerland.

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases, with a variable probability of transformation into acute leukemia, which is, in the vast majority of cases, of myeloid lineage. Nevertheless, rare cases of acute lymphoblastic leukemia in patients with previously diagnosed MDS have been reported. We describe a series of 3 cases of MDS/CMML marked with evolution to acute lymphoblastic leukemia (ALL) and provide a comprehensive review of the 49 cases documented in the literature so far. These sporadic events have only been published as single-case reports or small series to date. Such atypical cases emphasize the possibility of major phenotypic switches arising at the leukemic stem cell (LSC) and/or early progenitor levels, as a consequence of epigenetic and genomic events driving these changes in the bone marrow niche.
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http://dx.doi.org/10.1007/s00277-020-04114-2DOI Listing
January 2021

Monosomal karyotype and chromosome 17p loss or TP53 mutations in decitabine-treated patients with acute myeloid leukemia.

Ann Hematol 2020 Jul 6;99(7):1551-1560. Epub 2020 Jun 6.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.

TP53 aberrations reportedly predict favorable responses to decitabine (DAC) in acute myeloid leukemia (AML). We evaluated clinical features and outcomes associated with chromosome 17p loss or TP53 gene mutations in older, unfit DAC-treated AML patients in a phase II trial. Of 178 patients, 25 had loss of 17p in metaphase cytogenetics; 24 of these had a complex (CK+) and 21 a monosomal karyotype (MK+). In analyses in all patients and restricted to CK+ and MK+ patients, 17p loss tended to associate with higher rates of complete remission (CR), partial remission (PR), or antileukemic effect (ALE). Despite favorable response rates, there was no significant OS difference between patients with or without loss of 17p in the entire cohort or in the CK+ and MK+ cohort. TP53 mutations were identified in eight of 45 patients with material available. Five of the eight TP53-mutated patients had 17p loss. TP53-mutated patients had similar rates of CR/PR/ALE but shorter OS than those with TP53 wild type (P = 0.036). Moreover, patients with a subclone based on mutation data had shorter OS than those without (P = 0.05); only one patient with TP53-mutated AML had a subclone. In conclusion, 17p loss conferred a favorable impact on response rates, even among CK+ and MK+ patients that however could not be maintained. The effect of TP53 mutations appeared to be different; however, patient numbers were low. Future research needs to further dissect the impact of the various TP53 aberrations in HMA-based combination therapies. The limited duration of favorable responses to HMA treatment in adverse-risk genetics AML should prompt physicians to advance allografting for eligible patients in a timely fashion.
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http://dx.doi.org/10.1007/s00277-020-04082-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316846PMC
July 2020

Netboost: Boosting-supported Network Analysis Improves High-Dimensional Omics Prediction in Acute Myeloid Leukemia and Huntington's Disease.

IEEE/ACM Trans Comput Biol Bioinform 2020 May 3;PP. Epub 2020 May 3.

State-of-the art selection methods fail to identify weak but cumulative effects of features found in many high-dimensional omics datasets. Nevertheless, these features play an important role in certain diseases. We present Netboost, a three-step dimension reduction technique. First, a boosting-based filter is combined with the topological overlap measure to identify the essential edges of the network. Second, sparse hierarchical clustering is applied on the selected edges to identify modules and finally module information is aggregated by the first principal components. We demonstrate the application of the newly developed Netboost in combination with CoxBoost for survival prediction of DNA methylation and gene expression data from 180 acute myeloid leukemia (AML) patients and show, based on cross-validated prediction error curve estimates, its prediction superiority over variable selection on the full dataset as well as over an alternative clustering approach. The identified signature related to chromatin modifying enzymes was replicated in an independent dataset, the phase II AMLSG 12-09 study. In a second application we combine Netboost with Random Forest classification and improve the disease classification error in RNA-sequencing data of Huntington's disease mice. Netboost is a freely available Bioconductor R package for dimension reduction and hypothesis generation in high-dimensional omics applications.
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http://dx.doi.org/10.1109/TCBB.2020.2983010DOI Listing
May 2020

Oncogenic Kras causes myeloproliferation via NLRP3 inflammasome activation.

Nat Commun 2020 04 3;11(1):1659. Epub 2020 Apr 3.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Oncogenic Ras mutations occur in various leukemias. It was unclear if, besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the disease. Here, we identify a functional link between oncogenic Kras and NLRP3 inflammasome activation in murine and human cells. Mice expressing active Kras in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in Kras mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, Kras-RAC1 activation induces reactive oxygen species (ROS) production causing NLRP3 inflammasome-activation. In agreement with our observations in mice, patient-derived myeloid leukemia cells exhibit KRAS/RAC1/ROS/NLRP3/IL-1β axis activity. Our findings indicate that oncogenic KRAS not only act via its canonical oncogenic driver function, but also enhances the activation of the pro-inflammatory RAC1/ROS/NLRP3/IL-1β axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies.
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http://dx.doi.org/10.1038/s41467-020-15497-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125138PMC
April 2020

Nitroreductase-Mediated Release of Inhibitors of Lysine-Specific Demethylase 1 (LSD1) from Prodrugs in Transfected Acute Myeloid Leukaemia Cells.

Chembiochem 2020 08 27;21(16):2329-2347. Epub 2020 Apr 27.

Department of Chemistry and Pharmacy, University of Freiburg, Institute of Pharmaceutical Sciences, Albertstrasse 25, 79104, Freiburg, Germany.

Lysine-specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site-specific LSD1 inhibition, we developed an enzyme-prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell line THP1-NTR . The cellular activity of the NTR was proven with a new luminescent NTR probe. We synthesised a diverse set of nitroaromatic prodrugs that by design do not affect LSD1 and are reduced by the NTR to release an active LSD1 inhibitor. The emerging side products were differentially analysed using negative controls, thereby revealing cytotoxic effects. The 2-nitroimidazolyl prodrug of a potent LSD1 inhibitor emerged as one of the best prodrug candidates with a pronounced selectivity window between wild-type and transfected THP1 cells. Our prodrugs are selectively activated and release the LSD1 inhibitor locally, proving their suitability for future targeting approaches.
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http://dx.doi.org/10.1002/cbic.202000138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497180PMC
August 2020

Distinct bone marrow morphologic features discriminate myelodysplastic syndromes patients with and without an early platelet response to decitabine.

Br J Haematol 2020 06 24;189(5):e194-e197. Epub 2020 Mar 24.

Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1111/bjh.16615DOI Listing
June 2020

Gemtuzumab Ozogamicin in -Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09-09 Phase III Study.

J Clin Oncol 2020 02 18;38(6):623-632. Epub 2019 Dec 18.

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

Purpose: High CD33 expression in acute myeloid leukemia (AML) with mutated provides a rationale for the evaluation of gemtuzumab ozogamicin (GO) in this AML entity. We conducted a randomized trial to evaluate GO in combination with intensive induction and consolidation therapy in -mutated AML.

Patients And Methods: Between May 2010 and September 2017, patients ≥ 18 years old and considered eligible for intensive therapy were randomly assigned up front for induction therapy with idarubicin, cytarabine, etoposide, and all--retinoic acid with or without GO. The early ( = .02) primary end point of event-free survival (EFS) was evaluated 6 months after completion of patient recruitment.

Results: Five hundred eighty-eight patients were randomly assigned (standard arm, n = 296; GO arm, n = 292). EFS in the GO arm was not significantly different compared with that in the standard arm (hazard ratio, 0.83; 95% CI, 0.65 to 1.04; = .10). The early death rate during induction therapy was 10.3% in the GO arm and 5.7% in the standard arm ( = .05). Causes of death in both arms were mainly infections. The cumulative incidence of relapse (CIR) in patients achieving a complete remission (CR) or CR with incomplete hematologic recovery (CRi) was significantly reduced in the GO arm compared with the standard arm ( = .005), with no difference in the cumulative incidence of death ( = .80). Subgroup analysis revealed a significant beneficial effect of GO in female, younger (≤ 70 years), and internal tandem duplication-negative patients with respect to EFS and CIR.

Conclusion: The trial did not meet its early primary end point of EFS, mainly as a result of a higher early death rate in the GO arm. However, in patients achieving CR/CRi after induction therapy, significantly fewer relapses occurred in the GO compared with the standard arm.
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http://dx.doi.org/10.1200/JCO.19.01406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030890PMC
February 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

Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): results from the AML Study Group.

Blood 2019 11;134(19):1608-1618

Klinik für Innere Medizin III, Universitätsklinikum Ulm, Ulm, Germany.

We performed serial measurable residual disease (MRD) monitoring in bone marrow (BM) and peripheral blood (PB) samples of 155 intensively treated patients with RUNX1-RUNX1T1+ AML, using a qRT-PC-based assay with a sensitivity of up to 10-6. We assessed both reduction of RUNX1-RUNX1T1 transcript levels (TLs) and achievement of MRD negativity (MRD-) for impact on prognosis. Achievement of MR2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR3.0 after treatment cycle 2 were significantly associated with a reduced risk of relapse (P = .034 and P = .028, respectively). After completion of therapy, achievement of MRD- in both BM and PB was an independent, favorable prognostic factor in cumulative incidence of relapse (4-year cumulative incidence relapse: BM, 17% vs 36%, P = .021; PB, 23% vs 55%, P = .001) and overall survival (4-year overall survival rate BM, 93% vs 70%, P = .007; PB, 87% vs 47%, P < .0001). Finally, during follow-up, serial qRT-PCR analyses allowed prediction of relapse in 77% of patients exceeding a cutoff value of 150 RUNX1-RUNX1T1 TLs in BM, and in 84% of patients exceeding a value of 50 RUNX1-RUNX1T1 TLs in PB. The KIT mutation was a significant factor predicting a lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TLs during treatment. Virtually all relapses occurred within 1 year after the end of treatment, with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this time period. Based on our data, we propose a refined practical guideline for MRD assessment in RUNX1-RUNX1T1+ AML.
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http://dx.doi.org/10.1182/blood.2019001425DOI Listing
November 2019

Low-dose melphalan in elderly patients with relapsed or refractory acute myeloid leukemia: A well-tolerated and effective treatment after hypomethylating-agent failure.

Leuk Res 2019 10 10;85:106192. Epub 2019 Aug 10.

Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Frankfurt, Germany.

Relapsed or refractory (R/R) disease remains challenging in acute myeloid leukemia (AML), especially in elderly patients not considered eligible for intensive treatment options. We retrospectively evaluated the safety and efficacy of low-dose melphalan (LD-Mel) in a multicenter analysis in patients over 65 years with R/R AML, who previously had received ≥1 non-curative treatment line. The study included 31 patients (median age 77 years) with 1-4 previous treatment lines. Three patients (9.7%) achieved a complete remission. Two patients (6.5%) achieved a partial remission, nine patients (29.0%) had disease stabilization with reduction of peripheral or bone marrow blast burden, resulting in an overall response rate of 16.1% and 45.2% achieved clinical benefit. Responders showed a significantly longer median overall survival than non-responders (16.3 vs. 2.3 months, p < 0.001). Multivariate analysis identified complex karyotype as the only risk factor associated with inferior survival (p < 0.001), whereas prior treatment with hypomethylating agents (HMAs) in 25 of 31 patients was associated with superior OS, regardless of prior response to HMAs (p = 0.03). LD-Mel was well tolerated, with mild myelosuppressive side effects. Conclusively, LD-Mel is an effective treatment option in elderly patients with R/R AML, particularly after HMA therapy and in the absence of a complex karyotype.
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http://dx.doi.org/10.1016/j.leukres.2019.106192DOI Listing
October 2019

Clonal hematopoiesis of indeterminate potential in older patients having received an allogeneic stem cell transplantation from young donors.

Bone Marrow Transplant 2020 03 30;55(3):665-668. Epub 2019 May 30.

Department of Medicine I, Medical Center - University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1038/s41409-019-0575-4DOI Listing
March 2020

Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions.

Haematologica 2019 10 2;104(10):1935-1949. Epub 2019 May 2.

Department of Pathology, Hematopathology Unit and James P Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between 'normal', pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.
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http://dx.doi.org/10.3324/haematol.2019.222059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886439PMC
October 2019

Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes.

Genes Chromosomes Cancer 2019 10 30;58(10):689-697. Epub 2019 Apr 30.

Clinics of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.

The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the new comprehensive cytogenetic scoring system for MDS, chromosome 7 anomalies are no longer generally assigned to poor risk features but are thoroughly separated. However, der(1;7)(q10;p10), hereinafter der(1;7), is merged into the group labeled "any other single" and belongs to the intermediate risk group, just by definition due to lack of adequate clinical data. The aim of our international collaborative was to clarify the "real" prognostic impact of der(1;7) on a homogenous and well-documented data base. We performed detailed analysis of 63 MDS patients with isolated der(1;7) constituting the largest cohort hitherto reported. Furthermore, clinical data are compared with those of patients with isolated del(7q) and isolated monosomy 7. Median overall survival (OS) of patients with der(1;7) is 26 months (hazard ratio (HR) 0.91 for del(7q) vs der(1;7) and 2.53 for monosomy 7 vs der(1;7)). The der(1;7) is associated with profound thrombocytopenia most probably causing the reduced OS which is in striking contrast to the low risk for AML transformation (HR 3.89 for del(7q) vs der(1;7) and 5.88 for monosomy 7 vs der(1;7)). Molecular karyotyping indicates that der(1;7) is generated in a single step during mitosis and that a chromosomal imbalance rather than a single disrupted gene accounts for malignancy. Thus, the current cytogenetic scoring system assigning isolated der(1;7) to the intermediate risk group is now confirmed by a sufficient data set.
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http://dx.doi.org/10.1002/gcc.22760DOI Listing
October 2019

Can we predict responsiveness to hypomethylating agents in AML?

Semin Hematol 2019 04 27;56(2):118-124. Epub 2019 Feb 27.

Department of Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine and Medical Center-University of Freiburg, Freiburg, Germany; German Cancer Research Consortium (DKTK), Freiburg, Germany. Electronic address:

DNA-hypomethylating agents (HMAs) were developed as nonintensive treatment alternatives to standard chemotherapy in older, unfit patients with acute myeloid leukemia and myelodysplastic syndrome. Given their distinct effects on the methylome and transcriptome of malignant cells compared to cytarabine (Ara-C) and other cytotoxic drugs not inhibiting DNA methyltransferases, it is of great interest to define their specific clinical ``signature.'' Here, we present and discuss clinical, genetic, and epigenetic predictors of responsiveness to HMAs. Indeed, mounting evidence supports the notion that HMAs are not "just another kind of low-dose Ara-C." Not only patient factors (age, performance status, comorbidities, etc.), blast counts, and early platelet response, but also adverse genetics (monosomal karyotype and/or a TP53 mutation) have predictive potential. Given the surprising-and initially counterintuitive-responses observed in patients with the latter features, these are subject to mechanistic studies to elucidate their as yet unresolved interaction with HMAs. Finally, other potential biomarkers for HMA response such as elevated fetal hemoglobin might also contribute to overcome the present challenges in predicting responsiveness to HMAs.
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http://dx.doi.org/10.1053/j.seminhematol.2019.02.001DOI Listing
April 2019

10-day vs 5-day decitabine: equivalence cannot be concluded.

Lancet Haematol 2019 04;6(4):e177

Department of Hematology, Freiburg University Hospital, Freiburg, Germany.

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http://dx.doi.org/10.1016/S2352-3026(19)30024-9DOI Listing
April 2019

LSD1 inhibition by tranylcypromine derivatives interferes with GFI1-mediated repression of PU.1 target genes and induces differentiation in AML.

Leukemia 2019 06 24;33(6):1411-1426. Epub 2019 Jan 24.

Department of Medicine II, Hematology/Oncology, Goethe University, Frankfurt/Main, Germany.

LSD1 has emerged as a promising epigenetic target in the treatment of acute myeloid leukemia (AML). We used two murine AML models based on retroviral overexpression of Hoxa9/Meis1 (H9M) or MN1 to study LSD1 loss of function in AML. The conditional knockout of Lsd1 resulted in differentiation with both granulocytic and monocytic features and increased ATRA sensitivity and extended the survival of mice with H9M-driven AML. The conditional knockout led to an increased expression of multiple genes regulated by the important myeloid transcription factors GFI1 and PU.1. These include the transcription factors GFI1B and IRF8. We also compared the effect of different irreversible and reversible inhibitors of LSD1 in AML and could show that only tranylcypromine derivatives were capable of inducing a differentiation response. We employed a conditional knock-in model of inactive, mutant LSD1 to study the effect of only interfering with LSD1 enzymatic activity. While this was sufficient to initiate differentiation, it did not result in a survival benefit in mice. Hence, we believe that targeting both enzymatic and scaffolding functions of LSD1 is required to efficiently treat AML. This finding as well as the identified biomarkers may be relevant for the treatment of AML patients with LSD1 inhibitors.
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http://dx.doi.org/10.1038/s41375-018-0375-7DOI Listing
June 2019

Biology-Driven Approaches to Prevent and Treat Relapse of Myeloid Neoplasia after Allogeneic Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 04 15;25(4):e128-e140. Epub 2019 Jan 15.

Department of Internal Medicine IV, Hematology and Oncology, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany.

The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.016DOI Listing
April 2019

Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with -ITD.

Blood 2019 02 18;133(8):840-851. Epub 2018 Dec 18.

Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany.

Patients with acute myeloid leukemia (AML) and a internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed -ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval [CI], 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio [HR], 0.58; 95% CI, 0.48-0.70; < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.
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http://dx.doi.org/10.1182/blood-2018-08-869453DOI Listing
February 2019