Publications by authors named "Lisa Pleyer"

45 Publications

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

CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity.

Haematologica 2021 08 1;106(8):2102-2113. Epub 2021 Aug 1.

3rd Medical Department, SCRI-LIMCR, Paracelsus Medical University, Cancer Cluster Salzburg.

Adhesive properties of leukemia cells shape the degree of organ infiltration and the extent of leukocytosis. CD44 and the integrin VLA-4, a CD49d/CD29 heterodimer, are important factors of progenitor cell adhesion in bone marrow (BM). Here, we report their cooperation in acute myeloid leukemia (AML) by a novel non-classical CD44-mediated way of inside-out VLA-4 activation. In primary AML BM samples from patients and the OCI-AML3 cell line, CD44 engagement by hyaluronan induced inside-out activation of VLA-4 resulting in enhanced leukemia cell adhesion on VCAM-1. This was independent from VLA-4 affinity regulation but based on ligand-induced integrin clustering on the cell surface. CD44-induced VLA-4 activation could be inhibited by the Src family kinase inhibitor PP2 and the multikinase inhibitor midostaurin. In further consequence, the increased adhesion on VCAM-1 allowed AML cells to strongly bind stromal cells. Thereby VLA-4/VCAM-1 interaction promoted activation of Akt, MAPK, NF-kB and mTOR signaling and decreased AML cell apoptosis. Collectively, our investigations provide a mechanistic description of an unusual CD44 function in regulating VLA-4 avidity in AML, supporting AML cell retention in the supportive BM microenvironment.
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http://dx.doi.org/10.3324/haematol.2019.231944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327716PMC
August 2021

IDO in MDS/AML disease progression and its role in resistance to azacitidine: a potential new drug target?

Br J Haematol 2020 08 17;190(3):314-317. Epub 2020 May 17.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg, Austria.

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http://dx.doi.org/10.1111/bjh.16710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496607PMC
August 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

Rituximab maintenance overcomes the negative prognostic factor of obesity in CLL: Subgroup analysis of the international randomized AGMT CLL-8a mabtenance trial.

Cancer Med 2019 04 19;8(4):1401-1405. Epub 2019 Mar 19.

Faculty of Medicine and CEITEC, University Hospital Brno, Brno, Czech Republic.

No data are available regarding obesity and outcome in Chronic Lymphocytic Leukemia (CLL). We analyzed 263 patients from the AGMT CLL-8a Mabtenance trial for the impact of obesity. The trial included patients after rituximab-containing induction treatment in first or second line that had achieved at least a PR. A randomization to rituximab maintenance treatment (375 mg/m q3 months for 2 years) vs observation was performed. In this cohort 22% of the patients (58/263) were classified as obese. The baseline response to induction treatment was inferior in obese patients with a lower CR rate (43.1% vs 60.5% in obese vs non-obese, P = 0.018) and with a lower rate of patients achieving MRD negativity after chemoimmunotherapy induction treatment (19.6% vs 35.8%, P = 0.02). The PFS outcome of obese patients was significantly worse in the observation group of the trial (24 vs 39 months median PFS, P = 0.03). However, in the rituximab maintenance group the outcome for obese vs non-obese was not different (P = 0.4). In summary, obesity was overall associated with a worse outcome of chemoimmunotherapy induction. However, rituximab maintenance treatment seems to be able to overcome this negative effect.
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http://dx.doi.org/10.1002/cam4.1980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488104PMC
April 2019

Next Generation Sequencing in AML-On the Way to Becoming a New Standard for Treatment Initiation and/or Modulation?

Cancers (Basel) 2019 Feb 21;11(2). Epub 2019 Feb 21.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory of Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg 5020, Austria.

Acute myeloid leukemia (AML) is a clonal disease caused by genetic abberations occurring predominantly in the elderly. Next generation sequencing (NGS) analysis has led to a deeper genetic understanding of the pathogenesis and the role of recently discovered genetic precursor lesions (clonal hematopoiesis of indeterminate/oncogenic potential (CHIP/CHOP)) in the evolution of AML. These advances are reflected by the inclusion of certain mutations in the updated World Health Organization (WHO) 2016 classification and current treatment guidelines by the European Leukemia Net (ELN) and National Comprehensive Cancer Network (NCCN) and results of mutational testing are already influencing the choice and timing of (targeted) treatment. Genetic profiling and stratification of patients into molecularly defined subgroups are expected to gain ever more weight in daily clinical practice. Our aim is to provide a concise summary of current evidence regarding the relevance of NGS for the diagnosis, risk stratification, treatment planning and response assessment in AML, including minimal residual disease (MRD) guided approaches. We also summarize recently approved drugs targeting genetically defined patient populations with risk adapted- and individualized treatment strategies.
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http://dx.doi.org/10.3390/cancers11020252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406956PMC
February 2019

Durable remissions with venetoclax monotherapy in secondary AML refractory to hypomethylating agents and high expression of BCL-2 and/or BIM.

Eur J Haematol 2019 May 28;102(5):437-441. Epub 2019 Feb 28.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute - Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Cancer Cluster Salzburg, Paracelsus Medical University, Salzburg, Austria.

Acute myeloid leukemia (AML) is a disease of the elderly population and survival remains poor after failure of hypomethylating agents (HMA). The BCL-2 inhibitor venetoclax demonstrated activity as monotherapy and in combination with chemotherapy or HMA in AML. In this case series, patients with secondary AML (sAML) not eligible for intensive chemotherapy and refractory to HMA were treated with venetoclax within a named patient program at our tertiary cancer center in Salzburg, Austria. Between April 2017 and September 2018, seven patients with sAML received venetoclax therapy. Two out of seven patients achieved a complete remission upon venetoclax initiation with a PFS of 505 days and 352 days and another patient achieved complete peripheral blood blast clearing within nine days after start of venetoclax. Among the venetoclax responders, primary refractory disease to prior HMA therapy was documented, 2 patients harbored IDH1/IDH2 mutations and one patient had an antecedent myeloproliferative neoplasm. High BCL-2 and/or BIM expression in myeloblasts was found in venetoclax responders and response was significantly associated with overall survival (responders: 364 days versus non-responders: 24 days, P = 0.018). Venetoclax monotherapy is safe and is able to induce durable responses in elderly patients with secondary AML after treatment failure with HMA.
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http://dx.doi.org/10.1111/ejh.13218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849823PMC
May 2019

Supervised versus autonomous exercise training in breast cancer patients: A multicenter randomized clinical trial.

Cancer Med 2018 12 10;7(12):5962-5972. Epub 2018 Nov 10.

Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.

Background: There is a well-known correlation between obesity, sedentary lifestyle, and breast cancer incidence and outcome. The Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) exercise study was a multicenter, randomized clinical trial and assessed the feasibility and efficacy of physical training in 50 breast cancer patients undergoing aromatase inhibitor treatment.

Methods: Postmenopausal, estrogen receptor-positive breast cancer patients under aromatase inhibitor treatment were randomized 1:1 to counseling and unsupervised training for 48 weeks (unsupervised arm) or counseling and a sequential training (supervised arm) with a supervised phase (24 weeks) followed by unsupervised physical training (further 24 weeks). Primary endpoint was the individual maximum power output on a cycle ergometer after 24 weeks of exercise. A key secondary endpoint was the feasibility of achieving 12 METh/week (metabolic equivalent of task hours per week).

Results: Twenty-three patients (92%) in the unsupervised arm and 19 patients (76%) in the supervised arm with early-stage breast cancer completed the study. After 24 weeks, the supervised arm achieved a significantly higher maximum output in watt (mean 132 ±  standard deviation [SD] 34; 95% confidence interval [CI] 117-147) compared to baseline (107 ± 25; 95%CI 97-117; P = 0.012) with a numerically higher output than the unsupervised arm (week 24 115 ± 25; 95%CI 105-125; P = 0.059). Significantly higher METh/week was reported in the supervised arm compared to the unsupervised arm during the whole study period (week 1-24 unsupervised: 18.3 (7.6-58.3); supervised: 28.5 (6.7-40.1); P = 0.043; week 25-48; P = 0.041)).

Conclusion: This trial indicates that patients in an exercise program achieve higher fitness levels during supervised than unsupervised training.
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http://dx.doi.org/10.1002/cam4.1851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308077PMC
December 2018

Remission maintenance treatment options in chronic lymphocytic leukemia.

Cancer Treat Rev 2018 Nov 10;70:56-66. Epub 2018 Aug 10.

Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Disease, Rheumatology, Oncologic Center, Laboratory for Immunological and Molecular Cancer Research, Paracelsus Medical University Salzburg, Austria; Salzburg Cancer Research Institute and Cancer Cluster Salzburg, Austria. Electronic address:

Chronic lymphocytic leukemia (CLL) treatment has come a long way in the last two decades, producing increases in tumor control to the point of generating sizeable numbers of patients with undetectable minimal residual disease and creating overall survival benefits in randomized comparisons. Most of this has been achieved by limited-term treatment approaches including chemotherapeutic and immune-therapeutic drugs. More recently, novel therapies targeting signaling pathways essential for the survival of the neoplastic clones have opened avenues that provide disease control in long-term treatment designs, mostly without producing deep remissions. In this disease, where current treatments are largely unable to effect a cure, prolonged therapy designs using maintenance approaches are explored and 5 randomized studies of maintenance have recently been published. This review shall summarize available results from a systematic literature review in a clinical context and outline basic biology principles that should be heeded in this regard.
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http://dx.doi.org/10.1016/j.ctrv.2018.08.003DOI Listing
November 2018

Evaluation of induction chemotherapies after hypomethylating agent failure in myelodysplastic syndromes and acute myeloid leukemia.

Blood Adv 2018 08;2(16):2063-2071

Hematology Department, Yale New Haven Hospital, New Haven, CT.

Hypomethylating agent (HMA) failure in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) carries a poor prognosis with limited treatment options. Although intensive, remission induction chemotherapy is often used subsequently, in particular to bridge to allogeneic transplantation, it is not clear whether an advantage exists for any particular regimen. Based on an international collaboration, we retrospectively analyzed induction response rate and survival in 366 patients after HMA failure. Patients received 7+3, intermediate- to high-dose cytarabine (IDAC), or purine nucleoside analog-based regimens. For the MDS cohort (n = 307), the overall response rate (ORR) was 41%; median overall survival (OS) was 10.8 months, and 40% of responding patients bridged to allogeneic stem cell transplant (allo-SCT). For the AML cohort (n = 59), the ORR was 32%, OS 6 months, and 42% of responding patients bridged to allo-SCT. Prognostic factors for response in MDS included adverse cytogenetics (odds ratio [OR], 0.46, = .01), age ≥65 years (OR, 0.47; < .01), and use of IDAC (OR, 2.91, = .01). Shorter survival was associated with adverse cytogenetics (hazard ratio [HR], 1.43; = .06). In the AML cohort, OS was decreased by disease progression at time of HMA failure (HR, 2.66; = .02) and prolonged with use of an anthracycline-containing regimen (HR, 0.37; = .01). In conclusion, intensive chemotherapy after HMA failure may be a reasonable treatment option for selected patients as a bridge to allogeneic transplantation and should be considered a potential platform for future investigations.
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http://dx.doi.org/10.1182/bloodadvances.2018015529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113613PMC
August 2018

Correction to: Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study.

Ann Hematol 2018 09;97(9):1745

Department of Internal Medicine III with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner-Hauptstr. 48, 5020, Salzburg, Austria.

The original version of this article contained a mistake. The name of Tanja Nicole Hartman should have been Tanja Nicole Hartmann. The original article has been corrected.
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http://dx.doi.org/10.1007/s00277-018-3403-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828337PMC
September 2018

Fludarabine and rituximab with escalating doses of lenalidomide followed by lenalidomide/rituximab maintenance in previously untreated chronic lymphocytic leukaemia (CLL): the REVLIRIT CLL-5 AGMT phase I/II study.

Ann Hematol 2018 Oct 4;97(10):1825-1839. Epub 2018 Jun 4.

Department of Internal Medicine III with Hematology and Medical Oncology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner-Hauptstr. 48, 5020, Salzburg, Austria.

Despite recent advances, chemoimmunotherapy remains a standard for fit previously untreated chronic lymphocytic leukaemia patients. Lenalidomide had activity in early monotherapy trials, but tumour lysis and flare proved major obstacles in its development. We combined lenalidomide in increasing doses with six cycles of fludarabine and rituximab (FR), followed by lenalidomide/rituximab maintenance. In 45 chemo-naive patients, included in this trial, individual tolerability of the combination was highly divergent and no systematic toxicity determining a maximum tolerated dose was found. Grade 3/4 neutropenia (71%) was high, but only 7% experienced grade 3 infections. No tumour lysis or flare > grade 2 was observed, but skin toxicity proved dose-limiting in nine patients (20%). Overall and complete response rates after induction were 89 and 44% by intention-to-treat, respectively. At a median follow-up of 78.7 months, median progression-free survival (PFS) was 60.3 months. Minimal residual disease and immunoglobulin variable region heavy chain mutation state predicted PFS and TP53 mutation most strongly predicted OS. Baseline clinical factors did not predict tolerance to the immunomodulatory drug lenalidomide, but pretreatment immunophenotypes of T cells showed exhausted memory CD4 cells to predict early dose-limiting non-haematologic events. Overall, combining lenalidomide with FR was feasible and effective, but individual changes in the immune system seemed associated with limiting side effects. clinicaltrials.gov (NCT00738829) and EU Clinical Trials Register ( www.clinicaltrialsregister.eu , 2008-001430-27).
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http://dx.doi.org/10.1007/s00277-018-3380-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097797PMC
October 2018

Sequential immunotherapy in a patient with primary refractory Hodgkin lymphoma and novel mutations.

Oncotarget 2018 Apr 17;9(29):20928-20940. Epub 2018 Apr 17.

IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University, A-5020 Salzburg, Austria.

Primary resistant Hodgkin lymphoma is an aggressive disease with few treatment options and short survival. Neoplastic cells of classical Hodgkin lymphoma are heavily dependent on microenvironmental stimuli, regularly express PD-L1, and a relevant proportion of relapsed patients is sensitive to blocking of the PD1/PD-L1 axis. However, response duration is limited and further treatment options are unknown but urgently needed. We report a case of a patient without relevant response to five subsequent chemotherapy regimens who immediately and dramatically responded to an anti-PD1 mab. During the following two years she responded to the anti-CTLA-4 mab ipilimumab, the Jak2 inhibitor ruxolitinib, and a combination of lenalidomide plus cyclophosphamide given in subsequent relapses. A thorough genomic analysis demonstrated seven genomic alterations with six of them not previously described in this disease (i.e. BRIP1 G212fs*62, KRAS L19F, KDM5A R1239W, MYC A59T, ARIDA1A E1683fs*15 and TP53 277Y). Three alterations were considered actionable and one of them drugable. The number of mutations increased over time and the BRIP1 mutation was found to be a germline mutation.
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http://dx.doi.org/10.18632/oncotarget.25037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945535PMC
April 2018

Time to repeal and replace response criteria for acute myeloid leukemia?

Blood Rev 2018 09 27;32(5):416-425. Epub 2018 Mar 27.

The Alfred Hospital and Monash University, Melbourne, Australia. Electronic address:

The International Working Group (IWG) response criteria for acute myeloid leukemia, published in 2003, have remained the standard by which the efficacy of new drugs is measured in clinical trials. Over the last decade, concepts related to treatment response have been challenged by several factors; for example, the dissociation between early clinical response and survival outcome in older patients, the recognition that epigenetic and newer differentiating-agent therapies may produce delayed responses and also hematologic improvement/transfusion independence without a morphologic response, and evidence that remissions without minimal (or measurable) residual disease (MRD) may result in outcomes superior to those of morphologic remissions with persistent MRD. The evolving role of MRD status as a potential surrogate for predicting long-term survival has enhanced the clinical need to standardize and incorporate emerging technologies that enable deeper responses beyond those recognized by the IWG, and to pre-emptively identify patients at risk of early relapse. The potential for therapeutic interventions to erase MRD and alter the natural history represents an important and open research question. Reviewed here are some of the implications and challenges associated with establishing and incorporating new treatment response criteria, initially into clinical research, and eventually into real-world practice.
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http://dx.doi.org/10.1016/j.blre.2018.03.006DOI Listing
September 2018

Clonal evolution and heterogeneity in metastatic head and neck cancer-An analysis of the Austrian Study Group of Medical Tumour Therapy study group.

Eur J Cancer 2018 04 20;93:69-78. Epub 2018 Mar 20.

IIIrd Medical Department with Hematology and Medical Oncology, Paracelsus Medical University Salzburg, Salzburg, Austria; Salzburg Cancer Research Institute, Salzburg, Austria; Cancer Cluster Salzburg, Salzburg, Austria. Electronic address:

Background: Tumour heterogeneity and clonal evolution within a cancer patient are deemed responsible for relapse in malignancies and present challenges to the principles of targeted therapy, for which treatment modality is often decided based on the molecular pathology of the primary tumour. Nevertheless, the clonal architecture in distant relapse of head and neck cancer is fairly unknown.

Patients And Methods: For this project, we analysed a cohort of 386 patients within the Austrian Registry of head and neck cancer. We identified 26 patients with material from the primary tumour, the distant metastasis after curative first-line treatment and a germline sample for analysis of clonal evolution. After pathological analyses, these samples were analysed using a targeted massively parallel sequencing (MPS) panel of 257 genes known to be recurrently mutated in head and neck cancer plus a genome-wide SNP-set.

Results: Despite histological diagnosis of distant metastasis, no corresponding mutation in the supposed metastases was found in two of 23 (8.6%) evaluable patients suggesting a primary tumour of the lung instead of a distant metastasis of head and neck cancer. We observed a branched pattern of evolution in 31.6% of the analysed patients. This pattern was associated with a shorter time to distant metastasis, compared with a pattern of punctuated evolution. Structural genomic changes over time were also present in 7 of 12 (60%) evaluable patients with metachronous metastases.

Conclusion: Targeted MPS demonstrated substantial heterogeneity at the time of diagnosis and a complex pattern of evolution during disease progression in head and neck cancer. Copy number analyses revealed additional changes that were not detected by mutational analyses. Mutational and structural changes contribute to tumour heterogeneity at diagnosis and progression.
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http://dx.doi.org/10.1016/j.ejca.2018.01.064DOI Listing
April 2018

Establishment and validation of a novel risk model for estimating time to first treatment in 120 patients with chronic myelomonocytic leukaemia.

Wien Klin Wochenschr 2018 Feb 30;130(3-4):115-125. Epub 2018 Jan 30.

Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectious Disease, Rheumatology, Oncologic Center, Laboratory of Immunological and Molecular Cancer Research, Paracelsus Medical University Salzburg, Muellner Hauptstraße 48, 5020, Salzburg, Austria.

Chronic myelomonocytic leukaemia is a rare disease and data on the treatment are often extrapolated from myelodysplastic syndrome studies. Although several scores exist for the prognosis of overall survival in chronic myelomonocytic leukaemia, so far there is no designated score for the prediction of the time to first treatment. We tested clinical parameters and cytogenetic information for their ability to predict the time to first treatment in our single center cohort of 55 unselected consecutive chronic myelomonocytic leukaemia patients. In multivariate analysis we identified elevated lactate dehydrogenase (≥223 U/l), higher bone marrow blast percentage (≥7.5%) and thrombocytopenia (<55 G/l) at initial diagnosis as the most relevant parameters for the time to first treatment. Using these three parameters we developed a risk score that efficiently estimates the time to treatment initiation with azacitidine or hydroxyurea (p < 0.001; log-rank). In the high-risk group (≥2 risk factors) 85% of patients required treatment within 1 year, whereas this was the case in 48% in the intermediate-risk (1 risk factor) and in 0% in the low-risk group (0 risk factors). Our risk model was validated in an external test cohort of 65 patients and may serve as a simplified and easily applicable tool for identifying patients who may not require early treatment initiation.
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http://dx.doi.org/10.1007/s00508-018-1315-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816094PMC
February 2018

Sidedness and TP53 mutations impact OS in anti-EGFR but not anti-VEGF treated mCRC - an analysis of the KRAS registry of the AGMT (Arbeitsgemeinschaft Medikamentöse Tumortherapie).

BMC Cancer 2018 01 3;18(1):11. Epub 2018 Jan 3.

IIIrd Medical Department with Haematology, Medical Oncology, Haemostaseology, Infectious Diseases and Rheumatology, Oncologic Center, Paracelsus Medical University, 5020, Salzburg, Austria.

Background: In metastatic colorectal cancer (mCRC), the localization of the primary tumour has been shown to be of prognostic as well as predictive relevance.

Methods: With the aim to investigate clinical and molecular disease characteristics with respect to sidedness in a real-world cohort, we analyzed 161 mCRC patients included in the KRAS Registry of the Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) between January 2006 and October 2013.

Results: Right-sided mCRC displayed a worse median overall survival (OS) in comparison to left-sided disease (18.1 months [95%-CI: 14.3-40.7] versus 32.3 months [95%-CI: 25.5-38.6]; HR: 1.63 [95%-CI: 1.13-2.84]; p = 0.013). The choice of the biological agent in front-line therapy had a statistically significant impact on median OS in patients with right-sided tumours (anti-epidermal growth factor receptor (EGFR): 10.6 months [95%-CI: 5.2-NA]; anti-vascular endothelial growth factor (VEGF): 26.2 months [95%-CI: 17.9-NA]; HR: 2.69 [95%-CI: 1.30-12.28]; p = 0.015) but not in patients with left-sided tumours (anti-EGFR: 37.0 months [95%-CI: 20.2-56.6]; anti-VEGF: 32.3 months [95%-CI: 23.6-41.1]; HR: 0.97 [95%-CI: 0.56-1.66]; p = 0.905). When evaluating molecular characteristics of tumour samples, we found a clinically meaningful trend towards an inferior OS in TP53 mutant mCRC treated with anti-EGFR based therapy compared to anti-VEGF based therapy (17.1 months [95%-CI: 8.7-NA] versus 38.3 months [95%-CI: 23.6-48.0], HR = 1.95 [95%-CI: 0.95-5.88]; p = 0.066), which was not significantly dependent on sidedness. This was not the case in patients with TP53 wild-type tumours. Therefore we evaluated the combined impact of sidedness and TP53 mutation status in the anti-EGFR treated cohort and patients with left-sided/TP53 wild-type mCRC showed the longest median OS (38.9 months) of all groups (right-sided/TP53 mutant: 12.1 months; right-sided/TP53 wild-type: 8.9 months; left-sided/TP53 mutant: 18.4 months; p = 0.020).

Conclusions: TP53 mutation and right-sidedness are associated with shorter OS in patients treated with anti-EGFR based therapy but not with anti-VEGF based therapy. The confirmation of the predictive value of TP53 mutation status in a larger cohort is warranted.
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http://dx.doi.org/10.1186/s12885-017-3955-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753540PMC
January 2018

TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia.

Oncoimmunology 2017;7(1):e1371399. Epub 2017 Sep 21.

Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.

While research on T cell exhaustion in context of cancer particularly focuses on CD8+ cytotoxic T cells, the role of inhibitory receptors on CD4+ T-helper cells have remained largely unexplored. TIGIT is a recently identified inhibitory receptor on T cells and natural killer (NK) cells. In this study, we examined TIGIT expression on T cell subsets from CLL patients. While we did not observe any differences in TIGIT expression in CD8+ T cells of healthy controls and CLL cells, we found an enrichment of TIGIT+ T cells in the CD4+ T cell compartment in CLL. Intriguingly, CLL patients with an advanced disease stage displayed elevated numbers of CD4+ TIGIT+ T cells compared to low risk patients. Autologous CLL-T cell co-culture assays revealed that depleting CD4+ TIGIT+ expressing T cells from co-cultures significantly decreased CLL viability. Accordingly, a supportive effect of TIGIT+CD4+ T cells on CLL cells could be recapitulated by blocking the interaction of TIGIT with its ligands using TIGIT-Fc molecules, which also impeded the T cell specific production of CLL-prosurvival cytokines. Our data reveal that TIGIT+CD4+T cells provide a supportive microenvironment for CLL cells, representing a potential therapeutic target for CLL treatment.
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http://dx.doi.org/10.1080/2162402X.2017.1371399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739567PMC
September 2017

Real life experience with frontline azacitidine in a large series of older adults with acute myeloid leukemia stratified by MRC/LRF score: results from the expanded international E-ALMA series (E-ALMA+).

Leuk Lymphoma 2018 05 24;59(5):1113-1120. Epub 2017 Aug 24.

h Department of Hematology , University Hospital , León , Spain.

Azacitidine (AZA) prolonged overall survival (OS) in the AZA-AML-001 trial. However, few subjects were randomized to AZA or intensive chemotherapy (IC). The Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) developed a score for older AML patients receiving IC or non-intensive regimens, whereas the E-ALMA study validated a score for survival and response in elderly patients receiving AZA in daily practice. Both identified three groups with different risk estimates. This analysis evaluates the efficacy of frontline AZA in older AML patients (N = 710) unfit for IC from different national registries (E-ALMA + series) stratified by the MRC/LRF risk score. Median OS of patients categorized as good, standard and poor-risk groups by the MRC/LRF score was 13.4 (95% CI, 10.8-16), 12.4 (95% CI, 9.9-14.8), and 8.1 months (95% CI, 7-9.1), respectively (p = .0001). In conclusion, this is the largest retrospective cohort of older AML patients treated with AZA.
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http://dx.doi.org/10.1080/10428194.2017.1365854DOI Listing
May 2018

Azacitidine in adult patients with acute myeloid leukemia.

Crit Rev Oncol Hematol 2017 Aug 3;116:159-177. Epub 2017 Jun 3.

Hôpital Saint Louis, Institut Universitaire d'Hématologie, Paris, France.

Azacitidine is recommended front-line treatment for older patients with acute myeloid leukemia (AML) who are not candidates for intensive treatment regimens, and was recently granted approval in the European Union for treatment of adult AML. Reviewed here is azacitidine experience in AML, including: mechanistic and pharmacokinetic data; safety and efficacy in controlled trials; treatment effects in AML subpopulations defined by disease characteristics; experience in unselected patients treated in the community setting; clinical outcomes relative to other approved AML therapies; and experience with azacitidine-based combination treatment regimens. Collectively, these data suggest that (a) azacitidine may prolong overall survival to a similar or greater extent than do other approved AML treatments, but with less toxicity, (b) azacitidine may be the preferred treatment option for older patients with unfavorable cytogenetics, and (c) experience and outcomes with azacitidine in the clinic are similar to those seen in clinical trials. Continued investigation of combination regimens on an azacitidine backbone is warranted.
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http://dx.doi.org/10.1016/j.critrevonc.2017.05.010DOI Listing
August 2017

Clinical Outcomes of 217 Patients with Acute Erythroleukemia According to Treatment Type and Line: A Retrospective Multinational Study.

Int J Mol Sci 2017 Apr 14;18(4). Epub 2017 Apr 14.

Department of Internal Medicine I, Division of Hematology & Hemostaseology and Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Acute erythroleukemia (AEL) is a rare disease typically associated with a poor prognosis. The median survival ranges between 3-9 months from initial diagnosis. Hypomethylating agents (HMAs) have been shown to prolong survival in patients with myelodysplastic syndromes (MDS) and AML, but there is limited data of their efficacy in AEL. We collected data from 210 AEL patients treated at 28 international sites. Overall survival (OS) and PFS were estimated using the Kaplan-Meier method and the log-rank test was used for subgroup comparisons. Survival between treatment groups was compared using the Cox proportional hazards regression model. Eighty-eight patients were treated with HMAs, 44 front line, and 122 with intensive chemotherapy (ICT). ICT led to a higher overall response rate (complete or partial) compared to first-line HMA (72% vs. 46.2%, respectively; ≤ 0.001), but similar progression-free survival (8.0 vs. 9.4 months; = 0.342). Overall survival was similar for ICT vs. HMAs (10.5 vs. 13.7 months; = 0.564), but patients with high-risk cytogenetics treated with HMA first-line lived longer (7.5 for ICT vs. 13.3 months; = 0.039). Our results support the therapeutic value of HMA in AEL.
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http://dx.doi.org/10.3390/ijms18040837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412421PMC
April 2017

The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation.

Cell Commun Signal 2017 03 31;15(1):13. Epub 2017 Mar 31.

3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria.

Hypomethylating agents (HMAs) have been widely used over the last decade, approved for use in myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML). The proposed central mechanism of action of HMAs, is the reversal of aberrant methylation in tumor cells, thus reactivating CpG-island promoters and leading to (re)expression of tumor suppressor genes. Recent investigations into the mode of action of azacitidine (AZA) and decitabine (DAC) have revealed new molecular mechanisms that impinge on tumor immunity via induction of an interferon response, through activation of endogenous retroviral elements (ERVs) that are normally epigenetically silenced. Although the global demethylation of DNA by HMAs can induce anti-tumor effects, it can also upregulate the expression of inhibitory immune checkpoint receptors and their ligands, resulting in secondary resistance to HMAs. Recent studies have, however, suggested that this could be exploited to prime or (re)sensitize tumors to immune checkpoint inhibitor therapies. In recent years, immune checkpoints have been targeted by novel therapies, with the aim of (re)activating the host immune system to specifically eliminate malignant cells. Antibodies blocking checkpoint receptors have been FDA-approved for some solid tumors and a plethora of clinical trials testing these and other checkpoint inhibitors are under way. This review will discuss AZA and DAC novel mechanisms of action resulting from the re-expression of pathologically hypermethylated promoters of gene sets that are related to interferon signaling, antigen presentation and inflammation. We also review new insights into the molecular mechanisms of action of transient, low-dose HMAs on various tumor types and discuss the potential of new treatment options and combinations.
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http://dx.doi.org/10.1186/s12964-017-0168-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374693PMC
March 2017

Azacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group.

Int J Mol Sci 2017 Feb 15;18(2). Epub 2017 Feb 15.

3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg 5020, Austria.

We recently published a clinically-meaningful improvement in median overall survival (OS) for patients with acute myeloid leukaemia (AML), >30% bone marrow (BM) blasts and white blood cell (WBC) count ≤15 G/L, treated with front-line azacitidine versus conventional care regimens within a phase 3 clinical trial (AZA-AML-001; NCT01074047; registered: February 2010). As results obtained in clinical trials are facing increased pressure to be confirmed by real-world data, we aimed to test whether data obtained in the AZA-AML-001 trial accurately represent observations made in routine clinical practice by analysing additional AML patients treated with azacitidine front-line within the Austrian Azacitidine Registry (AAR; NCT01595295; registered: May 2012) and directly comparing patient-level data of both cohorts. We assessed the efficacy of front-line azacitidine in a total of 407 patients with newly-diagnosed AML. Firstly, we compared data from AML patients with WBC ≤ 15 G/L and >30% BM blasts included within the AZA-AML-001 trial treated with azacitidine ("AML-001" cohort; = 214) with AAR patients meeting the same inclusion criteria ("AAR (001-like)" cohort; = 95). The current analysis thus represents a new sub-analysis of the AML-001 trial, which is directly compared with a new sub-analysis of the AAR. Baseline characteristics, azacitidine application, response rates and OS were comparable between all patient cohorts within the trial or registry setting. Median OS was 9.9 versus 10.8 months ( = 0.616) for "AML-001" versus "AAR (001-like)" cohorts, respectively. Secondly, we pooled data from both cohorts ( = 309) and assessed the outcome. Median OS of the pooled cohorts was 10.3 (95% confidence interval: 8.7, 12.6) months, and the one-year survival rate was 45.8%. Thirdly, we compared data from AAR patients meeting AZA-AML-001 trial inclusion criteria ( = 95) versus all AAR patients with World Health Organization (WHO)-defined AML ("AAR (WHO-AML)" cohort; = 193). Within the registry population, median OS for AAR patients meeting trial inclusion criteria versus all WHO-AML patients was 10.8 versus 11.8 months ( = 0.599), respectively. We thus tested and confirmed the efficacy of azacitidine as a front-line agent in patients with AML, >30% BM blasts and WBC ≤ 15 G/L in a routine clinical practice setting. We further show that the efficacy of azacitidine does not appear to be limited to AML patients who meet stringent clinical trial inclusion criteria, but instead appears efficacious as front-line treatment in all patients with WHO-AML.
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http://dx.doi.org/10.3390/ijms18020415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343949PMC
February 2017

Reactivation of dormant anti-tumor immunity - a clinical perspective of therapeutic immune checkpoint modulation.

Cell Commun Signal 2017 Jan 19;15(1). Epub 2017 Jan 19.

Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Disease and Rheumatology, Oncologic Center, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria.

In favor of their outgrowth, cancer cells must resist immune surveillance and edit the immune response. Cancer immunoediting is characterized by fundamental changes in the cellular composition and the inflammatory cytokine profiles in the microenvironment of the primary tumor and metastatic niches, with an ever increasing complexity of interactions between tumor cells and the immune system. Recent data suggest that genetic instability and immunoediting are not necessarily disparate processes. Increasing mutational load may be associated with multiple neoepitopes expressed by the tumor cells and thus increased chances for the immune system to recognize and combat these cells. At the same time the immune system is more and more suppressed and exhausted by this process. Consequently, immune checkpoint modulation may have the potential to be most successful in genetically highly altered and usually extremely unfavorable types of cancer. Moreover, the fact that epitopes recognized by the immune system are preferentially encoded by passenger gene mutations opens windows of synergy in targeting cancer-specific signaling pathways by small molecules simultaneously with antibodies modifying T-cell activation or exhaustion.This review covers some aspects of the current understanding of the immunological basis necessary to understand the rapidly developing therapeutic endeavours in cancer treatment, the clinical achievements made, and raises some burning questions for translational research in this field.
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http://dx.doi.org/10.1186/s12964-016-0155-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244547PMC
January 2017

Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial.

Lancet Haematol 2016 Jul 16;3(7):e317-29. Epub 2016 Jun 16.

Salzburg Cancer Research Institute (SCRI), Salzburg, Austria; Cancer Cluster Salzburg (CCS), Salzburg, Austria.

Background: In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens.

Methods: In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234.

Findings: Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio [HR] 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]).

Interpretation: Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases.

Funding: Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.
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http://dx.doi.org/10.1016/S2352-3026(16)30045-XDOI Listing
July 2016

Mesenchymal Stem and Progenitor Cells in Normal and Dysplastic Hematopoiesis-Masters of Survival and Clonality?

Int J Mol Sci 2016 Jun 27;17(7). Epub 2016 Jun 27.

3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.

Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts. MSCs have potent immunomodulatory capacities and communicate with diverse immune cells, but also interact with various other cellular components of the microenvironment as well as with normal and leukemic stem and progenitor cells. Moreover, compared to normal MSCs, MSCs in MDS and AML often exhibit altered gene expression profiles, an aberrant phenotype, and abnormal functional properties. These alterations supposedly contribute to the "reprogramming" of the stem cell niche into a disease-permissive microenvironment where an altered immune system, abnormal stem cell niche interactions, and an impaired growth control lead to disease progression. The current article also reviews molecular targets that play a role in such cellular interactions and possibilities to interfere with abnormal stem cell niche interactions by using specific targeted drugs.
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http://dx.doi.org/10.3390/ijms17071009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964385PMC
June 2016

Azacitidine front-line in 339 patients with myelodysplastic syndromes and acute myeloid leukaemia: comparison of French-American-British and World Health Organization classifications.

J Hematol Oncol 2016 Apr 16;9:39. Epub 2016 Apr 16.

3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Salzburg, Salzburg, Austria.

Background: The MDS-IWG and NCCN currently endorse both FAB and WHO classifications of MDS and AML, thus allowing patients with 20-30 % bone marrow blasts (AML20-30, formerly MDS-RAEB-t) to be categorised and treated as either MDS or AML. In addition, an artificial distinction between AML20-30 and AML30+ was made by regulatory agencies by initially restricting approval of azacitidine to AML20-30. Thus, uncertainty prevails regarding the diagnosis, prognosis and optimal treatment timing and strategy for patients with AML20-30. Here, we aim to provide clarification for patients treated with azacitidine front-line.

Methods: The Austrian Azacitidine Registry is a multicentre database (ClinicalTrials.gov: NCT01595295). For this analysis, we selected 339 patients treated with azacitidine front-line. According to the WHO classification 53, 96 and 190 patients had MDS-RAEB-I, MDS-RAEB-II and AML (AML20-30: n = 79; AML30+: n = 111), respectively. According to the FAB classification, 131, 101 and 111 patients had MDS-RAEB, MDS-RAEB-t and AML, respectively.

Results: The median ages of patients with MDS and AML were 72 (range 37-87) and 77 (range 23-93) years, respectively. Overall, 80 % of classifiable patients (≤30 % bone marrow blasts) had intermediate-2 or high-risk IPSS scores. Most other baseline, treatment and response characteristics were similar between patients diagnosed with MDS or AML. WHO-classified patients with AML20-30 had significantly worse OS than patients with MDS-RAEB-II (13.1 vs 18.9 months; p = 0.010), but similar OS to patients with AML30+ (10.9 vs 13.1 months; p = 0.238). AML patients that showed MDS-related features did not have worse outcomes compared with patients who did not (13.2 vs 8.9 months; p = 0.104). FAB-classified patients with MDS-RAEB-t had similar survival to patients with AML30+ (12.8 vs 10.9 months; p = 0.376), but significantly worse OS than patients with MDS-RAEB (10.9 vs 24.4 months; p < 0.001).

Conclusions: Our data demonstrate the validity of the WHO classification of MDS and AML, and its superiority over the former FAB classification, for patients treated with azacitidine front-line. Neither bone marrow blast count nor presence of MDS-related features had an adverse prognostic impact on survival. Patients with AML20-30 should therefore be regarded as having 'true AML' and in our opinion treatment should be initiated without delay.
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http://dx.doi.org/10.1186/s13045-016-0263-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833933PMC
April 2016

Digging deep into "dirty" drugs - modulation of the methylation machinery.

Drug Metab Rev 2015 May 8;47(2):252-79. Epub 2015 Jan 8.

3rd Medical Department with Hematology and Medical Oncology, Hemostaseology, Rheumatology and Infectious Diseases, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University Hospital Salzburg, Center for Clinical Cancer and Immunology Trials at Salzburg Cancer Research Institute , Salzburg , Austria.

DNA methylation and histone modification are epigenetic mechanisms that result in altered gene expression and cellular phenotype. The exact role of methylation in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remains unclear. However, aberrations (e.g. loss-/gain-of-function or up-/down-regulation) in components of epigenetic transcriptional regulation in general, and of the methylation machinery in particular, have been implicated in the pathogenesis of these diseases. In addition, many of these components have been identified as therapeutic targets for patients with MDS/AML, and are also being assessed as potential biomarkers of response or resistance to hypomethylating agents (HMAs). The HMAs 5-azacitidine (AZA) and 2'-deoxy-5-azacitidine (decitabine, DAC) inhibit DNA methylation and have shown significant clinical benefits in patients with myeloid malignancies. Despite being viewed as mechanistically similar drugs, AZA and DAC have differing mechanisms of action. DAC is incorporated 100% into DNA, whereas AZA is incorporated into RNA (80-90%) as well as DNA (10-20%). As such, both drugs inhibit DNA methyltransferases (DNMTs; dependently or independently of DNA replication) resulting in the re-expression of tumor-suppressor genes; however, AZA also has an impact on mRNA and protein metabolism via its inhibition of ribonucleotide reductase, resulting in apoptosis. Herein, we first give an overview of transcriptional regulation, including DNA methylation, post-translational histone-tail modifications, the role of micro-RNA and long-range epigenetic gene silencing. We place special emphasis on epigenetic transcriptional regulation and discuss the implication of various components in the pathogenesis of MDS/AML, their potential as therapeutic targets, and their therapeutic modulation by HMAs and other substances (if known). The main focus of this review is laid on dissecting the rapidly evolving knowledge of AZA and DAC with a special focus on their differing mechanisms of action, and the effect of HMAs on transcriptional regulation.
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http://dx.doi.org/10.3109/03602532.2014.995379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733942PMC
May 2015

10th anniversary of the Austrian MDS Platform: aims and ongoing projects.

Wien Klin Wochenschr 2015 Jan 25;127(1-2):12-5. Epub 2014 Nov 25.

Department of Internal Medicine IV, Klinikum Wels-Grieskirchen, Wels, Austria,

The Austrian myelodysplastic syndromes (MDS) Platform was founded as a national working group in 2003 to initiate and coordinate common projects in the field. The incidence of MDS in Austria is approximately 400-500 new MDS cases per year. The overall low number of MDS patients underlines the importance of a national initiative to concentrate knowledge at certain specialized centres, where treatment of these patients mainly takes place. Clinical trials as well as basic research are facilitated by the cooperation of university and non-university hospitals. Other objectives are the generation of therapeutic standards, organization of meetings to spread this information to physicians and patients as well as promoting patient-support groups. Cooperation with international working groups is another important aim of the Platform. The 10th anniversary of the Austrian MDS Platform was organized as a meeting for all interested physicians throughout Austria providing an update on the disease and ongoing projects.
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http://dx.doi.org/10.1007/s00508-014-0627-0DOI Listing
January 2015
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