Publications by authors named "Veronika Buxhofer-Ausch"

47 Publications

Austrian recommendations for the management of essential thrombocythemia.

Wien Klin Wochenschr 2021 Jan 19;133(1-2):52-61. Epub 2020 Nov 19.

Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria.

According to the World Health Organization (WHO) classification, essential (primary) thrombocythemia (ET) is one of several Bcr-Abl negative chronic myeloproliferative neoplasms (MPN). The classical term MPN covers the subcategories of MPN: ET, polycythemia vera (PV), primary myelofibrosis (PMF), and prefibrotic PMF (pPMF). ET is marked by clonal proliferation of hematopoietic stem cells, leading to a chronic overproduction of platelets. At the molecular level a JAK2 (Janus Kinase 2), calreticulin, or MPL mutation is found in the majority of patients. Typical ongoing complications of the disease include thrombosis and hemorrhage. Primary and secondary prevention of these complications can be achieved with platelet function inhibitors and various cytoreductive drugs including anagrelide, hydroxyurea and interferon. After a long follow up, in a minority of ET patients the disease transforms into post-ET myelofibrosis or secondary leukemia. Overall, life expectancy with ET is only slightly decreased.
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http://dx.doi.org/10.1007/s00508-020-01761-3DOI Listing
January 2021

Two common polymorphic variants of OATP4A1 as potential risk factors for colorectal cancer.

Oncol Lett 2020 Nov 17;20(5):252. Epub 2020 Sep 17.

Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, A-1090 Vienna, Austria.

Genetic variations in the organic-anion-transporting polypeptide (OATP)-encoding solute carrier of organic anions () genes can promote cancer development and progression. The overexpression of solute carrier organic anion transporter family member 4A1 (OATP4A1), a transporter for steroid hormones, prostaglandins, and bile acids, has been previously associated with tumor recurrence and progression in colorectal cancer (CRC). Therefore, the present study aimed to investigate the association between 2 frequent single nucleotide polymorphisms (SNPs) in (rs34419428, R70Q; rs1047099G, V78I) and CRC predisposition. Following restriction fragment length polymorphism-PCR analysis in 178 patients with CRC [Union for International Cancer Control (UICC) stage I/II] and 65 healthy controls, no significant difference was observed in allele frequency and the number of heterozygous/homozygous individuals between the groups. Notably, the R70Q minor allele was identified to be associated with the V78I minor allele in the genome. Comparing of the individual genotypes of CRC patients to clinical data, including sex, UICC-stage and relapse revealed no increased risk for CRC. In addition, the OATP4A1 immunoreactivity assay in paraffin-embedded CRC and adjacent non-tumorous mucosa sections, examined using quantitative microscopy image analysis, did not reveal any association with these polymorphisms. No significant differences were observed in the expression levels, localization, and sodium fluorescein transport capacity among the OATP4A1 variants, which was studied using functional assays in Sf9-insect and A431 tumor cells overexpressing the 2 single and a double mutant OATP4A1 SNP variants. These results suggested that the 2 most frequent polymorphisms located in the first intracellular loop of OATP4A1 do not associate with CRC predisposition and tumor recurrence. They are unlikely to affect the outcome of CRC in patients.
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http://dx.doi.org/10.3892/ol.2020.12115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509609PMC
November 2020

Impact of platelets on major thrombosis in patients with a normal white blood cell count in essential thrombocythemia.

Eur J Haematol 2021 Jan 6;106(1):58-63. Epub 2020 Oct 6.

Department of Haematology and Blood Coagulation, Division of Internal Medicine I,, Medical University of Vienna, Vienna, Austria.

Objectives: Cell counts have a significant impact on the complex mechanism of thrombosis in patients with essential thrombocythemia (ET). We recently demonstrated a considerable impact of white blood cell (WBC) counts on thrombotic risk in patients with optimized platelet counts by analysing a large anagrelide registry. In contrast, the current analysis of the registry aimed to estimate the influence of platelet counts on thrombotic risk in patients with optimized WBC counts.

Methods: Cox regression analysis and Kaplan-Meier plot were applied on all patients in the registry with optimized WBC counts.

Results: By using the calculated cut-off of 593 G/L for platelets, Cox regression analysis revealed a clear influence of elevated platelet counts on the occurrence of a major thrombotic event (P < .001). A Kaplan-Meier plot revealed a markedly shorter time to a major thrombotic event for patients with platelet counts above the cut-off (P < .001).

Conclusions: The data show clear impact of platelet lowering on the thrombotic risk in ET patients with normal WBC counts. Therefore, selective platelet lowering with anagrelide appears sufficient for thrombotic risk reduction in WHO-diagnosed ET patients lacking leukocytosis.
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http://dx.doi.org/10.1111/ejh.13516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756407PMC
January 2021

Treatment of acquired thrombotic thrombocytopenic purpura without plasma exchange in selected patients under caplacizumab.

J Thromb Haemost 2020 11 6;18(11):3061-3066. Epub 2020 Sep 6.

Department of Haemostaseology and Haemophilia Center, University Hospital Frankfurt, Frankfurt am Main, Germany.

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening autoimmune thrombotic microangiopathy. Current standard of care is therapeutic plasma exchange, immunosuppression, and caplacizumab, an anti-von Willebrand factor nanobody, which is effective in treating aTTP episodes.

Patients/methods: Here we report on seven episodes of aTTP treated without plasma exchange in six female patients in Germany and Austria. Two episodes were initial presentations of aTTP; in five instances, patients experienced a relapse. In four episodes, moderate to severe organ dysfunction was observed; three cases presented with a mild course. All patients received caplacizumab immediately once aTTP was suspected or diagnosed, and plasma exchange was omitted based on shared decision making between patient and the treating physicians.

Results: We observed a rapid and robust increase of platelet counts already after the first dose of caplacizumab, leading to a doubling of platelet counts within 17 hours (median), platelet counts normalized (>150 G/L) after median 84 hours. Lactate dehydrogenase, as a surrogate parameter of organ damage, improved in parallel to the platelet counts, indicating resolving microangiopathy.

Conclusions: In conclusion, in selected cases of acute bouts of aTTP, it seems feasible to delay or omit plasma exchange if platelet counts increase and organ function is stable after start of caplacizumab therapy.
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http://dx.doi.org/10.1111/jth.15045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692904PMC
November 2020

A phase 1 study to evaluate the feasibility and efficacy of the addition of ropeginterferon alpha-2b to imatinib treatment in patients with chronic phase chronic myeloid leukemia (CML) not achieving a deep molecular response (molecular remission 4.5)-AGMT_CML 1.

Hematol Oncol 2020 Dec 19;38(5):792-798. Epub 2020 Aug 19.

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

The goal of current management of patients with chronic phase chronic myeloid leukemia (CML) is to reach treatment-free remission with sustained deep molecular remission (DMR) being the prerequisite therefor. Second-generation tyrosine kinase inhibitors can induce deeper and faster remission than imatinib, but are often associated with severe adverse events (AEs). The combination of pegylated interferon (IFN) with imatinib was shown to induce higher molecular remissions than imatinib alone in two studies. Treatment discontinuation rates due to IFN induced AEs were high in both studies. To investigate safety, tolerability (primary objective), and efficacy (secondary objective) of the combination of imatinib with ropeginterferon alpha-2b this phase I study was initiated. Twelve patients were planned to be enrolled. Nine patients completed the study according to protocol. Three patients terminated the study early, one due to occurrence of a dose-limiting toxicity (neutropenia grade 3), one due to an AE (panic attacks grade 2) and one due to the patient's decision. Tolerability was good, non-hematologic AEs were mainly grade 1/2, hematologic AEs were mainly neutropenias. No new AEs were reported for the combination of imatinib and ropeginterferon alpha-2b. In a nondose-dependent manner the addition of ropeginterferon alpha-2b led to the achievement of a DMR in four out of nine patients after a treatment duration of 18 months. The combination of imatinib and ropeginterferon alpha-2b is safe and showed in this phase I study the ability to deepen the molecular response in patients with chronic phase CML not achieving a DMR with imatinib alone.
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http://dx.doi.org/10.1002/hon.2786DOI Listing
December 2020

Successful kidney transplantation in a patient with pre-existing chronic myeloid leukemia treated with imatinib.

Am J Transplant 2021 01 4;21(1):405-409. Epub 2020 Aug 4.

Department of Nephrology and Hypertension Diseases, Transplantation Medicine and Rheumatology, Ordensklinikum Linz, Krankenhaus Elisabethinen, Linz, Austria.

Active malignancy is an absolute contraindication to kidney transplantation. As for chronic myeloid leukemia (CML), a Philadelphia chromosome-positive myeloproliferative neoplasm, the introduction of tyrosine kinase inhibitors has transformed CML from a lethal into a manageable chronic disease with a close-to-normal life expectancy. To date it is unknown whether kidney transplantation can be safely performed in patients with pre-existing CML. We describe the clinical course of a 57-year-old male patient with chronic kidney disease caused by reflux nephropathy. This patient had undergone first kidney transplantation 20 years earlier and had again been on chronic hemodialysis for 6 years when CML was diagnosed. First-line therapy with 400 mg imatinib daily was well tolerated and induced an optimal cytogenetic and molecular response 3 months after initiation. One and a half years after CML diagnosis, a second kidney transplantation from a deceased donor was performed. Immunosuppression included basiliximab, tacrolimus, mycophenolate mofetil, and corticosteroids. Currently, 2 years posttransplant, renal allograft function is stable (serum creatinine 1.09 mg/dL, estimated glomerular filtration rate 75 mL/min per 1.73 m ), and CML remains in deep molecular remission with imatinib. Imatinib-treated CML in deep molecular remission could be regarded as inactive malignancy and may therefore not be viewed as an absolute contraindication to kidney transplantation.
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http://dx.doi.org/10.1111/ajt.16194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818412PMC
January 2021

A multicenter retrospective evaluation of Chronic Myeloid Leukemia (CML) therapy in Austria assessing the impact of early treatment response on patient outcomes in a real-life setting : R-EFECT study.

Wien Klin Wochenschr 2020 Aug 12;132(15-16):415-422. Epub 2020 Jun 12.

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

Background: Several clinical trials in chronic phase (CP) chronic myeloid leukemia (CML) showed that early response to tyrosine kinase inhibitor (TKI) treatment results in an improved long-term survival and progression-free survival. This study assessed whether patients achieving early treatment response (ETR; partial cytogenetic response or BCR-ABL1 mRNA ≤10% at 3 months) in daily practice also have a long-term survival benefit.

Methods: The Retrospective Evaluation of Early response in CML for long-term Treatment outcome (R-EFECT), a multicenter, retrospective chart review, documented patients with newly diagnosed CML-CP starting first-line TKI therapy in routine clinical practice. The primary aim was to assess the 5‑year overall survival rate.

Results: Of the 211 patients from 12 centers across Austria (January 2004-May 2010), 176 (median age, 56 years) were included in the analysis. All patients received first-line therapy with imatinib. Overall, 136 patients (77.3%) achieved ETR (ETR+ group), whereas 40 (22.7%) did not reach ETR (ETR- group). The ETR+ group had higher 5‑year overall survival (92.5% vs. 77.5%, P = 0.018) and progression-free survival (95.6% vs. 87.5%, P = 0.06) rates compared with the ETR- group. As expected, more patients in the ETR- group were switched to another TKI. At the last contact, 120 patients were still on imatinib and 44 had switched to another TKI (25 to nilotinib, 15 to dasatinib, and 4 to bosutinib).

Conclusion: The data are in line with randomized trials demonstrating that ETR is associated with improved survival and thus confirmed these results in patients treated in daily clinical routine.
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http://dx.doi.org/10.1007/s00508-020-01690-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445202PMC
August 2020

SFRP1 promotor methylation analysis of FTA card touch-prep samples derived from colonic polyps.

Exp Mol Pathol 2020 06 30;114:104397. Epub 2020 Jan 30.

Institute of Clinical Chemistry and Laboratory Medicine, General Hospital, Steyr, Austria; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University, Graz, Austria.

Whatman FTA® cards provide the most reliable method for DNA storage and extraction, however, the literature lacks reports on the epigenetic analysis of FTA card-derived tumor DNA. Therefore, this study aimed at demonstrating that punches from colonic adenoma samples preserved on FTA filter cards are suitable for methylation analysis by real-time methylation-specific PCR (MSP). Genomic DNA was isolated from a total of 40 sporadic colorectal adenoma samples stored on FTA cards for a median of 59.60 (range 48-72) months. After bisulfite treatment, deaminated DNA was analyzed by SYBR Green real-time MSP using primers specific for methylated and unmethylated promotor sequences of the secreted frizzled-related protein 1 (SFRP1) gene. Amplifiable DNA could be isolated from all FTA card punches while SFRP1 promotor methylation was present in 34/40 (85.0%) colorectal adenomas. Our results indicate that genomic DNA isolated from colonic tumor samples preserved on FTA cards is suitable for downstream methylation detection methodologies such as MSP even after prolonged storage periods.
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http://dx.doi.org/10.1016/j.yexmp.2020.104397DOI Listing
June 2020

A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia - the TEAM-ET 2·0 trial.

Br J Haematol 2019 05 28;185(4):691-700. Epub 2019 Mar 28.

AOP Orphan Pharmaceuticals AG, Vienna, Austria.

Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing frequency and improving tolerability, without diminishing efficacy. This multicentre, randomized, double blind, active-controlled, non-inferiority trial investigated the efficacy, safety and tolerability of anagrelide prolonged release (A-PR) over a reference product in high-risk ET patients, either anagrelide-naïve or -experienced. In a 6 to 12-week titration period the individual dose for the consecutive 4-week maintenance period was identified. The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, 28). Of 112 included patients 106 were randomized. The mean screening platelet counts were 822 × 10 /l (95% confidence interval (CI) 707-936 × 10 /l) and 797 × 10 /l (95% CI 708-883 × 10 /l) for A-PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 10 /l for A-PR (95% CI 254-311) and 305 × 10 /l (95% CI 276-337) for the reference product (P < 0·0001, for non-inferiority). Safety and tolerability were comparable between both drugs. The novel prolonged-release formulation was equally effective and well tolerated compared to the reference product. A-PR provides a more convenient dosing schedule and will offer an alternative to licensed immediate-release anagrelide formulations.
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http://dx.doi.org/10.1111/bjh.15824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594023PMC
May 2019

Correction to: Ruxolitinib therapy formyelofibrosis in Austria : Consensus on therapy management.

Wien Klin Wochenschr 2019 01;131(1-2):47

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University Vienna, Vienna, Austria.

Correction to:Wien Klin Wochenschr 2018 https://doi.org/10.1007/s00508-018-1365-5 The original version of this article unfortunately contained a mistake. Table Nr. 1 was inconsistent. The corrected version of Table 1 is given below. We apologize for any inconveniences this may have ….
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http://dx.doi.org/10.1007/s00508-018-1428-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828473PMC
January 2019

Ruxolitinib therapy for myelofibrosis in Austria : Consensus on therapy management.

Wien Klin Wochenschr 2018 Sep 24;130(17-18):495-504. Epub 2018 Jul 24.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University Vienna, Vienna, Austria.

The oral Janus associated kinase (JAK1/2) inhibitor ruxolitinib has been available for treatment of patients with intermediate or high-risk myelofibrosis in Europe since 2012. Since its introduction, the expertise of prescribing doctors with respect to ruxolitinib function, efficacy and adverse effects has consistently been augmented, resulting in therapy modalities that are better tailored to individual patients as well as in increased safety of the treatment. The present consensus on ruxolitinib therapy management has been elaborated by Austrian experts in myeloproliferative neoplasms in line with international treatment guidelines. Our recommendations aim to contribute to an improved management of patients with myelofibrosis treated with ruxolitinib.
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http://dx.doi.org/10.1007/s00508-018-1365-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132876PMC
September 2018

Austrian recommendations for the management of polycythemia vera.

Wien Klin Wochenschr 2018 Sep 19;130(17-18):535-542. Epub 2018 Jul 19.

Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria.

Polycythemia vera (PV) is a clonal disease arising from hematopoietic stem cells. Erythrocytosis is the hallmark of the disease but leukocytosis, thrombocytosis and splenomegaly may also be present. Thromboembolic complications occur in about 20% of patients. Circulatory disturbances as well as pruritus represent frequent symptoms of the disease. Mutations in the JAK2 gene are present in 95% of patients in exon 14 (V617F) and in 3% in exon 12. The main goal of the treatment for patients with PV is the prevention of thromboembolic events, transformation to myelofibrosis and acute myeloid leukemia. Interferon alpha and hydroxyurea are used as first-line treatment for high risk patients. For patients unresponsive to first-line therapy ruxolitinib is available.
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http://dx.doi.org/10.1007/s00508-018-1359-3DOI Listing
September 2018

Abundance of the Organic Anion-transporting Polypeptide OATP4A1 in Early-Stage Colorectal Cancer Patients: Association With Disease Relapse.

Appl Immunohistochem Mol Morphol 2019 03;27(3):185-194

Department of Pathophysiology and Allergy Research, Medical University of Vienna.

The abundance of OATP4A1 in colorectal cancer (CRC) might be related to tumor progression. This was studied by immunohistochemistry on paraffin-embedded samples obtained from 178 patients (43 patients with a relapse within 5 y) with early-stage CRC. Positivity for OATP4A1 in tumor cells and noncancerous mucosal cells was proved by double-immunofluorescence staining with antibodies against OATP4A1 and keratin 8, whereas antibodies against appropriate CD markers were used to identify immune cells. Automated microscopic image analysis was used to measure the percentage of OATP4A1-positive cells and OATP4A1 staining intensity in tumor, immune, and adjacent normal-looking mucosal cells separately, as well as in the mucosal and immune cells of 14 nonmalignant tissue samples. In CRC the percentage of OATP4A1-positive cells, but not staining intensity, was significantly higher in tumor and mucosal cells adjacent to the tumor compared to the mucosa of nonmalignant samples (P<0.001 each). No difference was registered between immune cells in malignant and nonmalignant samples. Importantly, high levels of OATP4A1 in immune (odds ratio, 0.73; confidence interval, 0.63-0.85; P<0.001), and tumor cells (odds ratio, 0.79; confidence interval, 0.69-0.91; P<0.001) are significantly associated with a low risk of recurrence and also significantly enhance the discriminative power of other clinical parameters [such as International Union Against Cancer (UICC), adjuvant therapy, localization of the primary tumor] of the risk of relapse (receiver operating characteristics analysis; P=0.002). Using an advanced digital microscopic quantification procedure, we showed that OATP4A1 abundance is negatively associated with tumor recurrence in early-stage CRC. This digital scoring procedure may serve as a novel tool for the assessment of potential prognostic markers in early-stage CRC.
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http://dx.doi.org/10.1097/PAI.0000000000000557DOI Listing
March 2019

Impact of white blood cells on thrombotic risk in patients with optimized platelet count in essential thrombocythemia.

Eur J Haematol 2018 Mar 30. Epub 2018 Mar 30.

Division of Hematology and Blood Coagulation, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

Objectives: Risk of thrombosis is significantly enhanced by both elevated platelet (PLT) and white blood cell (WBC) counts according to a retrospective analysis of a large anagrelide registry in thrombocythemic MPN patients. We were interested in the impact of elevated WBC counts on thrombosis risk in patients where PLT counts were reduced below the calculated cutoff of 574.5 G/L by treatment with anagrelide.

Methods: Cox regression analysis and Kaplan-Meier plot were applied on all patients in the registry with optimized PLT counts.

Results: Using the calculated cutoff of 9.66 G/L for WBC, Cox regression analysis revealed a clear influence of elevated WBC counts on the occurrence of a major thrombotic event (P = .012). A Kaplan-Meier plot revealed a markedly shorter time to a major thrombotic event for patients with WBC counts above the cutoff (P = .001).

Conclusions: These data suggest that additional correction of elevated WBC counts is mandatory in patients with optimally managed PLT counts to reduce thrombotic risk. This study is the first investigation in a prospectively observed large patient cohort which was treated homogenously allowing for evaluation of single parameters for an effect on thrombophilia.
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http://dx.doi.org/10.1111/ejh.13070DOI Listing
March 2018

Intensive consolidation with G-CSF support: Tolerability, safety, reduced hospitalization, and efficacy in acute myeloid leukemia patients ≥60 years.

Am J Hematol 2017 Oct 17;92(10):E567-E574. Epub 2017 Aug 17.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Wien, Austria.

The aim of this study was to evaluate the efficacy and feasibility of intensified consolidation therapy employing fludarabine and ARA-C in cycle 1 and intermediate-dose ARA-C (IDAC) in cycles 2 through 4, in elderly acute myeloid leukemia (AML) patients and to analyze the effects of pegfilgrastim on the duration of neutropenia, overall toxicity, and hospitalization-time during consolidation in these patients. Thirty nine elderly patients with de novo AML (median age 69.9 years) who achieved complete remission (CR) after induction-chemotherapy were analyzed. To examine the effect of pegfilgrastim on neutropenia and hospitalization, we compared cycles 2 and 4 where pegfilgrastim was given routinely from day 6 (IDAC-P) with cycle 3 where pegfilgrastim was only administered in case of severe infections and/or prolonged neutropenia. All four planned cycles were administered in 23/39 patients (59.0%); 5/39 patients (12.8%) received 3 cycles, 3/39 (7.7%) 2 cycles, and 8/39 (20.5%) one consolidation-cycle. The median duration of severe neutropenia was 7 days in cycle 2 (IDAC-P), 11.5 days in cycle 3 (IDAC), and 7.5 days in cycle 4 (IDAC-P) (P < .05). Median overall survival was 1.1 years and differed significantly between patients aged <75 and ≥75 years (P < .05). The probability to be alive after 5 years was 32%. Together, intensified consolidation can be administered in AML patients ≥60, and those who are <75 may benefit from this therapy. Routine administration of pegfilgrastim during consolidation shortens the time of neutropenia and hospitalization in these patients.
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http://dx.doi.org/10.1002/ajh.24847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115890PMC
October 2017

Pre-fibrotic/early primary myelofibrosis vs. WHO-defined essential thrombocythemia: The impact of minor clinical diagnostic criteria on the outcome of the disease.

Am J Hematol 2017 Sep 9;92(9):885-891. Epub 2017 Jun 9.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

The 2016 revised WHO criteria for the diagnosis of pre-fibrotic/early primary myelofibrosis (pre-PMF) require at least one of the following four borderline expressed minor clinical criteria: anemia, leukocytosis, elevated lactate dehydrogenase and splenomegaly. In this study, we evaluated the relative frequency of these four criteria in a group of 170 pre-PMF patients and compared them to 225 ET cases. More than 91% of pre-PMF cases showed one or more of these features required for diagnosis, by contrast with only 48% of ET patients. According to clinical data the cumulative risk of progression to advanced/overt PMF in pre-PMF was 36.9% after 15 years. After fitting cox regression models to analyze the impact of the minor criteria on overall survival, only leukocytosis remained as a significant predictor of survival in both pre-PMF and ET. Molecular characterization showed differences in survival in pre-PMF but not ET, with CALR being a more favorable mutation than JAK2. The different outcome of pre-PMF versus ET and associated molecular genetic data supports the concept of two different entities, rather than a continuum of the same disease. Although slightly less than 50% of ET patients also show one or more minor clinical criteria, accurate distinction between ET and pre-PMF is possible by following an integrated approach including histomorphological diagnosis and presence of minor clinical criteria.
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http://dx.doi.org/10.1002/ajh.24788DOI Listing
September 2017

HLA-C KIR-Ligands Determine the Impact of Anti-Thymocyte Globulin (ATG) on Graft versus Host and Graft versus Leukemia Effects Following Hematopoietic Stem Cell Transplantation.

Biomedicines 2017 Mar 28;5(2). Epub 2017 Mar 28.

Department of Hematology and Oncology, Medical University, 6020 Innsbruck, Austria.

Rabbit anti-thymocyte globulins (ATGs) are widely used for the prevention of acute and chronic graft versus host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (HSCT). However, most prospective and retrospective studies did not reveal an overall survival (OS) benefit associated with ATG. Homozygosity for human leukocyte antigen (HLA)-C group 1 killer-cell immunoglobulin-like receptor ligands (KIR-L), i.e. C1/1 KIR-L status, was recently shown to be a risk factor for severe aGVHD. Congruously, we have previously reported favorable outcomes in C1/1 recipients after ATG-based transplants in a monocentric analysis. Here, within an extended cohort, we test the hypothesis that incorporation of ATG for GVHD prophylaxis may improve survival particularly in HSCT recipients with at least one C1 KIR-ligand. Retrospectively, 775 consecutive allogeneic (excluding haploidentical) HSCTs were analyzed, including peripheral blood and bone marrow grafts for adults with hematological diseases at two Austrian HSCT centers. ATG-Fresenius/Grafalon, Thymoglobuline, and alemtuzumab were applied in 256, 87, and 7 transplants, respectively (subsequently summarized as "ATG"), while 425 HSCT were performed without ATG. Median follow-up of surviving patients is 48 months. Adjusted for age, disease-risk, HLA-match, donor and graft type, sex match, cytomegalovirus serostatus, conditioning intensity, and type of post-grafting GVHD prophylaxis, Cox regression analysis of the entire cohort ( 775) revealed a significant association of ATG with decreased non-relapse mortality (NRM) (risk ratio (RR), 0.57; 0.001), and overall mortality (RR, 0.71; 0.014). Upon stratification for HLA-C KIR-L, the greatest benefit for ATG emerged in C1/1 recipients ( 291), by reduction of non-relapse (RR, 0.34; 0.0002) and overall mortality (RR, 0.50; 0.003). Less pronounced, ATG decreased NRM (RR, 0.60; 0.036) in HLA-C group 1/2 recipients ( 364), without significantly influencing overall mortality (RR, 0.70; 0.065). After exclusion of higher-dose ATG-based transplants, serotherapy significantly improved both NRM (RR, 0.54; 0.019; 322) and overall mortality (RR, 0.60; 0.018) in C1/2 recipients as well. In both, C1/1 (RR, 1.70; 0.10) and particularly in C1/2 recipients (RR, 0.94; 0.81), there was no statistically significant impact of ATG on relapse incidence. By contrast, in C2/2 recipients ( 121), ATG neither reduced NRM (RR, 1.10; 0.82) nor overall mortality (RR, 1.50; 0.17), but increased the risk for relapse (RR, 4.38; 0.02). These retrospective findings suggest ATG may provide a survival benefit in recipients with at least one C1 group KIR-L, by reducing NRM without significantly increasing the relapse risk.
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http://dx.doi.org/10.3390/biomedicines5020013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489799PMC
March 2017

Austrian recommendations for the management of primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis: an expert statement.

Wien Klin Wochenschr 2017 May 13;129(9-10):293-302. Epub 2016 Dec 13.

Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria.

The entity "myelofibrosis" represents a subgroup of the Philadelphia chromosome-negative myeloproliferative neoplasms. It comprises primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. This heterogeneous disease is characterized by clonal myeloproliferation, dysregulated kinase signalling and the abnormal expression of several proinflammatory cytokines. Clinically, patients present with symptoms related to thrombocytosis/leukocytosis, anemia and/or progressive splenomegaly. Mutations in Janus kinase 2, an enzyme that is essential for the normal development of erythrocytes, granulocytes, and platelets, notably the V617F mutation, have been identified in approximately 60% of patients with primary myelofibrosis. Recent molecular advances have not only elucidated critical pathways in the pathogenesis of the disease, but also contributed to a more precise assessment of a patient's individual risk. While allogeneic stem cell transplantation remains the only curative treatment, the natural course of the disease and the patient's survival and quality of life may be improved by new treatments, notably ruxolitinib, the first Janus kinase 1/2 inhibitor approved for the management of myelofibrosis. Additional treatment options are being explored.
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http://dx.doi.org/10.1007/s00508-016-1120-8DOI Listing
May 2017

Plerixafor as preemptive strategy results in high success rates in autologous stem cell mobilization failure.

J Clin Apher 2017 Aug 31;32(4):224-234. Epub 2016 Aug 31.

Division of Haematology, Medical University of Graz, Austria.

Plerixafor in combination with granulocyte-colony stimulating factor (G-CSF) is approved for autologous stem cell mobilization in poor mobilizing patients with multiple myeloma or malignant lymphoma. The purpose of this study was to evaluate efficacy and safety of plerixafor in an immediate rescue approach, administrated subsequently to G-CSF alone or chemotherapy and G-CSF in patients at risk for mobilization failure. Eighty-five patients mobilized with G-CSF alone or chemotherapy were included. Primary endpoint was the efficacy of the immediate rescue approach of plerixafor to achieve ≥2.0 × 10 CD34 cells/kg for a single or ≥5 × 10 CD34 cells/kg for a double transplantation and potential differences between G-CSF and chemotherapy-based mobilization. Secondary objectives included comparison of stem cell graft composition including CD34 cell and lymphocyte subsets with regard to the mobilization regimen applied. No significant adverse events were recorded. A median 3.9-fold increase in CD34 cells following plerixafor was observed, resulting in 97% patients achieving at least ≥2 × 10 CD34+ cells/kg. Significantly more differentiated granulocyte and monocyte forming myeloid progenitors were collected after chemomobilization whereas more CD19 and natural killer cells were collected after G-CSF. Fifty-two patients underwent transplantation showing rapid and durable engraftment, irrespectively of the stem cell mobilization regimen used. The addition of plerixafor in an immediate rescue model is efficient and safe after both, G-CSF and chemomobilization and results in extremely high success rates. Whether the differences in graft composition have a clinical impact on engraftment kinetics, immunologic recovery, and graft durability have to be analysed in larger prospective studies.
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http://dx.doi.org/10.1002/jca.21496DOI Listing
August 2017

Impact of white blood cell counts at diagnosis and during follow-up in patients with essential thrombocythaemia and prefibrotic primary myelofibrosis.

Br J Haematol 2017 10 19;179(1):166-169. Epub 2016 Jul 19.

Division of Haematology and Blood Coagulation, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1111/bjh.14202DOI Listing
October 2017

Influence of platelet and white blood cell counts on major thrombosis - analysis from a patient registry in essential thrombocythemia.

Eur J Haematol 2016 Dec 23;97(6):511-516. Epub 2016 May 23.

Division of Hematology and Blood Coagulation, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

Objectives: Although guidelines recommend normalization of platelet counts as an appropriate endpoint for treatment in high-risk essential thrombocythemia (ET), retrospective studies could not prove a correlation of diagnostic platelet counts with an increased thrombotic rate. There is, however, an increasing evidence that leukocytosis is an important risk factor for arterial thrombosis in myeloproliferative neoplasms.

Methods: This study considers the Austrian cohort of a European registry regarding the platelet-lowering therapeutic anagrelide. Influence of platelet and white blood cell (WBC) counts on thrombotic risk was assessed.

Results: Using the calculated cutoffs of 574.5 G/L for platelets and 8.48 G/L for WBC counts, respectively, the Cox regression analysis revealed a clear influence of elevated platelets (P = 0.008) and WBC counts (P = 0.011) on the occurrence of major thrombotic events. The time to a major thrombotic event was shortest (P < 0.001) and the frequency related to 100 patient-years was highest (P = <0.001) when both platelet and WBC counts ranged above the calculated cutoffs.

Conclusion: Our data add evidence to the impact of platelet and WBC counts on thrombosis in ET. We suspect a particular interaction between platelets and WBC which might be based on a biological interplay depending on particular cell counts.
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http://dx.doi.org/10.1111/ejh.12759DOI Listing
December 2016

Functional characterization, localization, and inhibitor sensitivity of the TPR-FGFR1 fusion in 8p11 myeloproliferative syndrome.

Genes Chromosomes Cancer 2016 Jan 22;55(1):60-8. Epub 2015 Sep 22.

Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I, Hospital Barmherzige Schwestern, Linz, Austria.

Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities.
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http://dx.doi.org/10.1002/gcc.22311DOI Listing
January 2016

Iron metabolism and iron supplementation in cancer patients.

Wien Klin Wochenschr 2015 Dec 15;127(23-24):907-19. Epub 2015 Sep 15.

Medizinische Klinik I, Westpfalz-Klinikum, Kaiserslautern, Germany.

Iron deficiency and iron deficiency-associated anemia are common complications in cancer patients. Most iron deficient cancer patients present with functional iron deficiency (FID), a status with adequate storage iron, but insufficient iron supply for erythroblasts and other iron dependent tissues. FID is the consequence of the cancer-associated cytokine release, while in absolute iron deficiency iron stores are depleted resulting in similar but often more severe symptoms of insufficient iron supply. Here we present a short review on the epidemiology, pathophysiology, diagnosis, clinical symptoms, and treatment of iron deficiency in cancer patients. Special emphasis is given to intravenous iron supplementation and on the benefits and limitations of different formulations. Based on these considerations and recommendations from current international guidelines we developed recommendations for clinical practice and classified the level of evidence and grade of recommendation according to the principles of evidence-based medicine.
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http://dx.doi.org/10.1007/s00508-015-0842-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679104PMC
December 2015

Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera.

Blood 2015 Oct 10;126(15):1762-9. Epub 2015 Aug 10.

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

In this prospective, open-label, multicenter phase 1/2 dose escalation study, we used a next-generation, mono-pegylated interferon (IFN) α-2b isoform, ropeginterferon alfa-2b. The unique feature of ropeginterferon alfa-2b is a longer elimination half-life, which allows administration every 2 weeks. We present data from 51 polycythemia vera patients. The main goal was to define the maximum tolerated dose and to assess safety and efficacy. A dose range of 50 to 540 µg was tested without the appearance of dose-limiting toxicities. All drug-related adverse events were known toxicities associated with IFN-α. The cumulative overall response rate was 90%, comprising complete response in 47% and partial response in 43% of patients; the best individual molecular response level was a complete response in 21% of patients and partial response in 47%. Notably, we did not observe any correlation between the dose level and the response rate or response duration, suggesting that already low levels of ropeginterferon alfa-2b are sufficient to induce significant hematologic and molecular responses. These data suggest promising efficacy and safety of ropeginterferon alfa-2b and support the development of the drug in a randomized phase 3 clinical trial. The study was disclosed at www.clinicaltrials.gov as #NCT01193699 before including the first patient.
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http://dx.doi.org/10.1182/blood-2015-04-637280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608390PMC
October 2015

Molecular responses and chromosomal aberrations in patients with polycythemia vera treated with peg-proline-interferon alpha-2b.

Am J Hematol 2015 Apr 2;90(4):288-94. Epub 2015 Mar 2.

CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Fifty-one polycythemia vera (PV) patients were enrolled in the phase I/II clinical study PEGINVERA to receive a new formulation of pegylated interferon alpha (peg-proline-IFNα-2b, AOP2014/P1101). Peg-proline-IFNα-2b treatment led to high response rates on both hematologic and molecular levels. Hematologic and molecular responses were achieved for 46 and 18 patients (90 and 35% of the whole cohort), respectively. Although interferon alpha (IFNα) is known to be an effective antineoplastic therapy for a long time, it is currently not well understood which genetic alterations influence therapeutic outcomes. Apart from somatic changes in specific genes, large chromosomal aberrations could impact responses to IFNα. Therefore, we evaluated the interplay of cytogenetic changes and IFNα responses in the PEGINVERA cohort. We performed high-resolution SNP microarrays to analyze chromosomal aberrations prior and during peg-proline-IFNα-2b therapy. Similar numbers and types of chromosomal aberrations in responding and non-responding patients were observed, suggesting that peg-proline-IFNα-2b responses are achieved independently of chromosomal aberrations. Furthermore, complete cytogenetic remissions were accomplished in three patients, of which two showed more than one chromosomal aberration. These results imply that peg-proline-IFNα-2b therapy is an effective drug for PV patients, possibly including patients with complex cytogenetic changes.
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http://dx.doi.org/10.1002/ajh.23928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657499PMC
April 2015

Specific expression of OATPs in primary small cell lung cancer (SCLC) cells as novel biomarkers for diagnosis and therapy.

Cancer Lett 2015 Jan 6;356(2 Pt B):517-24. Epub 2014 Oct 6.

Cluster for Translational Oncology, Ludwig Boltzmann Society, Vienna, Austria; Department of Internal Medicine 2, Donauspital, Vienna, Austria.

The expression of organic anion transporting polypeptides (OATPs) was elucidated in cell lines from small cell lung cancer (SCLC) and lung carcinoids and in paraffin-embedded samples from primary and metastatic SCLCs. We found a strong relationship between OATP expression and the origin of the cells, as cells from primary or metastatic SCLC and carcinoid tumors differ with respect to OATP levels. OATP4A1 is most prominent in non-malignant lung tissue and in all SCLC and carcinoid cell lines and tissues, OATP5A1 is most prominent in metastatic cells, and OATP6A1 is most prominent in SCLC cell lines and tumors. Treatment with topotecan, etoposide and cisplatin caused significant changes in the expression patterns of OATP4A1, OATP5A1, OATP6A1, chromogranin and synaptophysin. This effect was also evident in GLC-14 cells from an untreated SCLC patient before chemotherapy compared to GLC-16/-19 chemoresistant tumor cells from this patient after therapy. mRNA expression of OATP4A1, 5A1 and 6A1 correlates with protein expression as confirmed by quantitative microscopic image analysis and Western blots. OATPs might be novel biomarkers for tumor progression and the development of metastasis in SCLC patients.
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http://dx.doi.org/10.1016/j.canlet.2014.09.025DOI Listing
January 2015

Decanucleotide insertion polymorphism of F7 significantly influences the risk of thrombosis in patients with essential thrombocythemia.

Eur J Haematol 2014 Aug 23;93(2):103-11. Epub 2014 Apr 23.

Division of Hematology and Blood Coagulation, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria.

Objective: There is strong evidence that certain thrombophilic single nucleotide polymorphisms (SNPs) account for an increased risk of thrombosis. The additive impact of inherited thrombotic risk factors to a certain disease- immanent thrombotic risk is vastly unknown. Therefore, we aimed to investigate the influence of three novel, preselected SNPs on the risk of thrombosis in patients diagnosed with myeloproliferative neoplasm (MPN).

Method: In 167 patients with a diagnosis of essential thrombocythemia (ET) or prefibrotic primary myelofibrosis (PMF) thrombophilic SNPs in the genes of factor VII (F7), nitric oxide synthase 3 (NOS3) and FcɣRIIa (FCGR2A) were determined. Subsequently, the polymorphic variants were correlated with the incidence of major thrombosis after diagnosis.

Results: Decanucleotide insertion polymorphism of F7 emerged as an independent, significant risk factor for total thrombosis and arterial thrombosis in particular in the whole group of patients (P = 0.0007) as well as in the separate analysis of patients with ET (P = 0.0002).

Conclusion: Our results illustrate that the risk of thrombosis in MPN is significantly multiplied by inherited thrombophilic SNPs. This result points to the importance of a combined consideration of the inherited and the acquired hypercoagulable state in patients with MPN. Larger studies are needed to confirm and extend these important findings.
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http://dx.doi.org/10.1111/ejh.12307DOI Listing
August 2014

Tumor-specific expression of organic anion-transporting polypeptides: transporters as novel targets for cancer therapy.

J Drug Deliv 2013 3;2013:863539. Epub 2013 Feb 3.

Department of Medicine, Donauspital, Ludwig Boltzmann, Cluster for Translational Oncology, Vienna, Austria.

Members of the organic anion transporter family (OATP) mediate the transmembrane uptake of clinical important drugs and hormones thereby affecting drug disposition and tissue penetration. Particularly OATP subfamily 1 is known to mediate the cellular uptake of anticancer drugs (e.g., methotrexate, derivatives of taxol and camptothecin, flavopiridol, and imatinib). Tissue-specific expression was shown for OATP1B1/OATP1B3 in liver, OATP4C1 in kidney, and OATP6A1 in testis, while other OATPs, for example, OATP4A1, are expressed in multiple cells and organs. Many different tumor entities show an altered expression of OATPs. OATP1B1/OATP1B3 are downregulated in liver tumors, but highly expressed in cancers in the gastrointestinal tract, breast, prostate, and lung. Similarly, testis-specific OATP6A1 is expressed in cancers in the lung, brain, and bladder. Due to their presence in various cancer tissues and their limited expression in normal tissues, OATP1B1, OATP1B3, and OATP6A1 could be a target for tumor immunotherapy. Otherwise, high levels of ubiquitous expressed OATP4A1 are found in colorectal cancers and their metastases. Therefore, this OATP might serve as biomarkers for these tumors. Expression of OATP is regulated by nuclear receptors, inflammatory cytokines, tissue factors, and also posttranslational modifications of the proteins. Through these processes, the distribution of the transporter in the tissue will be altered, and a shift from the plasma membrane to cytoplasmic compartments is possible. It will modify OATP uptake properties and, subsequently, change intracellular concentrations of drugs, hormones, and various other OATP substrates. Therefore, screening tumors for OATP expression before therapy should lead to an OATP-targeted therapy with higher efficacy and decreased side effects.
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http://dx.doi.org/10.1155/2013/863539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574750PMC
February 2013