The impact of thrombosis on probabilities of death and disease progression in polycythemia vera: a multistate transition analysis of 1,545 patients

: We applied a parametric Markov five-state model, on a well-characterized international cohort of 1,545 patients with polycythemia vera (PV; median age 61 years; females 51%), in order to examine the impact of incident thrombosis on the trajectory of death or disease progression. At a median follow-up of 6.9 years, 347 (23%) deaths, 50 (3%) blast phase (BP), and 138 (9%) fibrotic (post-PV MF) transformations were recorded. Incident thrombosis occurred at a rate of 2.62% pt/yr (arterial 1.59% and venous 1.05%). The probability of death, in the first 10 years, for 280 (18%) patients who developed thrombosis during follow-up was 40%, which was two-fold higher than that seen in the absence of thrombosis or any other transition state (20%; p < 0.01); the adverse impact from thrombosis was more apparent for arterial (HR 1.74; p < 0.01) vs venous thrombosis (p=NS) and was independent of other fixed (i.e., age, prior venous thrombosis, leukocytosis) or time-dependent (i.e., progression to BP or MF) risk variables. The transition probability to post-PV MF increased over time, in a linear fashion, with a rate of 5% capped at 5 and 10 years, in patients with or without incident thrombosis, respectively. The impact of thrombosis on transition probability to death or post-PV MF tapered off beyond 10 years and appeared to reverse direction of impact on MF evolution at the 12-year time point. These observations suggest thrombosis in PV to be a marker of aggressive disease biology or a disease-associated inflammatory state that is consequential to both thrombosis and disease progression

Chemische Gasphasenabscheidung von zwei-dimensionalen Übergangsmetallcarbiden

Der Forschungsbereich der zweidimensionalen (2D) Materialen ist seit längerem im Aufschwung. Innerhalb dieser Materialklasse stellen Übergangsmetallcarbide ein weniger untersuchtes Feld dar. Dennoch weisen diese Materialen eine Vielzahl an interessanten Eigenschaften und möglichen Anwendungen auf. Chemische Gasphasenabscheidung (CVD) ist eine Synthesemethode, die sich für viele 2D-Materialen als äußerst vorteilhaft erwiesen hat. Dies ist zurückzuführen auf die Möglichkeit, hochwertige, großflächige Filme zu wachsen sowie auf eine gute Skalierbarkeit. CVD ist bereits ein etablierter Herstellungsprozess für Graphen, das erste und bestuntersuchte 2D-Material. Im Bereich der CVD-synthetisierten 2D-Übergangsmetallcarbide ist Mo2C die meistuntersuchte Verbindung. Die erste Publikation zur CVD-Synthese von Mo2C beschreibt den Prozess unter Verwendung eines flüssigen Kupferkatalysators und untersucht die supraleitenden Eigenschaften von Mo2C. Seit dieser Veröffentlich ist die Forschung zum verwendeten Synthesepfad erweitert worden. Es wurden bereits eine Mehrzahl an Parametern des Systems untersucht, Heterostrukturen gewachsen sowie elektrokatalytische Eigenschaften untersucht. Trotz dieser Fortschritte bestehen weiterhin Limitierungen beim Wachsen eines durchgängigen Films und der Kontrolle des Schichtwachstums. Darüber hinaus ist der genaue Wachstumsmechanismus noch nicht restlos geklärt. Andere 2D-Übergangsmetallcarbide wurden ebenfalls synthetisiert (WC, TaC), allerdings fällt Forschung zu diesen Materialien noch sehr spärlich aus. Diese Arbeit untersucht bisher unzugängliche Parameter für die CVD von 2D-Mo2C, CVD-Wachstum von großflächigen Mo2C-Kristallen sowie die CVD-Synthese anderer neuer Carbide.The field of two-dimensional (2D) materials has garnered exponential interest from the research community. Within the wide variety of 2D materials, transition metal carbides (TMCs) constitute a less studied subgroup but with many promising properties and possible applications. Chemical vapour deposition (CVD) synthesis is a very advantageous synthesis route for 2D materials due to its ability to grow high quality, large area films as well as its scalability. CVD is already well established for graphene, the first and most thoroughly studied member of the ever-growing family of 2D materials. In the world of CVD 2D TMCs, Mo2C is currently the most popular material. The first publication on its synthesis, which uses a molten copper catalyst, outlines Mo2C’s properties as a superconductor. Since then, this synthesis has been expanded on, studying various parameters of the system, growing Mo2C/graphene heterostructures and demonstrating promising electrocatalytic properties. Nevertheless, challenges like producing a closed film, layer control and a good understanding of the growth mechanism still persist. While other 2D carbides were also synthesised this way (WC, TaC), there is substantially less literature available on these and other 2D TMCs. In this work, we investigate previously unattainable but desired CVD parameters (pressure, temperature) for 2D Mo2C CVD, advanced CVD Mo2C growth towards a closed nanometre thick film as well as CVD synthesis of other novel 2D TMCs

Stratification for RRMM and Risk-Adapted Therapy: Sequencing of Therapies in RRMM

The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation

Stratification for RRMM and Risk-Adapted Therapy: Sequencing of Therapies in RRMM

The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation.</jats:p

Response to Harrison et al. ‘Clinically relevant differences between BCSH and WHO diagnostic criteria for ET

(VLID)486754

Successful treatment of acquired von Willebrand syndrome associated with monoclonal gammopathy

SummaryAcquired von Willebrand syndrome is exceedingly rare and accounts for only 1–3% of von Willebrand disease cases. In this short report, we present our own cases of acquired von Willebrand syndrome associated with monoclonal gammopathy. Both cases went into complete and sustained remission after intensive antimyeloma treatment. The first patient was not deemed fit for autologous stem cell transplantation and was managed with an extensive multidrug combination including daratumumab, carfilzomib, lenalidomide, cyclophosphamide and dexamethasone. After at least VGPR was achieved the coagulation studies rapidly normalized and remained normal after treatment de-escalation to lenalidomide/dexamethasone maintenance. The second patient successfully underwent ASCT after 5 cycles of induction with daratumumab, bortezomib, cyclophosphamide and dexamethasone and has remained in full hematologic and hemostaseologic remission ever since.The two cases highlight the efficacy of aggressive antimyeloma treatment in monoclonal gammopathy-associated acquired von Willebrand syndrome to achieve normalization of coagulation study, providing a possible way to manage these patients.</jats:p

Firstline Daratumumab Shows High Hematologic and Organ Response Rates in Advanced Cardiac AL Amyloidosis - a Retrospective Case Series

Background AL amyloidosis is a plasma cell dyscrasia and the most common form of amyloidosis. It is associated with deposition of light chain amyloid, which leads to organ dysfunction, most commonly of the heart and kidneys. Treatment focuses on the reduction of the production of the monoclonal light chains and includes the off-label use of antimyeloma drugs. Their use, however, is often limited by the advanced organ dysfunction frequently encountered in these patients. Daratumumab, a monoclonal CD38 antibody has shown efficacy in both newly diagnosed and relapsed AL amyloidosis in several reports. It is usually well tolerated in patients with advanced AL amyloidosis-related heart failure and requires no dose adjustment for impaired kidney function. Aims and Methods The aim of this study was to retrospectively assess the efficacy of daratumumab in a single-center cohort of newly diagnosed AL amyloidosis patients. A chart review was performed on all patients treated with frontline daratumumab as an individual healing attempt at the Department of Oncology at the Medical University of Vienna between April 2017 and May 2019. Results A total of 14 patients (nine male, five female) were evaluable. According to the 2004 Mayo staging system one patient was stage I, four patients were stage II and nine patients were stage III, two of which were in the very high risk group IIIb (NT-proBNP &gt; 8500 ng/L). Twelve patients produced monoclonal lambda light chains. Median number of organs involved was 2 (1-4), with heart (78.6%) and kidneys (64.3%) being the most common. All patients received daratumumab at the dose of 16 mg/m2 for at least 3 cycles (range 3-19). Dexamethasone was reduced to 20 mg per daratumumab infusion to increase tolerability. After a median follow-up of 12.5 months (range 2.17-25.17), eleven patients were still receiving daratumumab at time of analysis. One patient with stage IIIa proceeded to heart transplant after four cycles and later underwent autologous stem cell transplantation, while two patients were lost to follow-up (one patient had to withdraw from treatment due to psychiatric comorbidities; one patient moved to a different center). Seven patients were treated with daratumumab alone, seven patients received either additional proteasome inhibitors, additional IMIDs, or both during the course of their treatment. One patient was also briefly treated with oral cyclophosphamide. Two patients experienced infusion reaction at first administration. There was no severe toxicity leading to discontinuation observed, the most significant toxicity was susceptibility to infections for which six patients received intravenous immunoglobulins. Hematologic and organ response were assessed using previously published criteria (Comenzo et al 2012). All patients showed hematologic response at last follow-up. First hematologic response was classified as PR in 50% and VGPR in 50% after a median time of 44 days (7-252). Best hematologic response was VGPR in 78.6% and CR in 21.4%. The rates remained the same to last follow-up. Median time to best response was 277 days (14-412). In the group of high and very high risk patients 77.8% achieved VGPR and two stage IIIa patients (22.2%) achieved CR at last follow-up. Cardiac response was seen in five out of eleven evaluable patients, all classified as stage IIIa, while kidney response was seen in three out of nine (33.3%) patients with kidney involvement. Median time to heart and kidney response was 281 (88-348) and 196 (62-215) days respectively. Conclusion Daratumumab showed high efficacy as a firstline treatment in newly diagnosed AL amyloidosis yielding a 100% objective hematologic response rate and a significant organ response rate even in high risk patients that usually have a very poor prognosis and limited treatment options. Despite the limitations inherent to any retrospective study, our data underline the role of daratumumab as a safe, effective, and tolerable treatment option in AL amyloidosis both as a monotherapy as well as a combination partner for other agents, in particular in patients with advanced stage AL amyloidosis. Figure OffLabel Disclosure: Off-label use of daratumumab in AL Amyloidosis as an individual healing attempt </jats:sec

Long-Term Follow-up in Interferon-Alpha Treated Polycythemia Vera Patients - a Single Center Analysis

Abstract Introduction: Interferon-alpha (IFNα) has been successfully used to treat myeloproliferative neoplasms (MPN) for 30 years, although never officially registered for this indication. Studies with new pegylated interferons are underway to finally achieve IFNα registration for MPN. Aims: The aim of this retrospective analysis was to investigate the long-term survival of polycythemia vera (PV) patients that received IFNα while being treated at the outpatient clinic of the Medical University of Vienna, a center that has been treating MPN with IFNα since 1984, and to compare it to patients that received best available therapy (BAT). All treatments were based on international recommendations and standardized center specific guidelines. Methods: The medical histories of patients diagnosed with PV according to the PVSG- or WHO-criteria were investigated and information on the course of the disease and on cytoreductive treatment was collected. For a patient to be included in the analysis, IFNα (conventional or pegylated IFNα2a, -2b, or IFNα2c, or lymphoblastoid IFNα) had to be given for at least 365 days, or, in patients who were followed for more than 10 years, for at least 10% of the observation period after the diagnosis of PV. IFNα-patients who did not fulfill these criteria were not included. The IFNα-patients were compared to patients who received BAT consisting of other cytoreductive agents and/or phlebotomy. A portion of IFNα-patients also received other cytoreductive agents. The patients were then divided into three risk groups based on a previously published score based on age at diagnosis (&lt;57, 57-66, ≥67), venous thromboembolism at baseline and leukocyte counts at diagnosis ≥15 G/L (Fig. 1A). Kaplan-Meier plots were used to compute overall, fibrosis- and AML-free survival. Results: Of 129 patients, 67 received IFNα, 62 BAT (22 received no cytoreductive therapy). Median duration of IFNα treatment was 1981 days. Overall survival was generally better in patients treated with IFNα in all three risk groups. While the difference in the intermediate risk group did not reach significance (Fig. 1C), the survival benefit in the low risk group narrowly missed significance (p=0.127, Fig. 1B). More importantly, IFN-patients in the highest risk group lived significantly longer than patients receiving BAT (p=0.005, Fig. 1D). Median age in all three risk groups did not differ between the two groups, ruling out age as a possible confounder. Also, there were no other relevant differences between any of the groups. Although fibrosis-free survival differed in the low and intermediate risk group, no significant differences were observed. There was no benefit in leukemia-free survival in this analysis. Discussion: This study supports the theory that IFNα can have a beneficial impact not only on symptoms and blood counts of PV-patients, but also on the long-term outcome in regard of overall survival, even in high risk patients. However, due to the retrospective nature of this study, the low case number in some subgroups and the lack of information on the fitness of the individual patients, our results can only serve as an impulse on future studies investigating the long-term outcome of IFNα-patients in MPN. Disclosures Off Label Use: Interferon-alpha, use in myeloproliferative neoplasms. Gisslinger:AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy. </jats:sec