Publications by authors named "Ulrich Germing"

262 Publications

Impaired formation of neutrophil extracellular traps (NETs) in patients with myelodysplastic syndrome.

Blood Adv 2021 Oct 15. Epub 2021 Oct 15.

Heinrich Heine University Düsseldorf, Duesseldorf, Germany.

Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA and histone proteins, which bind pathogens. We investigated NET formation in 12 patients with MDS and 15 age-adjusted normal controls after stimulation with phorbol-12-myristate-13-acetate (PMA). Histones and neutrophil elastase were visualized by immuno-staining. Since NET formation is triggered by reactive oxygen species (ROS), mainly produced by NADPH-oxidase and myeloperoxidase (MPO), ROS were analysed by flow cytometry using hydroethidine (HE), 3`-(p-aminophenyl) fluorescein (APF) and 3`-(hydroxyphenyl) fluorescein (HPF). On fluorescence microscopy, PMA-stimulated MDS neutrophils generated fewer NETs than controls (stimulated increase from 17% to 67% versus 17% to 85%) (p=0.02) and showed less cellular swelling (p=0.04). The decrease in mean fluorescence intensity (MFI) of DAPI, indicating chromatin decondensation, was significantly less in MDS neutrophils than controls (DMFI 3467 vs. DMFI 4687, p=0.03). In addition, the decrease in MFI for FITC, indicating release of neutrophil elastase from cytoplasmic granules, was diminished in patients with MDS (p=0.00002). On flow cytometry, less cell swelling after PMA (p=0.02) and a smaller decrease in granularity after H2O2 stimulation (p=0.002) were confirmed. PMA-stimulated ROS production and oxidative burst activity did not reveal significant differences between MDS and controls. However, Inhibition of MPO activity was more easily achieved in patients with MDS (p=0.01), corroborating the notion of a partial MPO defect. We conclude that NET formation is significantly impaired in MDS neutrophils. Although we found abnormalities of MPO-dependent generation of HOCl, impaired ROS production may not be the only cause of deficient NETosis in MDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021005721DOI Listing
October 2021

Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia.

Blood Cancer J 2021 Oct 4;11(10):164. Epub 2021 Oct 4.

Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Medical Faculty, Heinrich Heine-University, Duesseldorf, Germany.

To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26-80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response (p = 0.0001), while pretreatment with hypomethylating agents (p = 0.02) and adverse European LeukemiaNet 2017 genetic risk (p < 0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients (p = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41408-021-00558-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490353PMC
October 2021

Germline variants in DNA repair genes, including BRCA1/2, may cause familial myeloproliferative neoplasms.

Blood Adv 2021 09;5(17):3373-3376

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

The molecular causes of myeloproliferative neoplasms (MPNs) have not yet been fully elucidated. Approximately 7% to 8% of the patients carry predisposing genetic germline variants that lead to driver mutations, which enhance JAK-STAT signaling. To identify additional predisposing genetic germline variants, we performed whole-exome sequencing in 5 families, each with parent-child or sibling pairs affected by MPNs and carrying the somatic JAK2 V617F mutation. In 4 families, we detected rare germline variants in known tumor predisposition genes of the DNA repair pathway, including the highly penetrant BRCA1 and BRCA2 genes. The identification of an underlying hereditary tumor predisposition is of major relevance for the individual patients as well as for their families in the context of therapeutic options and preventive care. Two patients with essential thrombocythemia or polycythemia vera experienced progression to acute myeloid leukemia, which may suggest a high risk of leukemic transformation in these familial MPNs. Our study demonstrates the relevance of genetic germline diagnostics in elucidating the causes of MPNs and suggests novel therapeutic options (eg, PARP inhibitors) in MPNs. Furthermore, we uncover a broader tumor spectrum upon the detection of a germline mutation in genes of the DNA repair pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525218PMC
September 2021

A predictive algorithm using clinical and laboratory parameters may assist in ruling out and in diagnosing MDS.

Blood Adv 2021 08;5(16):3066-3075

Department of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

We present a noninvasive Web-based app to help exclude or diagnose myelodysplastic syndrome (MDS), a bone marrow (BM) disorder with cytopenias and leukemic risk, diagnosed by BM examination. A sample of 502 MDS patients from the European MDS (EUMDS) registry (n > 2600) was combined with 502 controls (all BM proven). Gradient-boosted models (GBMs) were used to predict/exclude MDS using demographic, clinical, and laboratory variables. Area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were used to evaluate the models, and performance was validated using 100 times fivefold cross-validation. Model stability was assessed by repeating its fit using different randomly chosen groups of 502 EUMDS cases. AUC was 0.96 (95% confidence interval, 0.95-0.97). MDS is predicted/excluded accurately in 86% of patients with unexplained anemia. A GBM score (range, 0-1) of less than 0.68 (GBM < 0.68) resulted in a negative predictive value of 0.94, that is, MDS was excluded. GBM ≥ 0.82 provided a positive predictive value of 0.88, that is, MDS. The diagnosis of the remaining patients (0.68 ≤ GBM < 0.82) is indeterminate. The discriminating variables: age, sex, hemoglobin, white blood cells, platelets, mean corpuscular volume, neutrophils, monocytes, glucose, and creatinine. A Web-based app was developed; physicians could use it to exclude or predict MDS noninvasively in most patients without a BM examination. Future work will add peripheral blood cytogenetics/genetics, EUMDS-based prospective validation, and prognostication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020004055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405190PMC
August 2021

Influence of platelet count at diagnosis and during the course of disease on prognosis in MDS patients.

Ann Hematol 2021 Oct 29;100(10):2575-2584. Epub 2021 Jul 29.

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

Thrombocytopenia at diagnosis and platelet drop within the first 6 months have an adverse effect on prognosis of MDS patients. We therefore were interested in the association and impact on prognosis of morphologic findings of megakaryocytes and platelets with platelet count at diagnosis, bleeding complications, and the drop of platelets during the course of disease. This retrospective analysis was based on 334 MDS patients from the Duesseldorf MDS registry that were followed up for blood counts, bleeding, transfusion dependency, and AML evolution and correlated with morphology of the megakaryocytes and platelets. Thrombocytopenia was found more frequently in higher risk MDS and was associated with hypocellularity of the megakaryocytes in the bone marrow. Signs of bleeding were present at diagnosis in 14% and occurred during the disease in 48% of all MDS patients. Death due to bleeding was ranked third behind infections and AML. A decrement of platelets during the first 6 months was associated with an inferior overall survival of 21 vs. 49 months and with a higher cumulative 2-year AML rate of 22.2% vs. 8.3% (p = 0.001). In a multivariate analysis, besides bone marrow blasts and karyotype, decreasing platelets were also associated with an inferior outcome. Signs of bleeding are present in a relevant number of MDS patients and account for significant morbidity and mortality in MDS. We could demonstrate the prognostic importance of decreasing platelets during the course of disease in all MDS patients, identifying patients at higher risk for death or AML progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04608-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440262PMC
October 2021

Guidelines for Myelodysplastic Syndromes: Converting Evidence into Action?

Int J Environ Res Public Health 2021 07 18;18(14). Epub 2021 Jul 18.

Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, 40225 Düsseldorf, Germany.

The heterogeneous group of myelodysplastic syndromes (MDS) needs an individualized and patient-tailored therapeutic approach. Consensus-based guidelines for diagnosis and treatment provide a basis for clinical decision making. MDS guidelines are issued by expert panels. Our main objective was to examine how guidelines influence patients' adherence to expert recommendations and how they ensure healthcare quality. To approach this question, we reviewed the most common guidelines for diagnosing and treating MDS in adult patients. Furthermore, we critically looked at quality indicators for everyday practice and studied adherence in an everyday outpatient setting. Finally, we also paid close attention to patient-reported outcome measures and studied how they are used as endpoints in clinical trials. We can conclude that the combination of evidence-based diagnostic tools, standardized treatment recommendations, and patient-centered shared decision making will eventually lead to a healthcare standard that will significantly improve outcomes in adult patients with MDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18147629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306017PMC
July 2021

Luspatercept as a therapy for myelodysplastic syndromes with ring sideroblasts.

Expert Rev Hematol 2021 Jun 30;14(6):509-516. Epub 2021 Jun 30.

Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany.

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell diseases characterized by cell dysplasia, ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). The median age of 75 years at diagnosis is associated with the presence of comorbidities, which preclude intensive therapies like allogeneic hematopoietic stem cell transplantation in most MDS patients. Risk stratification using the (Revised) International Prognostic Scoring System (IPSS/IPSS-R) is necessary to plan individualized treatment.

Areas Covered: Luspatercept (ACE-536), a specific activin receptor fusion protein, promotes late-stage erythropoiesis. Two clinical trials, PACE-MDS (phase 2) and MEDALIST (phase 3), yielded positive results in terms of improved hemoglobin levels and loss of transfusion dependence, with hardly any side effects. A phase 3 trial to compare luspatercept to ESAs (COMMANDS study) is ongoing.

Expert Opinion: Luspatercept is a promising alternative to ESAs for a subset of transfusion-dependent patients with lower risk MDS, namely those with a sideroblastic phenotype who are either not suitable for or have already failed erythropoietin-based treatment. The favorable safety profile and convenient subcutaneous administration every 3 weeks are more conducive to patients' quality of life than chronic red blood cell transfusion therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17474086.2021.1947791DOI Listing
June 2021

Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells.

Stem Cells 2021 Sep 20;39(9):1270-1284. Epub 2021 May 20.

Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.

Acute myeloid leukemia (AML) is characterized by an expansion of leukemic cells and a simultaneous reduction of normal hematopoietic precursors in the bone marrow (BM) resulting in hematopoietic insufficiency, but the underlying mechanisms are poorly understood in humans. Assuming that leukemic cells functionally inhibit healthy CD34+ hematopoietic stem and progenitor cells (HSPC) via humoral factors, we exposed healthy BM-derived CD34+ HSPC to cell-free supernatants derived from AML cell lines as well as from 24 newly diagnosed AML patients. Exposure to AML-derived supernatants significantly inhibited proliferation, cell cycling, colony formation, and differentiation of healthy CD34+ HSPC. RNA sequencing of healthy CD34+ HSPC after exposure to leukemic conditions revealed a specific signature of genes related to proliferation, cell-cycle regulation, and differentiation, thereby reflecting their functional inhibition on a molecular level. Experiments with paired patient samples showed that these inhibitory effects are markedly related to the immunomagnetically enriched CD34+ leukemic cell population. Using PCR, ELISA, and RNA sequencing, we detected overexpression of TGFβ1 in leukemic cells on the transcriptional and protein level and, correspondingly, a molecular signature related to TGFβ1 signaling in healthy CD34+ HSPC. This inhibitory effect of TGFβ1 on healthy hematopoiesis was functionally corrobated and could be pharmacologically reverted by SD208, an inhibitor of TGFβ receptor 1 signaling. Overall, these data indicate that leukemic cells induce functional inhibition of healthy CD34+ HSPC, at least in part, through TGFβ1, suggesting that blockage of this pathway may improve hematopoiesis in AML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/stem.3387DOI Listing
September 2021

Impact of age on the cumulative risk of transformation in patients with chronic myelomonocytic leukaemia.

Eur J Haematol 2021 Aug 1;107(2):265-274. Epub 2021 Jun 1.

Department of Internal Medicine V with Hematology, Oncology and Palliative Medicine, Hospital Hietzing, Vienna, Austria.

In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age-related groups: <60 years, 60-79 years and ≥80 years, showed a significantly lower risk of transformation at higher age by competing risk analysis, with a 4-year risk of 39%, 23% and 13%, respectively (P < .0001). The lower probability of transformation was associated with a lower percentage of blast cells in the peripheral blood (PB) of older patients. Furthermore, we provide a simple score based on age, PB blasts and platelet counts that allowed us to define subgroups of CMML patients with a different cumulative transformation risk, including a low-risk group with a transformation risk of only 5%. Our findings may facilitate reasonable treatment decisions in elderly patients with CMML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480146PMC
August 2021

Eligibility for clinical trials is unsatisfactory for patients with myelodysplastic syndromes, even at a tertiary referral center.

Leuk Res 2021 09 11;108:106611. Epub 2021 May 11.

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

Participation in clinical trials may allow patients with MDS to gain access to therapies not otherwise available. However, access is limited by strict inclusion and exclusion criteria, reflecting academic or regulatory questions addressed by the respective studies. We performed a simulation in order to estimate the average proportion of MDS patients eligible for participation in a clinical trial. The simulation drew upon 1809 patients in the Düsseldorf MDS Registry whose clinical data allowed eligibility screening for a wide range of clinical trials. This cohort was assumed to be alive and available for study participation. The simulation also posited that all MDS trials (n = 47) conducted in our center between 1987 and 2016 were open for recruitment. In addition, study activities in the year 2016 were analyzed to determine the proportion of patients eligible for at least one of the 9 MDS trials open at that time. On average, each clinical trial was suitable for about 18 % of patients in the simulation cohort. Conversely, 34 % of the patients were eligible for at least one of the 9 clinical studies in 2016. Inclusion/exclusion criteria of studies initiated by the pharmaceutical industry excluded more than twice the fraction of patients compared with investigator initiated trials (potential inclusion of 10 % vs. 21 %, respectively). Karyotype (average exclusion rate 58 %), comorbidities (40 %), and prior therapies (55 %) were the main reasons for exclusion. We suggest that in- and exclusion criteria should be less restrictive, in order to meet the needs of the real-life population of elderly MDS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.leukres.2021.106611DOI Listing
September 2021

Prognostic impact of pretransplant measurable residual disease assessed by peripheral blood WT1-mRNA expression in patients with AML and MDS.

Eur J Haematol 2021 Aug 27;107(2):283-292. Epub 2021 May 27.

Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Medical Faculty, Heinrich Heine - University, Duesseldorf, Germany.

Objective: As peripheral blood (PB) Wilm's Tumor 1 (WT1)-mRNA expression is established as MRD-marker during conventional AML chemotherapy, impact of pretransplant WT1 expression remains unclear. Therefore, we aimed to assess prognostic impact of pretransplant WT1 expression on post-transplant outcome in patients with AML/MDS.

Methods: In 64 AML/MDS patients, pretransplant WT1 expression was retrospectively analyzed using a standardized assay offering high sensitivity, specificity, and a validated cut-off. Patients were divided into three groups determined by pretransplant remission and WT1 expression. Post-transplant outcome of these groups was compared regarding cumulative incidence of relapse (CIR), relapse-free (RFS), and overall survival (OS).

Results: Pretransplant forty-six patients (72%) showed hematologic remission, including 21 (46%) MRD-negative and 25 (54%) MRD-positive patients indicated by WT1 expression, while 18 refractory patients (28%) showed active disease. Two-year estimates of post-transplant CIR, RFS, and OS were similar in MRD-positive (61%, 37%, 54%) and refractory patients (70%, 26%, 56%), but significantly inferior compared with MRD-negative patients (10%, 89%, 90%). After multivariable adjustment, pretransplant MRD negativity measured by WT1 expression retained its prognostic impact on CIR (P = .008), RFS (P = .005), and OS (P = .049).

Conclusions: PB WT1 expression represents a useful method to estimate pretransplant MRD, which is highly predictable for post-transplant outcome and may help improving peri-transplant management in AML/MDS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13664DOI Listing
August 2021

Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q).

Ann Hematol 2021 Jun 27;100(6):1463-1471. Epub 2021 Apr 27.

Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.

Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00277-021-04492-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116243PMC
June 2021

Outcomes of patients with chronic myelomonocytic leukaemia treated with non-curative therapies: a retrospective cohort study.

Lancet Haematol 2021 Feb;8(2):e135-e148

Hematology Department, Vall d'Hebron Hospital Universitari, Experimental Hematology, Vall d'Hebron Institute of Oncology, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

Background: Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments.

Methods: For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, ≥20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytic leukaemia-Specific Prognostic Scoring System (CPSS). Patients were grouped by first received treatment with either hydroxyurea, hypomethylating agents, or intensive chemotherapy, and stratified by risk according to blast count, French-American-British subtype, CPSS, WHO 2016 subtype, and the eligibility criteria of the DACOTA trial (NCT02214407).

Findings: 949 patients diagnosed with chronic myelomonocytic leukaemia between April 13, 1981, and Oct 26, 2018, were included. Median follow-up was 23·4 months (IQR 11·5-42·3) from diagnosis and 16·2 months (6·6-31·6) from start of first-line treatment. 412 (43%) of 949 patients received hypomethylating agents as first treatment, 391 (41%) hydroxyurea, and 83 (9%) intensive chemotherapy. Adjusted median overall survival for patients treated with hydroxyurea versus hypomethylating agents was 15·6 months (95% CI 13·1-17·3) versus 20·7 months (17·9-23·4); hazard ratio (HR) 1·39 (1·17-1·65; p=0·0002) and 14·0 months (9·8-17·2) versus 20·7 months (17·9-23·4; HR 1·55 [1·16-2·05]; p=0·0027) for those treated with intensive chemotherapy versus hypomethylating agents. In patients with myeloproliferative chronic myelomonocytic leukaemia (myeloproliferative CMML), median overall survival was 12·6 months (10·7-15·0) versus 17·6 months (14·8-21·5; HR 1·38 [1·12-1·70]; p=0·0027) for patients treated with hydroxyurea versus hypomethylating agents, and 12·3 months (8·4-16·6) versus 17·6 months (14·8-21·5; HR 1·44 [1·02-2·03]; p=0·040) for intensive chemotherapy versus hypomethylating agents. Hypomethylating agents did not confer an overall survival advantage for patients classified as having lower-risk disease (ie, myelodysplastic chronic myelomonocytic leukaemia with <10% blasts, CMML-0, or lower-risk CPSS).

Interpretation: These data suggest hypomethylating agents as the preferred therapy for patients with higher-risk chronic myelomonocytic leukaemia and those with myeloproliferative CMML. Our findings also suggest that CPSS is a valuable tool to identify patients who are most likely to benefit from hypomethylating agents. Further evidence from prospective cohorts would be desirable.

Funding: The Austrian Group for Medical Tumor Therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-3026(20)30374-4DOI Listing
February 2021

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

J Clin Oncol 2021 01 27;39(1):48-56. Epub 2020 Oct 27.

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

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

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

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

Conclusion: Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.01895DOI Listing
January 2021

Long-Term Survival Benefit after Allogeneic Hematopoietic Cell Transplantation for Chronic Myelomonocytic Leukemia.

Transplant Cell Ther 2021 01 9;27(1):95.e1-95.e4. Epub 2020 Oct 9.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients age ≤70 years at diagnosis who underwent allo-HCT (n = 119) compared with those who did not (n = 142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower risk (CPSS low/intermediate-1) or higher risk (intermediate-2/high) showed significantly improved outcomes after transplantation in higher-risk patients, with a 37% reduced hazard for death. However, although higher CPSS was associated with worse outcomes in the nontransplantation group, the score was of limited utility for post-transplantation risk stratification. This study may provide further support for the potentially beneficial role of allo-HCT in terms of long-term survival in higher-risk patients but also underscores the need for transplantation-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of patients with CMML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2020.10.007DOI Listing
January 2021

Influence of somatic mutations and pretransplant strategies in patients allografted for myelodysplastic syndrome or secondary acute myeloid leukemia.

Am J Hematol 2021 01 30;96(1):E15-E17. Epub 2020 Oct 30.

Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Medical Faculty, Heinrich Heine - University, Duesseldorf, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.26013DOI Listing
January 2021

Wilm's Tumor 1-guided preemptive treatment with hypomethylating agents for molecular relapse of AML and MDS after allogeneic transplantation.

Bone Marrow Transplant 2021 02 2;56(2):442-450. Epub 2020 Sep 2.

Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf, Medical Faculty, Heinrich Heine-University, Duesseldorf, Germany.

Hypomethylating agents (HMA) for relapsed acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) after allogeneic transplantation (allo-SCT) are most effective when used at the stage of molecular relapse. As Wilm's Tumor 1 (WT1)- expression has proven to serve as broadly applicable, sensitive and specific minimal residual disease (MRD) marker, we measured WT1-expression in 35 AML and MDS patients using a standardized assay for the guidance of therapy with HMA and donor lymphocyte infusions (DLI). Molecular relapse was detected in median 168 days post-transplant prompting therapy with a median of six HMA cycles and at least one DLI (n = 22, 63%). Hereby, 13 patients (37%) achieved major response (=MRD complete remission [CR]), and 7 patients (20%) achieved minor response (=MRD CR), whereas 15 patients (43%) progressed into hematologic relapse. Two-year overall survival (OS) rate was 35% including 11 patients (31%) with ongoing MRD remission for a median of 21 months. Patients with the major response after six cycles had significantly better OS suggesting that those not achieving MRD negativity after six cycles are candidates for alternative therapies. Combining MRD-monitoring of WT1-expression and preemptive therapy with HMA and DLI appears as a practicable and efficient approach for imminent relapse after allo-SCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01039-2DOI Listing
February 2021

Guideline-based indicators for adult patients with myelodysplastic syndromes.

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

Department of Tumor Immunology, Nijmegen Center for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.

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

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448599PMC
August 2020

Prediction of Response and Survival Following Treatment with Azacitidine for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation.

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

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

To provide long-term outcome data and predictors for response and survival, we retrospectively analyzed all 151 patients with relapse of myeloid neoplasms after allogeneic hematopoietic stem cell transplantation (allo-HSCT) who were uniformly treated with first-line azacitidine (Aza) salvage therapy at our center. Patients were treated for molecular (39%) or hematologic relapse (61%), with a median of 5 cycles of Aza and at least one donor lymphocyte infusion in 70% of patients. Overall response was 46%, with 41% achieving complete (CR) and 5% achieving partial remission. CR was achieved after a median of 4 cycles and lasted for a median of 11 months (range 0.9 to 120 months). With a median follow-up of 22 months (range: 1 to 122 months), the 2-year survival rate was 38% ± 9%, including 17 patients with ongoing remission for >5 years. Based on results from multivariate analyses, molecular relapse and time to relapse were integrated into a score, clearly dividing patients into 3 subgroups with CR rates of 71%, 39%, and 29%; and 2-year survival rates of 64%, 38%, and 27%, respectively. In the subgroup of MDS and secondary AML, receiving upfront transplantation was associated with superior response and survival, and therefore pretransplant strategy was integrated together with relapse type into a MDS-sAML-specific score. Overall, Aza enables meaningful responses and long-term survival, which is a predictable with a simple-to-use scoring system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12082255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464210PMC
August 2020

Falciparum malaria-induced secondary hemophagocytic lymphohistiocytosis successfully treated with ruxolitinib.

Int J Infect Dis 2020 Nov 7;100:382-385. Epub 2020 Aug 7.

Department of Gastroenterology, Hepatology and Infectious Diseases, Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany.

JAK/STAT signaling plays a major role in the pathogenesis of secondary hemophagocytic lymphohistiocytosis. This case report on a critically ill patient with secondary hemophagocytic lymphohistiocytosis due to falciparum malaria treated successfully with ruxolitinib, demonstrates that JAK1/2 inhibition might be a promising treatment option for severe cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijid.2020.07.062DOI Listing
November 2020

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

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

Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece.

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

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-1008-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381722PMC
October 2020

Improving the accuracy of prognostication in chronic myelomonocytic leukemia.

Expert Rev Anticancer Ther 2020 08 6;20(8):703-714. Epub 2020 Aug 6.

Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, University of Duesseldorf , Duesseldorf, Germany.

Introduction: Chronic myelomonocytic leukemia (CMML) is a hematological malignancy that is extremely variable regarding its clinical course. It may present either as a chronic disorder with mild symptoms and low disease burden for several years, thereby justifying a watch-and-wait-strategy, or may soon progress to acute myeloid leukemia (AML) leaving allogeneic stem cell transplantation as the only curative treatment option.

Areas Covered: Attempts have been made to integrate clinical, cytogenetic, and molecular parameters into scoring systems aiming at providing reliable prognostic information. In this article, we discuss several prognostic parameters and validate prognostic scores in a cohort of 645 patients with CMML.

Expert Opinion: We show that the CPSS (CMML prognostic scoring system) is a useful prognostic tool. The integration of molecular data into the new CPSS-mol will further improve prognostic accuracy, primarily by identifying an increased proportion of higher-risk patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14737140.2020.1796644DOI Listing
August 2020

Clinical spectrum of primary adrenal lymphoma: results of a multicenter cohort study.

Eur J Endocrinol 2020 10;183(4):453-462

Department of Hematology, Oncology and Clinical Immunology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Purpose: We sought to refine the clinical picture of primary adrenal lymphoma (PAL), a rare lymphoid malignancy with predominant adrenal manifestation and risk of adrenal insufficiency.

Methods: Ninety-seven patients from 14 centers in Europe, Canada and the United States were included in this retrospective analysis between 1994 and 2017.

Results: Of the 81 patients with imaging data, 19 (23%) had isolated adrenal involvement (iPAL), while 62 (77%) had additional extra-adrenal involvement (PAL+). Among patients who had both CT and PET scans, 18FDG-PET revealed extra-adrenal involvement not detected by CT scan in 9/18 cases (50%). The most common clinical manifestations were B symptoms (55%), fatigue (45%), and abdominal pain (35%). Endocrinological assessment was often inadequate. With a median follow-up of 41.6 months, 3-year progression-free (PFS) and overall (OS) survival rates in the entire cohort were 35.5% and 39.4%, respectively. The hazard ratios of iPAL for PFS and OS were 40.1 (95% CI: 2.63-613.7, P = 0.008) and 2.69 (95% CI: 0.61-11.89, P = 0.191), respectively. PFS was much shorter in iPAL vs PAL+ (median 4 months vs not reached, P = 0.006), and OS also appeared to be shorter (median 16 months vs not reached), but the difference did not reach statistical significance (P = 0.16). Isolated PAL was more frequent in females (OR = 3.81; P = 0.01) and less frequently associated with B symptoms (OR = 0.159; P = 0.004).

Conclusion: We found unexpected heterogeneity in the clinical spectrum of PAL. Further studies are needed to clarify whether clinical distinction between iPAL and PAL+ is corroborated by differences in molecular biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EJE-19-0506DOI Listing
October 2020
-->