First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment and maintain responses in ~50% of cases. While the feasibility and safety of TKI cessation have been largely demonstrated, the strategies of TFR optimization are yet to be clarified. Studies (eg. DESTINY) investigating de-escalation, mainly after imatinib, suggested that a stepwise approach may favor TFR outcome. We present the interim results of the phase 2, prospective, multicenter DANTE study (NCT03874858) evaluating de-escalation and TFR in Italian pts with CML in chronic phase (CML-CP) treated with nilotinib (NIL). Methods: Adults with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR for ≥1 year (≥MR 4.0;BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation, pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sDMR entered TFR phase and discontinued NIL;indeed, pts with at least major molecular response (MMR;BCR-ABL ≤0.1% IS), but without sDMR, continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96, and then every 3 months. Pts on half-dose or full-dose NIL were monitored every 3 months. The primary endpoint is the percentage of pts in full treatment-free remission (FTFR) 96 wks after the start of consolidation phase. FTFR is defined as pts with MMR or better, including those who remained in discontinuation during TFR phase and those who are treated with half the standard dose. Key secondary endpoints include percentage of pts with sDMR at wk 48;TFR rate at wk 96 and 144;BCR-ABL kinetics and safety. The predictive role of digital droplet PCR is also evaluated as an exploratory objective. Results: Overall, 113 pts were screened and 107 entered consolidation phase. This interim analysis included 52 pts who reached the end of consolidation phase by data cut-off period (February 8, 2021). Of these 52 pts, 49 (94.2%) were ongoing by data cut-off and 3 (5.8%) discontinued the study (1 patient due to adverse event (AE) and 2 per patient's decision). Median age at study entry was 49.5 years. Median time from diagnosis was 5.6 years and median dose of prior NIL treatment was 600 mg/day for all pts except one who was on NIL 450 mg/day at baseline. Median duration of last sustained MR4 and MR4.5 were 30 and 16.5 months, respectively. Further details are listed in Table 1. At screening, molecular response categories were MR4.0 in 13.7%, MR4.5 in 23.1% and undetectable MR4.5 in 63.5% of pts. During consolidation phase, 5 (9.6%) pts discontinued prematurely: 2 pts restarted NIL full dose (3.8%) for MMR loss, 2 (3.8%) discontinued for AEs and 1 (1.9%) for pt decision. Overall, 47 pts completed consolidation: of them 40 (76.9%) sustained DMR and 7 (13.5%) maintained MMR but not sDMR. Of the 7 pts not sustaining DMR during consolidation, 6 regained DMR after a median of 4.4 months, while 1 pt was still in MMR by data cutoff. The 2 pts who lost MMR after 5 and 8 months regained MMR and 1 regained DMR by data cutoff after increasing NIL to 300 mg bid. Median time spent in consolidation phase was 11.7 months, and the evolution of response categories over time is shown in Figure 1. During consolidation phase, AEs were observed in 16 pts (30.8%), of them 2 (3.8%) pts had serious AEs: 1 patient had skin ulcers and COVID-19 related pneumonia, while 1 patient had unstable angina. No deaths and disease progressions were observed. Conclusions: DANTE is the first study that showed the safety and feasibility of NIL de-escalation before TFR in CML-CP pts with sDMR. Inter m results suggest that loss of MMR during de-escalation is rare. De-escalation strategy may lead to further improvement of TFR outcome and tolerability and may also preemptively support the identification of pts who may not be ready for discontinuation, with a tailored approach. To date, accuracy in predicting TFR outcome is still low, and the de-escalation setting may sharpen biological and clinical predictive factors, including the potential role of digital PCR. [Formula presented] Disclosures: Breccia: Abbvie: Honoraria;Pfizer: Honoraria;Novartis: Honoraria;Incyte: Honoraria;Bristol Myers Squibb/Celgene: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel;Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Incyte: Speakers Bureau;Novartis: Speakers Bureau;Pfizer: Speakers Bureau;Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria. Lemoli: Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau;Celgene: Other: Support for attending meetings and/or travel. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Chiodi: Novartis: Current Employment.

Activation de la voie alterne du complément dans les formes sévères de COVID-19

Introduction Le SARS-CoV-2 est désormais responsable de plus de 4 millions de décès dans le monde. Les formes sévères de COVID-19 sont caractérisées par un état d’hyperinflammation, et l’utilisation de la corticothérapie a réduit significativement la mortalité. Des thérapies complémentaires plus spécifiques pourraient permettre d’améliorer la prise en charge des patients présentant des formes sévères. Dans ce contexte, les voies de signalisation en lien avec le système du complément semblent etre une cible idéale : on retrouve une surreprésentation des voies du compléments dans les cellules épithéliales pulmonaires, une élévation des marqueurs d’activation de la cascade du complément dans le plasma des patients atteints de COVID-19, et des déficits congénitaux dans les protéines de régulation du complément ont été associées à des formes plus sévères de la maladie. Cependant, nos connaissances des voies spécifiques activées du complément et leur lien avec la sévérité de la maladie restent limitées. Patients et méthodes Durant la première vague épidémique en France, nous avons recueilli les prélèvements de 32 patients COVID-19 présentant des niveaux de sévérité différents de la maladie. Nous avons déterminé l’expression ARN de 28 gènes du système du complément et les concentrations sériques de 6 protéines, représentant les trois voies du complément. Résultats L’expression des gènes du complément étaient régulées de façon différentielle selon la gravité de la COVID-19 : alors que la voie classique était activée chez tous les patients infectés, la forme sévère de la maladie était associée à une suractivation de la voie de la lectine et de la voie alterne, dont l’expression corrélait avec les marqueurs de l’inflammation et de coagulation. De plus, la properdine, régulateur positif majeur de la voie alterne, était exprimé à des niveaux élevés (ARN) chez les patients les plus graves, tandis que leurs niveaux protéiques étaient diminués, suggérant une consommation importante et la déposition au niveau des sites de l’activation du complément. De façon intéressante, les concentrations sériques basses de properdine étaient significativement associées au recours à la ventilation mécanique. Conclusion Cette étude apporte un éclairage sur le rôle potentiel de la voie alterne du complément dans les formes graves de COVID-19. Bien que des études histologiques et mécanistiques ainsi qu’une confirmation de ces résultats sur une plus grande cohorte soient nécessaires, ces résultats sont en faveur d’essais ciblant la voie alterne du complément chez les patients présentant des formes sévères de COVID-19.