Impact of age on efficacy and toxicity of nilotinib in patients with chronic myeloid leukemia in chronic phase : ENEST1st subanalysis

Purpose Achievement of deep molecular response with a tyrosine kinase inhibitor in patients with chronic myeloid leukemia (CML) is required to attempt discontinuation of therapy in these patients. The current subanalysis from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study evaluated whether age has an impact on the achievement of deeper molecular responses or safety with frontline nilotinib in patients with CML. Methods ENEST1st is an open-label, multicenter, single-arm, prospective study of nilotinib 300 mg twice daily in patients with newly diagnosed CML in chronic phase. The patients were stratified into the following 4 groups based on age: young (18-39 years), middle age (40-59 years), elderly (60-74 years), and old (>= 75 years). The primary end point was the rate of molecular response 4 ([MR4] BCR-ABL1 Results Of the 1091 patients enrolled, 1089 were considered in the analysis, of whom, 23% (n = 243), 45% (n = 494), 27% (n = 300), and 5% (n = 52) were categorized as young, middle age, elderly, and old, respectively. At 18 months, the rates of MR4 were 33.9% (95% confidence interval [CI], 27.8-40.0%) in the young, 39.6% (95% CI, 35.3-44.0%) in the middle-aged, 40.5% (95% CI, 34.8-46.1%) in the elderly, and 35.4% (95% CI, 21.9-48.9%) in the old patients. Although the incidence of adverse events was slightly different, no new specific safety signals were observed across the 4 age groups. Conclusions This subanalysis of the ENEST1st study showed that age did not have a relevant impact on the deep molecular response rates associated with nilotinib therapy in newly diagnosed patients with CML and eventually on the eligibility of the patients to attempt treatment discontinuation.Peer reviewe

Interaction of murine regulatory T cells with Dendritic Cells

Ziel dieser Arbeit war es, die Interaktionen von regulatorischen T-Zellen mit Dendritischen Zellen zu untersuchen. Zu diesem Zweck wurden OVA-spezifische DO11.10 T-Zellen in eine Treg- und Teff-Fraktion mit Hilfe von Magnetkugeln aufgetrennt. Die so gewonnenen Zellen wurden zusammen mit OVA-beladenen Knochenmarks-DZ in Balb/c Mäuse zusammen oder einzeln transferiert. Die Aktivierung der T-Zellen und die darauf folgende Proliferation wurden anhand der Expression von Oberflächenmolekülen und der CFSE-Verdünnung evaluiert. Außerdem wurden die Zellkontakte in vivo durch Präparation der Milzen 24h nach Injektion und anschließender Auswertung unter dem Fluoreszenzmikroskop betrachtet. Die mit unterschiedlichen Fluoreszenzfarbstoffen markierten DZ, Treg und Teff konnten so statistisch erfasst werden. Dies ermöglichte eine Aussage über die Häufigkeit der Zellkontakte untereinander. Diese Arbeit konnte zeigen, dass es für die Aktivierung und Expansion von Treg der Stimulation von vollständig reifen DZ bedarf. Die Treg als auch die Teff hatten eine Vielzahl von Zellkontakte mit den DZ. Die Häufigkeit der Bindung der Treg an die DZ änderte sich jedoch auch bei Suppression koinjizierter Teff nicht wesentlich. Interessanterweise erhöhte sich bei Suppression durch die Treg deren Häufigkeit der Bindung an die Teff nicht. Vor allem eine Reduzierung der Zellkontakte der Teff bei einer Suppression durch die Treg mit den DZ war zu beobachten. Dieses Ergebnis wird durch eine fast vollständige Reduzierung der Proliferation der Teff durch voraktivierte Treg bestätigt. Ohne DZ-Teff Kontakte finden auch keine Aktivierung und keine klonale Expansion statt. Ein Mechanismus der Suppression in vivo könnte die Reduzierung der kostimulatorischen Moleküle auf den antigentragenden DZ durch die Treg sein. Die im Rahmen dieser Arbeit durchgeführten Versuche belegen, dass die Reduzierung der Kostimulatoren auf der DZ Oberfläche antigenspezifisch und durch die Treg verursacht wird. Eine Überprüfung der apoptotischen Stadien der DZ bewies, das Apoptose als Grund für die geringere Expression der Oberflächenmoleküle auszuschließen war. Die Herunterregulation der kostimulatorischen Moleküle, so wie die Suppression der Teff durch die Treg ließ sich durch eine Ligation der DZ durch CD40 verhindern. Dies lässt den Schluss zu, dass Regulation von DZ durch Treg abhängig von der CD40-Lizensierung ist. Nur bei TNF oder LPS-, nicht jedoch bei LPS/CD40-Reifung war ein regulatorischer Effekt der Treg zu beobachten. Dies bedeutet, dass Feedback-Signale aktivierter Teff die Immunogenität von DZ im Verlauf der Immunreaktion erhöhen können.The priming of CD4+ effector T cells (Teff) in vivo is induced by mature dendritic cells (DC) and controlled by CD4+CD25+Foxp3+ regulatory T cells (Treg). It remains unclear,however, how Teff priming vs Treg suppression are regulated during Ag presentation by DC in secondary lymphoid organs at the simultaneous presence of Teff and Treg. In this study, we used an peptide-specific DO11.10 TCR-transgenic adoptive transfer model to follow the Teff priming kinetics and the mechanisms of suppression by Treg. Teff activation was slower as compared with Teff and could not influence the early Teff expansion but limited the Teff response leading to lower Teff numbers in the memory phase. DC-Teff cell contacts remained unaltered during suppression by Teff and led to a down-regulation of the costimulatory molecules CD80, CD86, PD-L1, and PD-L2 but not MHC II, CD40, ICOS-L, or CD70 from the mature DC surface. This effect was observed only after DC maturation with TNF or LPS but not after additional CD40 licensing. Together, our data indicate that Teff suppression against nonself Ags in vivo occurs delayed due to the slower Teff response, is mediated to a large extent through DC modulation, but is controlled by the type of DC maturation

Overuse of corticosteroids in patients with immune thrombocytopenia (ITP) between 2011 and 2017 in the United States

Abstract Corticosteroids (CSs) are standard first‐line therapy for immune thrombocytopenia (ITP). Prolonged exposure is associated with substantial toxicity; thus guidelines recommend avoidance of prolonged CS treatment and early use of second‐line therapies. However, real‐world evidence on ITP treatment patterns remains limited. We aimed to assess real‐world treatment patterns in patients with newly‐diagnosed ITP, using two large US healthcare databases (Explorys and MarketScan) between January 1, 2011 and July 31, 2017. Adults with ITP, ≥12 months of database registration prior to diagnosis, ≥1 ITP treatment, and ≥1 month enrollment following initiation of first ITP treatment were included (n = 4066 Explorys; n = 7837 MarketScan). Information on lines of treatment (LoTs) was collected. As expected, CSs were the most common first‐line treatment (Explorys, 87.9%; MarketScan, 84.5%). However, CSs remained by far the most common treatment (Explorys ≥77%; MarketScan ≥85%) across all subsequent LoTs. Second‐line treatments such as rituximab (12.0% Explorys; 24.5% MarketScan), thrombopoietin receptor agonists (11.3% Explorys; 15.6% MarketScan), and splenectomy (2.5% Explorys; 8.1% MarketScan) were used much less frequently. CS use is widespread in the US in patients with ITP across all LoTs. Quality improvement initiatives are needed to reduce CS exposure and bolster use of second‐line treatments

Immune thrombocytopenia (ITP) World Impact Survey (I-WISh): Impact of ITP on health-related quality of life

Immune thrombocytopenia (ITP) has a substantial, multifaceted impact on patients' health‐related quality of life (HRQoL). Data describing which aspects of ITP physicians and patients perceive as having the greatest impact are limited. The ITP World Impact Survey (I‐WISh) was a cross‐sectional survey, including 1507 patients and 472 physicians, to establish the impact of ITP on HRQoL and productivity from patient and physician perspectives. Patients reported that ITP reduced their energy levels (85% of patients), capacity to exercise (77%), and limited their ability to perform daily tasks (75%). Eighty percent of physicians reported that ITP symptoms reduced patient HRQoL, with 66% reporting ITP‐related fatigue substantially reduced patient HRQoL. Patients believed ITP had a substantial impact on emotional well‐being (49%) and 63% worried their condition would worsen. Because of ITP, 49% of patients had already reduced, or seriously considered reducing their working hours, and 29% had considered terminating their employment. Thirty‐six percent of patients employed at the time of the survey felt ITP decreased their work productivity, while 51% of patients with high/very high symptom burden reported that ITP affected their productivity. Note, I‐WISh demonstrated substantive impact of ITP on patients' HRQoL both directly for patients and from the viewpoint of their physicians. Patients reported reduced energy levels, expressed fears their condition might worsen, and those who worked experienced reduced productivity. Physicians should be aware not only of platelet counts and bleeding but also the multi‐dimensional impact of ITP on patients' lives as an integral component of disease management

Results of the European survey on the assessment of deep molecular response in chronic phase CML patients during tyrosine kinase inhibitor therapy (EUREKA registry)

Purpose: the advent of tyrosine kinase inhibitor (TKI) therapies has revolutionized the treatment of chronic myeloid leukemia (CML). The European LeukemiaNet (ELN) recommends quantification of BCR–ABL1 transcripts by real-time quantitative PCR every three months during TKI treatment. Since a proportion of patients in deep molecular response (DMR: MR4, MR4.5, MR5 ) maintain remission after treatment stop,assessment of DMR is crucial. However, systematically collected molecular data,monitored with sensitive standardized assays, are not available outside clinical trials. Methods: data were collected on the standardized assessment of molecular response in the context of real life practice. BCR-ABL1 transcript levels after >2 years of TKI therapy were evaluated for DMR. Since standardized molecular monitoring is a prerequisite for treatment discontinuation, central surveillance of the performance of the participating laboratories was carried out. Results: between 2014-2017, 3,377 peripheral blood samples from 1,117 CML patients were shipped to 11 standardized reference laboratories in six European countries. BCRABL1 transcript types were b3a2 (41.63%), b2a2 (29.99%), b2a2/b3a2 (3.58%) and atypical (0.54%). For 23.72% of patients, the initial transcript type had not been reported. Response levels (EUTOS laboratory) were: no MMR, n=197 (6.51%); MMR, n=496 (16.40%); MR4 , n=685 (22.64%); MR4.5, n=937 (30.98%); MR5 , n=710 (23.47%). With a Cohen’s kappa coefficient of 0.708, a substantial agreement between EUTOScertified and local laboratories was shown. Conclusions: multicenter DMR assessment is feasible in the context of real life clinical practice in Europe. Information on the BCR-ABL1 transcript type at diagnosis is crucial to accurately monitor patients’ molecular response during or after TKI therap