Introduction Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts, risk of vascular events and disease progression to myelofibrosis or acute leukemia. Most available therapies primarily focus on reducing platelet counts without any demonstrated impact on disease progression. Moreover, these treatments are often limited by intolerance, resistance or contraindications, leaving a substantial proportion of patients without satisfactory therapeutic options. Ropeginterferon alfa-2b (BESREMi®), a mono-pegylated, next-generation interferon alfa, approved globally for polycythemia vera with the potential to modify disease course, is being studied to address this unmet need. Methods This fully recruited, ongoing, phase 3, prospective, multicenter, single-arm study (ROP-ET; NCT06514807) enrolled adults with ET according to WHO 2016 criteria requiring cytoreduction, who were intolerant or resistant and/or ineligible for all locally approved cytoreductive therapies including hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman (PB). A single-arm design was selected due to lack of an ethically acceptable comparator. Ropeginterferon alfa-2b is administered subcutaneously every two weeks starting at 125μg, with dose escalation to 250μg and 500μg if needed to achieve hematologic response. The primary endpoint is a composite durable hematologic and clinical response after 12 months based on modified European LeukemiaNet (ELN) criteria, including peripheral blood count remission, absence of thrombotic/hemorrhagic events and disease progression, and symptom improvement measured by the MPN-SAF Total Symptom Score (MPN-SAF TSS). The sample size was determined to ensure at least 93 evaluable patients for 12-month primary analysis (10% precision), with target enrollment of at least 117 to account for 20% dropout. The observed 12-month response rate will be statistically compared to a historical efficacy of 40%. Secondary endpoints include molecular response, quality of life, safety, and long-term outcomes. The total study duration is three years. Results A total of 132 ET patients received ropeginterferon alfa-2b. The study population had a median age of 56.5 years (range 22-87), included 58.3% females, and the median time from diagnosis was 3.3 years (range 0-25). Baseline median platelet count was 579 ×109/L (range 201-1958) and median white blood cell count was 7.3 ×109/L (range 3.2-20.5). At baseline, splenomegaly was present in 25.8% of patients and median MPN-SAF TSS was 8.0 (range 0-66). Driver mutations were distributed as follows: JAK2 (59.8%), CALR (27.9%), and MPL (1.6%). Risk stratification per revised IPSET-thrombosis criteria identified 43.8% patients as high, 13.8% as intermediate, 22.3% as low and 20% as very low risk. Of 132 patients 110 (83.3%) had prior cytoreductive therapy with either HU (32.6%), ANA (13.6%), HU and ANA (36.4%), or HU and PB (0.8%) but none received BUS. Among pre-treated patients, 107 (97.3%) patients were cytoreductive treatment resistant and/or intolerant with intolerance being most prominent (77.2% and 78.8% among HU and ANA pre-treated patients, respectively). All patients were interferon-naïve per inclusion criteria; 22 (16.7%) patients had not received any other cytoreductive therapy and were ineligible for all locally approved cytoreductive agents for ET. As of data cut-off (median exposure 301 days) treatment-emergent adverse events led to discontinuation in only 4 (3%) patients. The last patient 12-month visit will occur in Q3 2025 and primary endpoint results will be presented at the meeting. Conclusions Our study highlights the unmet need among ET patients of all risk levels for additional therapeutic options, since all patients enrolled required cytoreduction but were unable to receive locally approved agents. Aside reduction of thrombotic risk, ET patients, in particular younger individuals, have a significant lifetime risk of disease progression, requiring a disease modifying therapy. In this last-line population, treatment with ropeginterferon alfa-2b was well tolerated, with few discontinuations due to adverse events. The planned primary endpoint analysis will provide data on the efficacy of ropeginterferon alfa-2b in this underserved population.

OBJECTIVES:The acquired, somatic JAK2V617F mutation is the most common molecular aberration in patients with myeloproliferative neoplasms (MPN) and also significantly involved in the regulation of T cell immunity. PD-1, PD-L1 and CTLA-4 are key immune checkpoint regulators that are elevated in patients with solid tumors, infectious diseases and chronic inflammation. We aimed further investigating the significance of immune checkpoint expression in JAK2V617F positive MPN. METHODS:The surface expression of PD-L1, PD-1 and CTLA-4 on peripheral blood leukocytes was determined by flow cytometry in 27 patients with JAK2V617F positive MPN and in a control group of 26 healthy individuals and analyzed by immune checkpoint and leukocyte subpopulation. In addition, the concentration of soluble PD-L1 (sPD-L1) in plasma was examined by ELISA. RESULTS:PD-1, PD-L1 and CTLA-4 are significantly overexpressed on the surface of granulocytes in JAK2 positive patients compared to the control group. Soluble PD-L1 (sPD-L1) is elevated in the plasma of JAK2 positive patients and increases with decreased renal function. In CD8+ T-cells and CD4+ T-cells there is a significant negative correlation between PD-1 expression or sPD-L1 concentration and their corresponding cell count. CONCLUSIONS:Our study shows a significant increase of immune checkpoint regulators on the cellular surface as well as soluble PD-L1 in JAK2 mutated patients compared to healthy individuals. Increased activation of the JAK2/STAT signaling pathway by JAK2V617F appears to be a mechanism of reduced immune activation in patients with MPN. Immune checkpoint inhibition might therefore represent a potential additional therapeutic target in this disease group.

Background: Treatment of multiple myeloma has advanced tremendously with the approval of anti-CD38 antibodies. Their efficacy is impressive but still controversial in the 1q amplification subgroup (amp1q). This retrospective study aims to provide real-world data. Methods: This trial is analyzing 74 patients with relapsed/refractory multiple myeloma treated with CD38Abs at the Medical University of Innsbruck (2016–2023). High-risk (HR) cytogenetics according to R-ISS (t(4;14), t(14;16), t(14;20), del(17p)), the presence of amp(1q21), the frequency of two HR markers (double hit), and the high-risk criteria agreed at IMS 2024 (HR-IMS24) were considered. Results: The median age of the 74 patients (62.1% male) was 62 years, with a median follow-up of six years. Most patients received third-line therapy (37.8%). R-ISS HR was documented in 39.2% of patients, double hit in 13.5% of patients, and HR-IMS24 in 32.4% of patients, while amp1q was detected in 35.1% of patients. The median OS was 66 months (35–89), and the median PFS was 17 months (6.5–26.9). While neither R-ISS HR nor isolated amp1q had an impact on progression-free survival (e.g., amp1q 7.03: 1.95–22.44; p = 0.347), the occurrence of a double-hit pattern significantly impaired PFS and OS (6.2: 1.4–16.4 months; p = 0.044; OS, 42.8: 25.9–74.6 months; p = 0.035). Patients fulfilling the HR-IMS24 criteria (32.4%, 24 patients) also exhibited an impaired PFS and OS (7: 2.7–18.1 months, p = 0.023; 40.12: 21.1–74.5 months, p = 0.01). Conclusions: This retrospective study highlights the durable effect of daratumumab on cytogenetic abnormalities, particularly amp1q. However, patients who meet the criteria for double-hit myeloma or the high-risk IMS2024 criteria remain a difficult-to-treat patient population who require early access to new treatment approaches.

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

Monoclonal antibodies, as tixagevimab/cilgavimab, have been introduced as prophylaxis against COVID-19 infections in high-risk populations. However, data on efficacy are limited. This study investigates efficacy and tolerability of tixagevimab/cilgavimab in hematological patients under real-life conditions. Tixagevimab/cilgavimab was administered to 155 hematological patients (March-August 2022) at two Austrian centres. S/RBD-antibody assessments were performed before (T0), four weeks (T1), and six months (T2) after application. Side effects, the occurrence of COVID-19 infections, and the course of S/RBD-antibody titres were analysed retrospectively in relation to clinical variables. 155 hematological patients, who refused tixagevimab/cilgavimab, were included as a control group to compare the frequency of COVID-19 infections. Of all immunised patients (52.3

High quality research data management (RDM) is essential to support state of the art comprehensible and reproducible research processes and, thus, foster the sustainable production of novel and trustworthy research findings. While there are lots of national and international initiatives supporting researchers in all respects of RDM, the local infrastructures provide the foundation for these concepts. In this contribution, we present preliminary results of a study that collects the requirements of researchers on these local infrastructures in all seven higher education research institutions in Mecklenburg-Vorpommern (MV).

Background In general, urinary and faecal incontinence is a multifaceted problem that is associated with increasing burdens for those affected, a massive impairment of quality of life and economic consequences. Incontinence is associated with a high level of shame, which in particular reduces the self-esteem of those being incontinent and leads to additional vulnerability. Those affected by incontinence often perceive incontinence and the care they receiveas humiliating, hence they can no longer control their own urination; nursing care and cleansing support then lead to additional dependency. People with incontinence in need of care not uncommonly experience a poor communication and many taboos surrounding the issue as well as the use of force when incontinence products are changed. Aims and methods This RCT aims to validate the benefits of using a digital assistance system to optimise incontinence care and to enable statements concerning the effect of the assistance technology on nursing and social structures and processes as well as on the quality of life from the perspective of the person in need of care. In a two-arm, stratified, randomised, controlled interventional study, primarily incontinence-affected residents of four inpatient nursing facilities will be examined ( n = 80). One intervention group will be equipped with a sensor-based digital assistance system, which will transmit care-related information to the nursing staff (via smartphone). The collected data will be compared to the data of the control group. Primary endpoints are falls occurring; secondary endpoints are quality of life and sleep, sleep disturbances and material consumption. In addition, nursing staff ( n = 15–20) will be interviewed regarding the effects, experience, acceptance and satisfaction. Discussion The RCT aims at the applicability and effect of assistance technologies on nursing structures and processes. It is assumed that, amongst other things, this technology may lead to a reduction of unnecessary checks and material changes, an improvement of life quality, an avoidance of sleep disturbances and thus an improvement of sleep quality as well as to a reduced risk of falling for people with incontinence in need of care. The further development of incontinence care systems is of social interest as this offers the prospect of improving the quality of care for nursing home residents with incontinence. Trail registration Approval of the RCT is granted by the Ethics Committee at the University of Applied Sciences Neubrandenburg (Reg.-Nr.: HSNB/190/22). This RCT is registered at the German Clinical Trials Register on July 8 th , 2022, under the identification number DRKS00029635.

Treatment of myeloproliferative neoplasia (MPN) is based on patients' individual risk-stratification and includes cytoreductive agents for high-risk essential thrombocythemia (ET), polycythemia vera (PV) and Myelofibrosis (MF). Classical cytoreductive drugs largely fail to modify the basic clonal composition of the disease. In contrast, in PV for example treatment with Ropeg-Interferon not only results in higher hematological response rates compared to hydroxyurea but in addition significantly reduces JAK2 allele-burden in high-risk PV patients as well as it depletes concurrent cytogenetic and molecular abnormalities. Treatment with Ropeg-Interferon so far is only approved for high-risk PV. A very recent trial however also demonstrated this disease-modifying effect also in low-risk PV patients in addition to an increased rate of transfusion independence. Thus, Ropeg-Interferon is the current standard for first line treatment of high-risk PV and we assume that the data in low-risk PV will lead also to a broader clinical use of Ropeg-Interferon this particular patient group, as it may decrease transformation to MF or even MPN-blast crisis.Myelofibrosis management has been extended by novel JAKi. Fedratinib is the first second generation JAK-inhibitor approved for Ruxolitinib-intolerant or refractory patients. Fedratinib reduces both spleen volume as well as symptom burden. Two other second generation JAK-inhibitors are in clinical development for MPN treatment. Pacritinib has demonstrated efficacy in reducing both spleen volume and symptom score in MF including a cohort of Ruxolitinib-pretreated patients and Momelotinib is the only JAK-inhibitor which has been shown to alleviate anemia in addition to its effect on improving spleen volume and symptom. So far, neither Pacritinib nor Momelotinib are currently EMA-approved for MPN treatment.Finally, it has recently been acknowledged that inflammation is a key driver of MPN pathogenesis. Both, mutated as well as non-clonal inflammatory and other stromal cells produce significant amounts of local cytokines. Also the initiation of the neoplastic process itself seems to depend on inflammatory cytokines. Recent scRNASeq data revealed components of the alarmin complex (S100A8 und S100A9) drive this local sterile inflammation process, which also represents a potential therapeutic target, as the S100A8 and A9 inhibitor Tasquinimod reduced fibrosis in a pre-clinical animal model.

The global COVID-19 pandemic caused by SARS-CoV-2 is still ongoing and challenges societies and their health systems. While overall mortality rate is 1%–3% in the general population, death rates are up to 37% among hematological patients.1,2 These patients are prone to severe COVID-19 associated complications, for example, higher hospitalization and invasive ventilation rates. Considering the constant appearance of new mutations with potentially higher infection and mortality rates, and the fact that vaccination represents the most effective preventive measure for severe COVID-19, identification and prioritization of vulnerable patients is of utmost importance.3,4 In most hematological patients, a compromised immune system due to the disease per se, the treatment, or a combination of both, might be responsible for an increased risk for severe or even life-threatening COVID-19. Thus, identification of patient subgroups with appropriate vaccination responses is of clinical relevance. Numerous studies have meanwhile shown that immunocompromised (including hematologic or oncologic) patients have a risk to completely fail or mount only a suboptimal humoral immune responses to SARS-CoV-2 vaccines.5–8 At the time when COVID-19 vaccines became available for hematological patients in Austria, studies had not been published. At our department all hematological patients, irrespective of the underlying disease, current therapy status or age were vaccinated. Pursuing this strategy, we conducted a retrospective analysis in adult patients with malignant hematological diseases who received two doses of either BNT162b2 (Biontech/Pfizer), mRNA-1273 (Moderna Biotech) or AZD1222 (AstraZeneca) between January 2021 and May 2021 (Suppl. Figure S1A and B and Table S1). The trial protocol was approved by the ethics committee at Innsbruck Medical University (approval: 1331/2021). In total, we analyzed n = 123 patients, of these n = 43 patients suffered from myeloid, n = 63 from lymphoid malignancies, and n = 17 have undergone allogeneic peripheral blood stem cell transplantation (allo-SCT) (Suppl. Figure S1A). Antibodies against the nucleocapsid protein and the receptor-binding domain of the spike protein of SARS-CoV-2 were detected in serum using the Roche Elecsys Anti-SARS-CoV-2 assay on the Cobas e602 platform and the Abbott SARS-CoV-2 IgG II Quant assay on the ARCHITECT i platform, respectively (for details, see Suppl. Digital Methods). After the second vaccine dose (median: 35 d; interquartile range: 25–52 d) 102 patients (82.9%) mounted a humoral response to vaccination [defined by >7 binding antibody unit (BAU)/ml]. Patients with lymphoid malignancies have a significantly lower response rate as compared to myeloid malignancies or allo-SCT (71.4% lymphoid, 97.7% myeloid, and 88.2% allo-SCT, P = 0.0068; Figure 1A). Antibodies against the nucleocapsid protein were seen only in few patients (n = 4/2/2 in myeloid/lymphoid/allo-SCT), all of them mounting a vaccination response, excluding that differences between the groups are due to imbalances in previous SARS-CoV-2 infection.Figure 1.: Humoral vaccination responses according to disease and treatment. Frequency of positive vaccination response (>7 BAU/mL) according to underlying malignancy (A) and treatment status (B). (C) Antispike antibody titer in the individuals with positive antibody response (C) was investigates in the study participants stratified by malignancy type and therapy status. Statistical significance was determined by χ2 (A) and one-way ANOVA and corrected for multiple testing with Benjamin Hochberg method (C). Significant test P values are presented in the plot captions.As treatment status has been found to be a relevant predictor for serological response rate to SARS-CoV-2-vaccination, we further subdivided the disease cohorts into the following categories: “treatment naive,” “off treatment > 6 months,” and “on therapy” (ie, currently receiving or having received therapy within the last 6 mo). Therapy status neither affected antibody titer width nor the overall vaccination response rate (Suppl. Figure S2B). However, in the lymphoid malignancy subset, we could observe a tendency towards lower SARS-CoV-2 vaccination response in patients under treatment (53.8% vs 77.8% in naive and 14.3% in therapy-off, Figure 1B). In contrast, patients with myeloid malignancies have a favorable humoral response rate, despite ongoing therapy. The negative correlation of lymphoid disease with positive response rate was corroborated by univariate logistic modeling (odds ratio [OR]: 0.0595; 95% confidence interval [CI] 0.0032–0.308 vs. myeloid; Figure 2A, Suppl. Table S3). In addition, lymphoid disease patients tended to correlate with lower antibody titers (β: −0.26, 95% CI −0.59 to 0.072 vs myeloid, Figure 2B) and this phenomenon was especially evident in patients undergoing treatment during vaccination (Figure 1C). This underscores that patients suffering from lymphoid malignancies have an impaired vaccination response. To which extent this translates into an increased risk of infection and/or severe COVID-19 remains unclear, as it is currently unknown which antibody titers confer sufficient protection. Antibody responses to SARS-CoV-2 vaccines are substantially impaired in patients receiving inhibitors of Bruton tyrosine kinase, Janus kinase, or Bcl-2, or antibodies targeting CD20 or CD38.5–10 This data are in line with our results, where only one patient on anti-CD20 therapy mounted a weak antibody response (titer of 7.2 BAU/ml), despite complete absence of measurable circulating CD19+ B cells (CD19+Bc). The remaining n = 8 individuals being currently treated (CD20-antibodies or Bcl-2-inhibitor) did not mount a measurable humoral response.Figure 2.: Univariable modeling of the positive vaccination response and post-vaccination antibody titer. Correlation of the candidate factors affecting the probability of positive vaccination response (A, > 7 BAU/mL) and antispike antibody titer in the individuals with positive antibody response (B) was investigated by a series of univariable logistic and linear regression models, respectively. Significance of the model estimates was determined by Wald Z test (logistic regression: OR/odds ratio) or T test (linear regression: β), as appropriate, and corrected for multiple testing with Benjamini-Hochberg method. Estimate values with 95% confidence intervals are presented in Forest plots. Ranges of complete observations are indicated under the plots. (C) Antispike antibody titer in the individuals with positive antibody response was investigated in the study participants stratified by pre-vaccination circulating IgG, CD19+B cells and CD3+HLA-DR+ T-cells levels. Statistical significance was determined by two-tailed T test. Test p values are presented in the plot captions. allo-SCT = allogeneic stem cell transplantation; B = B cells; IgG = immunoglobulin G; LYM = lymphoid malignancy; NK = natural killer cells; T = T cells; Tc = cytotoxic T-cells; Th = T helper cells; WBC = white blood cells.We next sought to define easy to measure immunological predictors for vaccine-responders. To this end, qualitative and quantitative analysis of the lymphocyte subpopulations in the peripheral blood in form of a cellular immune profile was carried out using a Canto II flow cytometer and lyophilized 8-color tubes from Becton Dickinson (for details, see Suppl. Digital File). Univariable logistic modeling revealed that the probability of vaccination response is negatively influenced by low CD19+Bc (<100/µL; OR: 0.301 95% CI 0.07–0.562; Figure 2A, Suppl. Table S3). This result was substantiated by univariate linear modeling of the antispike levels in individuals with positive antibody response: low CD19+Bc (β: −0.57, 95% CI −0.88 to −0.27) and also low IgG values (<600 mg/dL, β: −0.91, 95% CI −1.3 to −0.48) and high HLA-DR3+ T-cells (>190/µL, β: −0.42, 95% CI −0.72 to 0.11) are negatively linked to antibody titer height (Figure 2B and C). Importantly, lymphoid malignancy (OR = 0.077), bone marrow transplantation (OR = 0.16), and low CD19+ Bc counts were identified independent negative predictors of vaccination response in the study cohort identified by LASSO (least absolute shrinkage and selection operator) multivariate modeling (for details, see Suppl. Digital Methods and Table S4). Furthermore, elevated counts of T cells and low circulating NK cell levels were associated with the lower probability of the vaccination response in the multivariate setting (Suppl. Table S4). In turn, low circulating CD19+Bc and low IgG were the sole independent unfavorable correlates of antispike titers in the multivariate analysis (Suppl. Table S4). These results are partly in contrast to results obtained by Benda et al,11 reporting a negative influence of low lymphocyte but also an influence of lower NK-cell counts on vaccination response. Importantly, the multiparameter LASSO model displayed a superior sensitivity (0.8) and accuracy (area under the curve = 0.92 [0.86–0.98]) at predicting the vaccination response over single risk factors such as Bc levels or malignancy type (Suppl. Figure S3A). The multiparameter LASSO model was also substantially better at predicting the antibody titer than IgG and CD19+ Bc levels alone (Suppl. Figure S3). Collectively, this suggest that comprehensive immunoprofiling may help to identify vaccination responders amongst hematological patients. Patients receiving B-cell-targeting agents and having reduced or even absent circulating CD19+Bc are particularly prone to insufficient antibody responses. Thus, we took a more detailed look into patients with low CD19+Bc. Of these 50 patients, 35 patients were responder (titer > 7 BAU/mL), which is in line with rheumatological patients receiving rituximab, showing that once peripheral CD19+Bc are present (even at very low amounts of 1%), a humoral vaccination response can be mounted.12 However, data interpretations are limited by the lack of knowledge how peripheral CD19+Bc reflect CD19+Bc and plasma cell abundance in the bone marrow. Notably, individual patients (COAK_45) mounted an antibody titer (37.6 BAU/mL) even though circulating CD19+Bc were absent. This patient, after rituximab treatment until June 2017 and idelalisib until October 2019 currently undergoes PD-1 antibody therapy for metastatic skin cancer. Checkpoint inhibitor therapies may impact serological outcome after vaccination,13 whereas in our patient, it may explain the humoral response even in the absence of CD19+Bc. In summary, our data put forward lymphoid malignancy, low CD19+Bc and IgG values as clinically applicable predictors for an insufficient immune response to SARS-CoV-2 vaccination and characteristic of the patient subset requiring dense serological monitoring, boosting vaccination and additional preventive measures. Moreover, hematological patients without humoral immune response to the SARS-CoV-2 vaccine may mount T cell-mediated immunity.14 Future studies will demonstrate how the subsequent booster-vaccination(s) may overcome insufficient humoral responses particularly in patients with lymphoid diseases and how efficient (fully) vaccinated hematological patients are protected from severe COVID-19 as the humoral response is only one of the manifold adaptive and innate immunological mechanisms induced by vaccines.15 Finally, the great majority of the investigated individuals mounted a measurable humoral response to the immunization despite ongoing therapy or lymphoid disease. Hence, we advise all patients to be vaccinated irrespective of their underlying malignancy type, their therapy and immune status. ACKNOWLEDGMENTS The authors declare to external funding sources. Figure S1 was created with BioRender.com. AUTHOR CONTRIBUTIONS VP, NS, SS, and DW contributed equally. DISCLOSURES PT owns a data science enterprise DAAS Tirol. All the other authors have no conflicts of interest to disclose.

Patients with haemophilia A (HA) undergoing neurosurgical procedures have a high risk of haemorrhage with potential fatal outcome. Here, we present a successful perioperative haemostatic concept applying an extended half-life factor VIII (EHL FVIII), Efmoroctocog alfa, in two patients with HA undergoing neurosurgery for paramedian right-sided disc herniation (case 1) and astrocytoma (case 2). After adequate EHL FVIII treatment the surgical procedures were performed without any bleeding complications despite the high-risk interventions. Laboratory measurements confirmed stable FVIII levels throughout the hospital stay. We suggest close interdisciplinary collaboration between involved clinicians as mandatory prerequisite for an optimized perioperative management in patients with HA. The presented cases indicate, that the increased stability, safety and fewer injections provide a rationale to use EHL FVIII products in HA patients undergoing surgical interventions with a very high bleeding risk.

Morbidity and mortality of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are mainly determined by thromboembolic complications. Thrombus formation is facilitated by a neutrophil-specific form of cell death linked to neutrophil extracellular trap (NET) formation (NETosis). Preclinical and clinical data suggested a potential link between NETosis and thrombosis in MPNs. In this study, we aimed to define the impact of NETosis on clinical end points in a large MPN cohort. NETosis was induced in vitro by ionomycin and quantified by enzyme-linked immunosorbent assay-based nucleosome release assays as well as fluorescent staining of free DNA in samples from 103 MPN patients and 28 healthy donors. NETosis rate was correlated with a broad set of clinical data, such as MPN subtype, mutational status, laboratory variables, history of thrombotic events, and treatment types. Triggered NETosis levels were clearly higher in MPN patients than in healthy donors. Positivity for JAK2 V617F or exon 12 as well as CALR mutations correlate with increased NET formation. However, neither JAK2 allelic burden nor history of thromboembolic complication nor the presence of other risk factors for thrombosis (eg, leukocytosis) were associated with the rate of NETosis. In addition, none of the analyzed laboratory parameters nor the type of treatment significantly impacted the rate of NETosis formation. The biology of MPNs has an impact on NET formation because genetic driver mutations favor induction of NETosis, but this does not seems to translate into important clinical end points such as thromboembolic complications. Therefore, NETosis may play a role in facilitating thrombosis, but it is not a sole causative determinant in MPN-associated thrombophilia.

Glucocorticoids (GCs) are an essential component of acute lymphoblastic leukemia (ALL) therapy. To identify genes mediating the anti-leukemic GC effects in vivo , we performed gene expression profiling of lymphoblasts from 46 children during the first 6-24h of systemic GC mono-therapy. Differential gene expression analysis across all patients revealed a considerable number of GC-regulated genes (190 induced, 179 repressed at 24h). However, when 4 leukemia subtypes (T-ALL, ETV6-RUNX1 + , hyperdiploid, other preB-ALLs) were analyzed individually only 17 genes were regulated in all of them showing subtype-specificity of the transcriptional response. “Cell cycle-related” genes were down-regulated in the majority of patients, while no common changes in apoptosis genes could be identified. Surprisingly, none of the cell cycle or apoptosis genes correlated well with the reduction of peripheral blasts used as parameter for treatment response. These data suggest that (a) GC effects on cell cycle are independent of the cell death response and (b) GC-induced cell death cannot be explained by a single transcriptional pathway conserved in all subtypes. To unravel more complex, potentially novel pathways, we employed machine learning algorithms using an iterative elastic net approach, which identified gene expression signatures that correlated with the clinical response.

Summary 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 R etrospective E valuation o f E arly response in C ML for long-term T reatment 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.

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.

Treatment recommendations in chronic myeloid leukemia (CML) treatment have not changed substantially since treatment-free remission (TFR) has become a therapeutic option. Hence, allowing more patients to enter TFR is gaining significance. Although, Asciminib as a first-in-class new type of tyrosine kinase inhibitor (TKI) is in clinical development, currently combination treatment with TKIs and Interferon-alpha2b appears the best option to deepen molecular response and broaden the basis of potential TFR candidates. Improving the chances of a first successful TFR has to be the primary goal in TFR optimization as even re-induction of a deep molecular response after TFR failure using second generation TKIs shows disillusioning results.