The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Aims: The absolute number of chronic phase CML patients (pts) reaching the treatment-free remission (TFR) criteria has been substantially increased by the use of second-generation TKI (TKI2), initiated since diagnosis, comparing to Imatinib first-line. However, the relative rate of unsuccessful TFR (i. e. pts loosing their MMR after TKI2 cessation) still remains around 50% at 2 years and beyond, whatever the TKI2 was. The aim of this study is to analyse the rate of successful TFR in pts receiving Nilotinib (Nilo) or Dasatinib (Dasa) first-line obtaining the appropriate criteria. Methods: Observational retrospective study in 3 reference centers of the French group of CML lead between 2010 and 2021. Eligible pts were CP CML pts initiating either Nilo 300 mg BID or Dasa 100 mg daily since diagnosis, until cessation for sustained MR4.5 (i.e. ≥2 years on ≥4 datapoints). Data were retrospectively collected according to the national regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2009, 2013 and 2020 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) for TFR. In this regard, the TKI2 was resumed in case of loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. All patients were harbouring major BCR-ABL1 transcripts. The primary endpoint was the survival without loss of MMR after TKI2 cessation. The secondary endpoints were the kinetics of MMR loss, and the identification of factors influencing MMR loss. Results: Seventy-two pts were reported (47 Nilo, 25 Dasa) with 57% females with a median age at diagnosis of 48 (36.75-61.25) years. The median follow-up since diagnosis was 9.26 (3.75-13.75) years (8.8 for Nilo and 9.47 for Dasa p=ns) and after TKI2 cessation 3.94 (0.7-8.8) years (3.92 for Nilo and 3.90 for Dasa p=ns). Sokal scores were 42% Low, 41% Intermediate, 17% High in Nilo and 39% L, 25% I and 35% H in Dasa pts (p=ns). ELTS scores were 50% L, 22% I, 9.5% H (18.5% Uk) in Nilo and 46.5% L, 28.5% I and 3.5% H (21.5% Uk) in Dasa pts (p=0.95). Five (9%) pts harboured ACA at diagnosis in the Nilo group and 2 (7%) in the Dasa group (p=1.00). The median time from TKI2 initiation to sustained MR4.5 was 19 (3.12-36) months in the Nilo group and 16 (6.3-39) months in the Dasa group (p=0.644). The duration of sustained MR4.5 until cessation was 3.04 (1.5-9.3) years for Nilo and 2.65 (1.11-7.95) for Dasa (p=0.96). The median dosing of Nilo was 600 (300-800) mg daily and 80 (20-100) mg at TKI2 cessation. None of these patients switched to another TKI during the follow-up. TKI2 cessation occurred after 60.5 (43-74.5) months in the Nilo group and 68 (39-90) months in the Dasa group (p=0.581). Thirty-seven pts out of 47 (79%) were BCR-ABL1 undetectable at Nilo cessation 18/25 (72%) at Dasa cessation (p=0.60). At M3 after discontinuation, 58% of pts remained undetectable after Nilo cessation and 30.4% after Dasa cessation (p=0.05).The median survival of pts without loss of MMR was not reached in the Nilo group, and was 14 (4.73-NR) months in the Dasa group, (p=0.042) as analysed by the KM method (Figure 1.). Two patients died (1 Nilo, 1 Dasa) from competing events (solid tumours) after unsuccessful TFR. Twenty-eight pts (14 Dasa, 14 Nilo) restarted their TKI2 after MMR loss and all regained ≥ MMR after 3 months of Dasa at a median dose of 75 (40-100) mg daily and all except one (who regained MMR at M12) after resumption of Nilo at a median dose of 350 (300-600) mg daily. Univariate analysis identified pts with H+I Sokal (as compared to low) as an unfavourable factor for successful TKI2 cessation [HR=0.35 (0.15-0.83), p=0.017] and type of TKI2 (Nilo as reference vs Dasa) was discriminant [HR=2.1 (1.01-4.35), p=0.047]. Multivariate analysis identified the type of TKI2 as a significant factor impacting on TFR outcome [HR 2.11 (0.97-4.55], p=0.05]. Conclusions: As it is likely that no prospective head-to-head comparison will be performed in this setting, on this limited series of pts, we conclude that the outcome of TFR seems to be different according to the TKI2 used since diagnosis, suggesting the impact of distinct biological variables modified by the type of TKI2 on the long run (such as immunological system, BM micro-environment, others) on TFR outcome. Figure 1 Figure 1. Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Reply to Baklouti et al., “Why Is It Desirable To Do the External Evaluation of a Population Pharmacokinetic Model?”

We thank Baklouti et al. (1) for commenting on our population pharmacokinetic study of dalbavancin for optimal treatment of adult patients with staphylococcal osteoarticular infections (2) and for suggesting that our model tends to underestimate the concentrations observed in a group of French patients (French group).…

Acquisition of attributive adjectives and noun adjuncts by L3 learners of French and German: further evidence for the typological primacy model (TPM)

This investigation explored the impact of prior acquired languages in the acquisition of third language (L3) at initial stages. The required data were gathered via two groups of L3 learners: 27 learners of L3 French and 26 learners of L3 German during a grammaticality judgement task (GJT) and an element rearrangement task (ERT) to test the placement of noun adjuncts and attributive adjectives. Both groups had acquired Persian as the first language and English as the second language. The participants were assigned to two L2 proficiency level groups (intermediate and advanced). The findings revealed that L3 German participants outperformed L3 French learners in the attributive adjective placement in both tasks as well as the noun adjunct in the GJT task. The L3 groups showed similar levels of performance in the ERT noun adjunct task. Additionally, the effect of L2 level of proficiency was not significant. The results also indicated that the typological similarity of L2 English to German rather than French rendered a facilitative effect on task performance in the L3 German group and a non-facilitative effect in the L3 French group. This study provides evidence for the Typological Primacy Model (TPM) of L3 acquisition suggesting that L3 learners are influenced by the typological similarities of the previous languages they have already acquired.

The effect of L4 on translation students’ L1/L2 writing scripts

The aim of this study was to determine whether learning how to use certain microparametric aspects – adverbial pronouns – in L4 (French) had an effect on students’ L1/L2 (Catalan) writing scripts. The study was conducted on 427 learners who had Catalan as their L1 or L2, English as an L3, and were studying a translation degree at University. The students were divided into two groups according to whether they were studying French or German as their L4. Altogether 1620 texts produced over four academic years were reviewed. Although both French and Catalan, unlike German, have similar adverbial pronouns, the results of the analysis show that there is no statistically significant difference in the use of adverbial pronouns between the German group and the French group. However, there is some evidence of a more intense use of these pronouns among the Catalan learners in the French group.

How history of mathematics can help to face a crisis situation: the case of the polemic between Bernoulli and d’Alembert about the smallpox epidemic

In this article, I present the eighteenth century’s polemic of Bernoulli and d’Alembert concerning the smallpox epidemic and a prevention method called inoculation. Through an analysis of the polemic and the related resources, I show that this historical debate has various interests for mathematics education; and more specifically it can help teachers to confront dilemmas emerging with the COVID-19 pandemic (for example if a teacher should talk about it in class or not, how to help students to interpret the statistical data and the mathematical models connected to the pandemic and more generally, how to deal with the confusions and concerns emerging in connection to the pandemic). I describe the documents related to the historical polemic as transitional objects, having a potential to reveal the teachers’ own professional or personal experiences, reflections and questions, and to stimulate dialogue with them on these issues. I illustrate this proposition by the presentation of an online reading seminar realized with a French group of teachers in April 2020.

Electroacoustic Experiments of the Art Zoyd and Their Implementation in Soundtracks for Silent Films

The article is devoted to the work of Art Zoyd, a French group whose experimental style is often defined by modern researchers as “la musique nouvelle” (from the French — “new music”) and is viewed through the prism of the genre-style dialogue between rock and contemporary academic music. The idea of “metamusic”, expressed in the co-creation of several composers, as well as in the unity of visual, plastic, and musical components, is also important for understanding the style of the group. This trend is especially closely related to the personality of one of the founders of the group, Gerard Hourbette, who combines the gift of a composer with the talent of a programmer. The obvious reliance on the achievements of electroacoustic music, the desire to combine the scientific understanding of the phenomenon of sound with the implementation of practical musical projects (expressed in the creation of the research and creative center Art Zoyd Studios), make him related to the figure of the pioneer of musique concrète and the founding father of Groupe de Recherches Musicales, Pierre Schaeffer. The idea of the synthesis of the arts is reflected in the innovative multimedia performances of the group, as well as in the soundtracks to silent films. The article analyzes the sound scores for the films Nosferatu by Friedrich Murnau, Häxan by Benjamin Christensen, The Fall of the House of Usher by Jean Epstein.

New classifications of axillary lymph nodes and their anatomical-clinical correlations in breast surgery

Background In the last decade, two research groups, the French group by Clough et al. (Br J Surg. 97:1659–65, 2010) and the Chinese one by Li et al. (ISRN Oncol 2013:279013, 2013), proposed two types of classification of axillary lymph nodes in breast cancer, identifying novel anatomic landmarks for dividing the axillary space in lymph node dissection. Main body Knowledge of the exact location of the sentinel node helps to focus the surgical dissection and to reduce the morbidity of sentinel lymph node biopsy procedures, in particular the risk of arm lymphedema, without compromising sensitivity. Conclusion In this article, we aimed at focusing on the clinical impact that the most recent classifications of axillary lymph nodes have obtained in literature, highlighting the importance of defining new demarcations to preserve the axillary lymph nodes as much as possible in breast surgery.