INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL 6560 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and \u3b3-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade 653, 18.2%) and 27.3% (grade 653, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107

RETRACTED ARTICLE: Privacy-preserving routing using jointly established protocol in IoT network environment

Abstract In this paper, network energy assesses the capacity of a node to convey messages to others. In most cases, network energy is created when two nodes interact with one another. If a node is part of the same network as the node it is connecting with, then it will be able to make an inter-network energy connection with the node it is meeting. In the case that this does not take place, there will be an accumulation of energy within the part of the network that is facing the node. A node with higher inter-network energy is considered suitable for forwarding. The energy optimisation is achieved using efficient identification of source and destination pairs. This work has considered two scenarios, i.e. lossless transmission and lossy transmission, for our experiments and evaluated the detection probability. The performance of the proposed PPM is evaluated in terms of delivery ratio, overhead and hops count performance measures. When the buffer size is set to 100 MB, PPM delivers 59% of messages with message overhead of 750 and it has a hop count of 2, which is comparable to the state-of-the-art methods. With lengthy lifetimes of IOT networks, PPM is capable of giving higher performance while maintaining the privacy of network. The detection probability for the lossy observations model is applied to a 10-node, 20-node, 30-node and 40-node IoT network

25486 Correlation of the Vitiligo Area Scoring Index with patient- and physician-reported measures of clinical improvement in a randomized, double-blind phase 2 study

The Vitiligo Area Scoring Index (VASI) is a quantitative clinical tool that estimates the overall area of vitiligo patches (ie, skin depigmentation) and the degree of macular repigmentation within these patches over time. This analysis aimed to evaluate the correlation between facial and total VASI (F-VASI and T-VASI, respectively) with patient- and physician-reported measures of clinical improvement (Patient Global Impression of Change-Vitiligo [PaGIC-V; 7-point scale] and Physician’s Global Vitiligo Assessment [PhGVA]) in a randomized, double-blind phase 2 study of 157 patients with vitiligo. Among stable patients (ie, no change from baseline in PaGIC-V [score of 4]), VASI scores showed excellent test-retest reliability (≥0.95) at Weeks 12 and 24. Significant differences in VASI were detected among PhGVA categories (mild, moderate, severe) at baseline. The VASI detected change in disease status during the treatment period; the changes were significantly different between patients who showed improvement (PaGIC-V, 1-3) or worsening (PaGIC-V, 5-6) and were related to the PaGIC-V (Pearson’s r ∼0.45, P ˂.0001). To assess interpretability, an anchor-based approach used PaGIC-V (score of 1 or 2) to define clinically meaningful change (CMC) on the VASI at Week 24; mean percentage CMC was 57% for F-VASI and 42% for T-VASI. Results indicated that a higher percentage of patients treated with 1.5% ruxolitinib cream met or exceeded CMC thresholds vs vehicle on F-VASI (39.4% vs 3.1%; P =.0005) and T-VASI (27.3% vs 0%; P =.002). Analyses of efficacy using the F-VASI and T-VASI reflect meaningful and relevant changes in patients with vitiligo

Longitudinal Change of PTSD Symptoms in Community Members after the World Trade Center Destruction

The World Trade Center (WTC) Environmental Health Center (EHC) is a treatment program for community members with exposure to the 9/11 terrorist attack and its physical and emotional aftermath. Compared to the general responders program, the WTC EHC is diverse with equal gender distribution, representation of many races and ethnicities, and a wide range of social economic status. Patients in the WTC EHC were initially enrolled for physical symptoms, most of which were respiratory, however a large portion of the enrollees scored positive for probable posttraumatic stress disorder (PTSD). In this paper we identify patient characteristics associated with probable PTSD. We also determine the characteristics associated with the longitudinal change of PTSD symptoms, including persistence and remittance, using the widely used Posttraumatic Check List-17 (PCL) cut-off value of 44, as well as changes in PCL total score and symptom cluster scores in patients of Low and High PTSD symptom severity. Few patients with elevated scores achieved a score below 44. However, longitudinal improvement in PCL score at follow-up was identified for patients with High PTSD scores (PCL > 57.5). Changes in PCL symptom clusters differed between those with High and Low PCL scores. These data suggest improvement over time in PCL score that differs depending on the severity of the score and variable responses in the PCL symptom clusters

A randomized, placebo-controlled, phase 2 study of the Janus Kinase 1 inhibitor INCB054707 for patients with moderate-to-severe hidradenitis suppurativa

Background: Janus kinase (JAK)-mediated cytokine signaling contributes to local and systemic inflammation in hidradenitis suppurativa (HS). Objectives: We describe results from a multicenter phase 2 trial of the JAK1 inhibitor INCB054707 in patients with HS. Methods: This was a placebo-controlled, dose-escalation study; patients received INCB054707 once daily (30-, 60- or 90-mg cohorts) or placebo (3:1 randomization per cohort) for 8 weeks, with a 30-day safety follow-up. Patients aged 18-75 years with moderate-to-severe HS of ≤yen;6-months\u27 duration, lesions in ≤yen;2 anatomic locations (Hurley stage II/III), and total abscess and inflammatory nodule count of ≤yen;3 were eligible. The primary endpoint was safety and tolerability. Additional endpoints included HS Clinical Response (HiSCR), HS quality of life (HiSQoL), and peripheral blood biomarkers. Results: Thirty-five patients were enrolled (median [range] age, 45.0 [18-64] years; 80% female; 89% white; 71% Hurley stage II at baseline). Nine patients were randomized to placebo and 26 to INCB054707 (30 mg, n = 9; 60 mg, n = 9; 90 mg, n = 8). Overall, 81% of patients receiving INCB054707 had ≤yen;1 treatment-emergent adverse event (TEAE; 12% grade 3, all thrombocytopenia at 90 mg); no discontinuations resulted from TEAEs. More patients receiving 90 mg INCB054707 than placebo had Week 8 HiSCR (88% vs 57%; Figure 1). Mean change from baseline in Week 8 HiSQoL was greater for patients treated with INCB054707 (range across doses, -28.0 to -39.0) vs placebo (-3.4). Biomarker analysis demonstrated dose-dependent differences in the modulation of inflammatory mediators. Conclusion: INCB054707 was well generally tolerated, demonstrated preliminary efficacy, and improved QoL in patients with moderate-to-severe HS

Janus kinase 1 inhibitor INCB054707 for patients with moderate-to-severe hidradenitis suppurativa: results from two phase 2 studies

BACKGROUND: Janus kinase (JAK)-mediated cytokine signaling contributes to local and systemic inflammation in hidradenitis suppurativa (HS). OBJECTIVES: To describe safety and efficacy results from two multicenter phase 2 trials of the JAK1 inhibitor INCB054707 in patients with moderate-to-severe HS. METHODS: Patients received open-label 15 mg INCB054707 once daily (QD; Study 1) or were randomized to 30, 60, or 90 mg INCB054707 QD or placebo (3:1 within each cohort; Study 2) for 8 weeks. Eligible patients were aged 18-75 years with moderate-to-severe HS (Hurley stage II/III disease), lesions present in ≥2 anatomic locations, and a total abscess and inflammatory nodule count ≥3. The primary endpoint for both studies was safety and tolerability. Secondary endpoints included HS Clinical Response (HiSCR) and other efficacy measures. RESULTS: Ten patients were enrolled in Study 1 (15 mg INCB054707) and 35 in Study 2 (INCB054707: 30 mg, n=9; 60 mg, n=9; 90 mg, n=8; placebo: n=9). Overall, 70·0% of patients in Study 1 and 80·8% of patients receiving INCB054707 in Study 2 experienced ≥1 treatment-emergent adverse event (TEAE); 30·0% and 42·3% of patients, respectively, had ≥1 treatment-related TEAE. Among evaluable patients, 3 patients (42∙9%) in Study 1 and 17 patients (overall 65·4%: 30 mg, 55·6%; 60 mg, 55·6%; 90 mg, 87·5%) receiving INCB054707 versus 4 patients (57·1%) receiving placebo in Study 2 achieved HiSCR at Week 8. CONCLUSIONS: INCB054707 was well tolerated, with responses observed in patients with moderate-to-severe HS. Safety and efficacy findings from these studies demonstrate proof of concept for JAK1 inhibition in HS (ClinicalTrials.gov identifiers, NCT03569371, NCT03607487)