Improvement In Total Symptom Score Research Articles

Consistency of Spleen and Symptom Reduction Regardless of Cytopenia in Patients With Myelofibrosis Treated With Pacritinib

BackgroundPacritinib is a JAK2/IRAK1/ACVR1 inhibitor that is approved in the United States for the treatment of patients with myelofibrosis who have a platelet count < 50 × 109/L. Phase 3 clinical studies of pacritinib included patients across a wide range of baseline platelet and hemoglobin levels. Patients and MethodsIn order to assess the impact of baseline blood counts on pacritinib efficacy, an analysis of efficacy outcomes by baseline platelet and hemoglobin levels was performed using data pooled from 2 Phase 3 studies of pacritinib in patients with MF (PERSIST-1 and PERSIST-2). ResultsOf 276 patients evaluable for spleen response, spleen volume reduction occurred consistently across platelet subgroups (< 100 × 109/L or ≥ 100 × 109/L) and hemoglobin subgroups (< 8 g/dL, ≥ 8 to < 10 g/dL, or > 10 g/dL), with no diminution in treatment effect in patients with severe thrombocytopenia or anemia. Among 159 patients evaluable for symptoms response, improvement in total symptom score (TTS) was similar across platelet subgroups. A ≥ 50% improvement of TSS occurred more frequently in patients with baseline hemoglobin < 8 g/dL compared with those with baseline hemoglobin ≥ 8 to < 10 g/dL or > 10 g/dL. Patients with baseline hemoglobin < 8 g/dL also experienced improved hemoglobin sustained over 24 weeks, whereas subgroups with less severe anemia had stable hemoglobin levels over time. Symptom improvement as assessed using the Patient Global Impression of Change instrument was generally consistent across platelet and hemoglobin subgroups. ConclusionPacritinib demonstrates consistent efficacy in patients with MF regardless of baseline platelet and hemoglobin counts.

Interdigital-type antifungal socks for prevention and treatment of tinea pedis

BackgroundInterdigital tinea pedis is the most common type of foot infection, which is often treated by topical or systemic antifungals. Due to the increase in antifungal resistance, antifungal socks are becoming potential alternatives for the daily management of tinea pedis. MethodsIn this study, antifungal fibres were adopted to produce interdigital hygiene socks to split the third and fourth toe seams of the feet. In vitro antifungal activity was first examined to verify the effectiveness of the socks. Preventive efficacy against tinea pedis was then evaluated among healthy participants, followed by therapeutic effect detection in patients diagnosed with tinea pedis by analysing the improvement in total symptom scores (TTS). ResultsThe interdigital-type hygiene socks exhibited apparent antifungal activities in vitro. An in vivo study demonstrated significant preventive effects against tinea pedis for interdigital socks compared to plain socks (P = 0.011) and a lower TTS than noninterdigital (P = 0.04) or plain socks (P < 0.0001). Moreover, interdigital socks showed a total effectiveness rate of 72.9% in patients with tinea pedis, with most of the symptoms alleviated. ConclusionInterdigital-type hygiene socks not only exhibited in vitro antifungal activities but also showed significant prophylactic and therapeutic effects against interdigital tinea pedis in vivo.

Improvement in Individual Symptoms and Total Symptom Score (TSS) and Matching-Adjusted Indirect Comparison (MAIC) Analysis to Compare TSS As a Continuous Endpoint in Patients with Myelofibrosis Treated with Pelabresib in Combination with Ruxolitinib Versus Janus Kinase Inhibitor Monotherapy

Background: Pelabresib (CPI-0610; PELA) is a bromodomain and extraterminal domain (BET) inhibitor in development for the treatment of myelofibrosis (MF). PELA combined with ruxolitinib (RUX) has shown a 56% response rate for ≥50% reduction in total symptom score (TSS) at Wk 24 from baseline (BL; TSS50) in Janus kinase inhibitor (JAKi) treatment-naïve patients (pts) with intermediate or high-risk MF in Arm 3 of the open-label Phase 2 MANIFEST study (NCT02158858). TSS50 is a standard measure of symptom improvement; however, the 50% response threshold does not capture clinical benefit in pts with TSS reduction <50% or pts who achieve TSS50 but could benefit from further symptom improvement (Dueck A, et al. European Hematology Association 2017. Poster E1331). Here, we present percentage change in TSS and subdomains as a continuous endpoint from Arm 3 of MANIFEST and indirect comparisons with historical double-blind JAKi trials in MF. Aims: To assess clinically meaningful changes in TSS with PELA in combination with RUX. TSS subdomains were analyzed to assess the underlying impact of PELA + RUX on symptom scores. In the absence of head-to-head studies of PELA + RUX vs JAKi monotherapy, naïve and matching-adjusted indirect comparison (MAIC) analysis (correcting for potential imbalances in baseline characteristics) were used to investigate improvement in TSS as a continuous endpoint in pts treated with PELA + RUX in Arm 3 of the MANIFEST study with historical double-blind Phase 3 JAKi trials: COMFORT-I (RUX), SIMPLIFY-1 (RUX, momelotinib [MOM]) and JAKARTA (fedratinib [FED]). Methods: In MANIFEST, percentage change in TSS and subdomains (fatigue, night sweats, itching, abdominal discomfort, pain under ribs, feeling of fullness and bone pain) from BL at Week (Wk) 12, 24, 36 and 48 were calculated. Pts with BL score = 0 were excluded. For the MAIC analysis, individual pt level data were available for MANIFEST Arm 3, and study-level data were extracted from published waterfall plots using WebPlotDigitizer (Rohatgia A. https://automeris.io/) for COMFORT-I, SIMPLIFY-1 and JAKARTA (FED 400 mg arm). Unanchored MAIC was conducted, whereby pts were reweighted to adjust for imbalances in key prognostic BL characteristics: gender, MF subtype, International Prognostic Scoring System risk status (IPSS), previous hydroxyurea use, platelet count, hemoglobin levels, spleen volume and JAK2V617F status; as a result, bias due to potential unmeasured differences is unlikely. The weights were used to calculate the effective sample size. Pts with IPSS intermediate-1 were excluded from the analysis. Weighted and unweighted treatment effects in terms of difference in least square (LS) means with their 95% confidence intervals using robust sandwich estimators for variance are presented. Studies used different TSS questionnaire versions; however, variations are subtle, and so comparisons across versions are valid (Dueck A, et al.Blood 2017;130:2168). Results: Comparable mean BL TSS scores were observed: 16.1 in MANIFEST Arm 3 and 17.5-19.4 across comparator Phase 3 studies. In MANIFEST Arm 3, a median reduction from BL of >50% was observed for TSS and all subdomains, and this reduction remained consistent across Wk 12 to Wk 48. TSS distribution in MANIFEST at Wk 24 showed greater median and mean reductions from BL vs JAKi monotherapy studies (Figure 1 shows comparison with RUX in SIMPLIFY-1). Complete summary level balance was achieved in the weighted distributions of the prognostic factors in MANIFEST Arm 3 versus comparators. After adjusting for imbalances, >20% greater reduction in LS mean percentage change in TSS from BL at Wk 24 was observed for all comparisons of MANIFEST Arm 3 vs historical studies, as shown in Figure 2. P values for all MAIC analyses were statistically significant. Conclusions: Analyzing TSS as a continuous endpoint in addition to responder analysis overcomes limitations of using TSS50 alone. TSS50 rates in MANIFEST Arm 3 were higher than all comparator MF studies, and clinically relevant improvements in TSS and its subdomains were observed as early as Wk 12 and were durable over time. When indirectly comparing Arm 3 of the Phase 2 MANIFEST study with historical Phase 3 MF studies using MAIC analysis, improved estimates of changes in TSS with PELA + RUX vs RUX, MOM or FED monotherapy were observed. A randomized Phase 3 MANIFEST-2 study of PELA + RUX vs RUX monotherapy in JAKi-naïve pts is ongoing (NCT04603495). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Correlation of Quality of Life between Treatment Outcomes in the Majic Study Which Compared Ruxolitinib to Best Available Therapy in Polycythemia Vera

Correlation of Quality of Life between Treatment Outcomes in the Majic Study Which Compared Ruxolitinib to Best Available Therapy in Polycythemia Vera

Potential Disease-Modifying Activity of Navtemadlin (KRT-232), a First-in-Class MDM2 Inhibitor, Correlates with Clinical Benefits in Relapsed/Refractory Myelofibrosis (MF)

Potential Disease-Modifying Activity of Navtemadlin (KRT-232), a First-in-Class MDM2 Inhibitor, Correlates with Clinical Benefits in Relapsed/Refractory Myelofibrosis (MF)

Safety and Efficacy of Ruxolitinib in Patients with Myelofibrosis and Low Platelet Counts (50 – 100 × 109/L): Final Analysis of an Open-Label Phase 2 Study

IntroductionTreatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50 – 100 × 109/L) are reported. Patients and MethodsPatients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 109/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety. ResultsOf 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were −20.5% (−55.8% to 38.5%, n=51) and −39.8% (−98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3). ConclusionA starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.

621 PL02.05 LONG-TERM TREATMENT OF PATIENTS WITH EOSINOPHILIC GASTRITIS AND/OR EOSINOPHILIC DUODENITIS WITH LIRENTELIMAB, A MONOCLONAL ANTIBODY AGAINST SIGLEC-8

Abstract Eosinophilic esophagitis (EoE), gastritis (EG), and/or duodenitis (EoD) are associated with accumulation and activation of eosinophils and mast cells in the esophagus, stomach, and/or duodenum, respectively. Lirentelimab (AK002), an antibody against siglec-8, depletes eosinophils and inhibits mast cells. We performed an open-label extension (OLE) study of subjects who completed ENIGMA (a randomized, double-blind, placebo-controlled phase 2 study of lirentelimab in adults with symptomatic, biopsy-confirmed EG and/or EoD, with or without EoE) to evaluate long-term responses. Methods Subjects who received 4 monthly infusions of lirentelimab or placebo during ENIGMA (n = 59) were eligible for the OLE; they received monthly, escalating doses of lirentelimab (0.3 or 1 mg/kg escalating to 3 mg/kg). Symptoms were assessed weekly using an electronic daily patient-reported outcome questionnaire and total symptom scores (TSS) were calculated. Patients underwent upper endoscopy with biopsy at screening and at the end of ENIGMA (day 99, week 16, blinded); in the OLE, endoscopies were performed on day 323 (30 weeks after the first dose in the OLE). Histopathology was assessed by a single pathologist. Results Fifty-eight subjects entered the OLE; 45 completed ≥52 weeks lirentelimab (including exposure during ENIGMA) and 29 completed 70 weeks. Mean TSS improved through week 70 (Figure 1). Subjects receiving 70 weeks lirentelimab (ENIGMA+OLE) had further improvements in TSS from baseline (mean reductions: 68% at weeks 29–30, 70% at weeks 51–52, 75% at weeks 69–70). Symptom scores (abdominal pain, nausea, vomiting, early satiety, appetite loss, abdominal cramping, bloating, diarrhea) decreased significantly from baseline. Treatment response was not associated with concomitant EoE. The most common adverse event was mild to moderate infusion-related reactions, usually with the first infusion. Conclusion In the OLE of the ENIGMA study, patients with EG and or EoD (with or without concomitant EoE) who received lirentelimab had sustained tissue eosinophil depletion and significant long-term symptom improvement. Symptoms continued to improve with duration of treatment. Lirentelimab appears to be a promising targeted treatment for EG and/or EoD.

An Open-Label, Phase II Study Of The JAK1 Inhibitor INCB039110 In Patients With Myelofibrosis

An Open-Label, Phase II Study Of The JAK1 Inhibitor INCB039110 In Patients With Myelofibrosis

Response To Ruxolitinib In Patients With Intermediate-1, Intermediate-2 and High-Risk Myelofibrosis: Interim Results Of The UK Robust Trial

BackgroundRuxolitinib is a selective small molecule inhibitor of Janus kinase 1 (JAK1) and 2 (JAK2). Ruxolitinib suppresses the activity of the JAK/STAT pathway, and thus targets the underlying pathogenic cause of myelofibrosis (MF). The efficacy and safety of ruxolitinib for the treatment of MF has been demonstrated in two pivotal phase III clinical trials, COMFORT-I and COMFORT-II. Ruxolitinib demonstrated a statistically significant reduction in splenomegaly compared with placebo (in COMFORT-I) and compared with best supportive care (in COMFORT-II) and has been approved for the treatment of patients with primary myelofibrosis (PMF), post polycythaemia myelofibrosis (PPV MF) or post-essential thrombocythaemia myelofibrosis (PET-MF) based on the results of these studies. Both pivotal studies involved patients with intermediate-2 or high-risk disease according to International Prognostic Scoring System criteria. However, a number of myelofibrosis patients with intermediate-1 risk disease have significant constitutional symptoms or pain relating to splenomegaly. The ROBUST trial, a UK open label, multicentre exploratory phase 2 study of ruxolitinib for patients with PMF, PPV MF or PET-MF further investigates the response to ruxolitinib in patients with MF and includes patients with intermediate-1 risk disease in addition to patients with intermediate-2 and high-risk disease. MethodsThis open-label multicentre UK study enrolled adult patients diagnosed with PMF, PPV MF or PET-MF (World Health Organization criteria) with or without prior therapy and who had intermediate-1, intermediate-2 or high-risk disease according to the International Working Group for Myelofibrosis Research & Treatment criteria. Patients received ruxolitinib at a dose of 15 or 20 mg twice daily (according to baseline platelet counts) and continued treatment until disease progression, unacceptable toxicity, death, or withdrawal from the study. Spleen size was assessed at baseline and at 4-week intervals by palpation, and symptoms were assessed by patients using the Myelofibrosis Symptom Assessment Form (MF-SAF) at baseline and weeks 4, 12 and 24. This interim analysis presents data at 24 weeks. ResultsA total of 48 patients (risk classification: intermediate-1, n = 20; intermediate-2, n = 11; high, n = 17) were included in the study. Mean ± SD age was 69.1 ± 10.4 years and 43.8% of patients were female. Most patients had an ECOG performance status at baseline of 0 (52.1%) or 1 (35.4%). Mean spleen length at baseline was 13.9 ± 6.9 cm and mean ± SD MF-SAF total symptom score (TSS) was 16.4 ± 11.5. A ≥50% decrease in spleen length from baseline at any time was achieved in 27/48 (56.3%) patients overall, and was similar across all risk groups. At week 24 a decrease in mean spleen length from baseline of 6.4 ± 5.2 was observed overall and was similar across the three risk groups (Table). A mean ± SD improvement in TSS at 24 weeks of 9.1 ± 11.3 was observed overall and improvements were similar in patients with intermediate-1 risk and with high-risk disease (Table). ConclusionsThese results indicate that in patients with MF, ruxolitinib provides marked and sustained reductions in splenomegaly and disease-related symptoms. Symptom and spleen responses were observed across risk categories, including intermediate-1 patients, providing further evidence of the clinical benefit of ruxolitinib in patients with MF. Missing data will be updated prior to the ASH2013 meeting, allowing more robust comparison across risk groups for the different endpoints. Disclosures:Harrison:S Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chacko:Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Knapper:Novartis: Funding for travel to overseas conference Other, Honoraria. Milojkovic:BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria. Farquharson:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ali:Novartis: Honoraria. Andrews:Novartis Pharmaceuticals UK Limited: Employment, Equity Ownership. Graham:Novartis Pharmaceuticals UK Limited: Employment. Mead:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Open Label Phase I Study of Single Agent Oral RG7388 (idasanutlin) in Patients with Polycythemia Vera and Essential Thrombocythemia

Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with an increased risk of thrombosis, progression to myelofibrosis (MF) and significant symptom burden. While hydroxyurea, interferon, and JAK2 inhibitors are used to treat these myeloproliferative neoplasms (MPNs), hematopoietic stem cell-depleting therapies may result in an alternative mechanism to alter disease course and improve outcome. MDM2, a negative regulator of P53, is overexpressed in CD34+ MPN cells harboring wild type P53. It is the target of idasanutlin (IDA), an oral MDM2 antagonist that results in up-regulation of P53 and down-stream activators of apoptosis. Preclinical data from our laboratory group supports the clinical evaluation of IDA in patients (pts) with ET/PV (Lu et al Blood. 2014;124(5):771-9). We evaluated the safety and tolerability of IDA in a phase I dose escalation trial of pts with JAK2V617F-positive ET or PV [NCT02407080].Methods: 13 pts (1 withdrew prior to treatment) resistant/intolerant to hydroxyurea and/or interferon therapy and without prior JAK2 inhibitor therapy were enrolled in a single institution phase I trial of oral IDA at two dose levels of 100 mg and 150 mg daily for five consecutive days and repeated every 28 day cycles. The first cycle consisted of 56 days for the evaluation of dose limiting toxicities (DLT). A DLT was defined as any non-hematologic AE of grade 3+ or a hematologic AE of grade 2+ thrombocytopenia, or grade 3+ neutropenia or anemia. The absence of DLT in the initial cohort of 100 mg daily in 3 evaluable pts allowed for dose escalation in a new cohort to 150 mg and after a total of 6 pts were treated at this level an additional 3 pts were treated at 100mg to complete the intended study. Pts that did not attain at least a partial response (PR) by modified European LeukemiaNet (ELN) criteria after cycle 6 and met eligibility were able to continue receiving IDA in combination with pegylated interferon-α (PEG) at 45ug weekly. Correlative studies included baseline mutational profiling, MDM2 protein levels, changes in serum MIC-1 levels and JAK2V617F variant allele frequency (VAF) with therapy.Results: 12 pts (6 at 100 mg; 6 at 150 mg) were treated and their baseline characteristics are shown in Table 1. Pts received a median of 7 cycles (range, 1-12) over a median of 33 weeks (range, 8-107) on study. Three pts discontinued treatment due to pt decision (n=2) and physician decision (n=1). A DLT was not identified for either dose level during cycle 1, and no hematologic treatment emergent adverse events (TEAE) were seen at any time point. Table 2 shows the non-hematologic TEAEs that occurred in at least 2 pts regardless of attribution. Grade 3 fatigue (n=1) and grade 3 headache (n=1) were the only significant TEAE noted at any time on study (both in 100mg cohort). The overall response rate by modified ELN criteria by cycle 7 for the 9 evaluable pts was 7/9 (78%). 7 of 10 (70%) evaluable pts achieved a ≥50% improvement in total symptom score (TSS) from baseline. There were no thrombotic or major hemorrhagic episodes, or progression to MF. Bone marrow pathologic response was assessed in 2 pts after 5 cycles. One case showed histological improvement, with normalization of overall marrow cellularity and megakaryocyte number, and less pronounced megakaryocytic atypia. The median JAK2V617F VAF at baseline, 7 cycles, and 9 cycles of therapy was 45% (n=12), 12% (n=6) and 13% (n=6), respectively. One pt was eligible to receive combination therapy and achieved phlebotomy freedom, normalization of palpable spleen (baseline 18cm), leukocyte count (baseline 44 x109/L), and PV-related symptoms by cycle 8. This pt also attained a 20% reduction in JAK2V617F VAF.The percentage of mononuclear cells expressing MDM2 was dramatically increased as compared to normal controls (p=0.01) (Figure 1). Serum levels of MIC-1 was used to assess pharmacodynamic effects of IDA therapy. Serum MIC-1 levels were elevated (~ 5 fold) after 5 days of administration of IDA in 85% of the pts (Figure 2), indicating activation of P53 by the low doses of IDA administered. Persistent elevation in MIC-1 levels was observed on day 15 in 6 of the 12 pts treated.Conclusion: IDA is well tolerated and demonstrates a clear signal of clinical activity in pts with therapy refractory PV. Correlatives support on-target activity. Mature follow up on the entire cohort will be presented. A multicenter phase II trial of IDA at a dose of 150 mg is underway [Display omitted] DisclosuresMascarenhas:CTI Biopharma: Research Funding; Janssen: Research Funding; Promedior: Research Funding; Novartis: Other: DSMB member , Research Funding; Merck: Research Funding; Incyte: Other: Clinical Trial Steering Committee , Research Funding.

PCN19 Beyond a Binary Endpoint: Longitudinal and Individual Symptom Analyses from the Simplify-1 Study Demonstrate Clinically Comparable Symptomatic Benefit of Momelotinib to Ruxolitinib in JAK Inhibitor Naive Myelofibrosis Patients

Clinical trials investigating JAK1/JAK2 inhibitors for myelofibrosis subjects have measured symptom improvement as a minimum 50% reduction in total symptom score (TSS) at the end of a 24-week treatment period. However, this landmark response analysis is based on post-baseline score changes occurring only between Week 21 (W21) through W24 and does not account for variation in baseline TSS. To better understand the clinical relevance of TSS improvement we applied individual item analyses and Mixed-effect Models for Repeated Measures (MMRM) to SIMPLIFY-1, a phase 3 study which randomized 432 intermediate and high risk JAK inhibitor-naive MF patients 1:1 to momelotinib or ruxolitinib. Analyses were conducted in the intention-to-treat (ITT) population and in symptomatic subjects (baseline TSS ≥ 10). The distributions of TSS items were examined at baseline, and shift in scores at W24 (health state shifts) were determined. Odds ratios from generalized estimating equations for improvement on momelotinib relative to ruxolitinib were calculated for each item of the TSS using multiple predictive imputations for missing data. The MMRM compared mean change in TSS from baseline through W24. The meaningful change threshold (MCT) was determined using Patient Global Impression of Change. While the prespecified non-inferiority endpoint for TSS response rate was not met for momelotinib (28%) vs ruxolitinib (42%), item-level health state shifts and responder analyses showed similar improvements for momelotinib and ruxolitinib. No significant differences on any items were seen; odds ratios for each between-group comparison ranged from 0.74 to 1.20. MMRM mean TSS change score at W24 was 6.35 (momelotinib) vs 7.87 (ruxolitinib) in the ITT and 8.80 (momelotinib) vs 10.46 (ruxolitinib) in the symptomatic subset. TSS improvements were near the within-subject MCT of 8 points in the ITT and exceeded the MCT in the symptomatic subset. Item analyses and MMRM showed clinically important and comparable improvements in TSS.

Fedratinib Improves Myelofibrosis-related Symptoms and Health-related Quality of Life in Patients with Myelofibrosis Previously Treated with Ruxolitinib: Patient-reported Outcomes from the Phase II JAKARTA2 Trial.

Myelofibrosis symptoms compromise health-related quality of life (HRQoL). Ruxolitinib can reduce myelofibrosis symptom severity, but many patients discontinue ruxolitinib due to loss of response or unacceptable toxicity. Fedratinib is an oral, selective JAK2 inhibitor approved in the United States for treatment of patients with intermediate-2 or high-risk myelofibrosis. The single-arm, phase II JAKARTA2 trial assessed fedratinib 400 mg/d (starting dose) in patients with myelofibrosis previously treated with ruxolitinib. Patient-reported changes in myelofibrosis symptom severity using the modified Myelofibrosis Symptom Assessment Form (MFSAF), and overall HRQoL and functional status using the EORTC QLQ-C30, were evaluated at each cycle. Clinically meaningful changes from baseline HRQoL scores were based on effect sizes. Ninety patients were MFSAF-evaluable. Myelofibrosis symptoms were mild-to-moderate at baseline. Patients showed statistically significant and clinically meaningful improvements in total symptom scores from baseline on the MFSAF at all post baseline visits through the end of cycle 6 (EOC6). Baseline global health status/QoL and functional domain scores on the EORTC QLQ-C30 were meaningfully worse than in the general population. At EOC6, 44% of patients reported clinically meaningful improvements in global health status/QoL, and 30%–53% of patients experienced clinically meaningful improvement in QLQ-C30 functional domains across post baseline timepoints. Over 80% of ongoing patients perceived fedratinib as beneficial on the Patient’s Global Impression of Change questionnaire. Fedratinib effects were consistent among prognostically relevant patient subgroups. Patients with myelofibrosis previously treated with ruxolitinib experienced clinically meaningful improvements in myelofibrosis symptom burden, overall HRQoL, and functional status in the first 6 months of fedratinib treatment.

Patient-reported Effects of Fedratinib, an Oral, Selective Inhibitor of Janus Kinase 2, on Myelofibrosis-related Symptoms and Health-related Quality of Life in the Randomized, Placebo-controlled, Phase III JAKARTA Trial.

Patients with myelofibrosis (MF) experience an array of symptoms that impair health-related quality of life (HRQoL). Fedratinib, an oral, selective Janus-kinase 2 (JAK2) inhibitor, was investigated in the randomized, placebo-controlled, phase III JAKARTA study in adult patients with intermediate- or high-risk JAK-inhibitor-naïve MF. The effect of fedratinib 400 mg/d on patient-reported MF symptoms and HRQoL in JAKARTA was assessed. Participants completed the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0), which evaluates 6 key MF symptoms (night sweats, early satiety, pruritus, pain under ribs on the left side, abdominal discomfort, bone/muscle pain). The modified MFSAF v2.0 was completed during the first 6 treatment cycles and at end of cycle 6 (EOC6). Symptom response was a ≥50% improvement from baseline in total symptom score (TSS). Overall HRQoL was assessed by EQ-5D-3L health utility index (HUI) score. The MFSAF-evaluable population comprised 91/96 patients randomized to fedratinib 400 mg and 85/96 patients randomized to placebo. Mean baseline TSS was 17.6 and 14.7 for fedratinib and placebo, respectively, and mean EQ-5D-3L HUI was 0.70 and 0.72. Fedratinib elicited statistically significant and clinically meaningful improvements in TSS from baseline versus placebo at all postbaseline visits. Symptom response rates at EOC6 were 40.4% with fedratinib and 8.6% with placebo (OR 7.0 [95% CI, 2.9-16.9]; P < 0.001), and a significantly higher proportion of fedratinib-treated patients achieved clinically meaningful improvement from baseline on the EQ-5D-3L HUI at EOC6 (23.2% versus 6.5%; P = 0.002). Fedratinib provided clinically meaningful improvements in MF symptoms and overall HRQoL versus placebo in patients with JAK-inhibitor-naïve MF.

Loratadine vs Rupatadine: Unearthing the Capital Choice in Chronic Idiopathic Urticaria (CIU) - A Randomized Controlled Trial.

Background:Chronic Idiopathic Urticaria (CIU) is a debilitating disease characterised by almost daily presence of urticarial symptoms like short-lived wheals, itching, and erythema for at least 6 weeks without an identifiable cause there by leading to impairment of quality of life of the patient.Aim:To evaluate the efficacy and safety of loratadine and rupatadine in chronic idiopathic urticaria.Methods:This is a prospective, randomized, single-blind, parallel arm study conducted to evaluate the efficacy and safety of loratadine and rupatadine in patients with CIU. The study was registered prospectively with Clinical Trial registry of India (CTRI/2017/05/008624). Institutional Ethics Committee clearance was obtained. Written informed consent was obtained from all the participants before enrolment into the trial. The study was conducted in the outpatient department of Dermatology, SRM Medical College, Kattankulathur, Tamil Nadu, India, during the period from June 2017 to August 2018. Patients with CIU enrolled into the study based on inclusion-exclusion criteria were given the intervention drugs; Loratadine 10 mg once daily or rupatadine10 mg once daily orally for 6 weeks.Results:Rupatadine is more efficacious than loratadine in the reduction of Total Leucocyte Count, Differential Count and Absolute Eosinophil Count, the key determinants of allergy. Rupatadine also produced better improvement in Total symptom Score, Dermatology Life Quality Index in patients with CIU.Conclusion:Analysis of all the parameters of efficacy and safety establishes the probable superiority of rupatadine over loratadine for the treatment of urticaria.

Pacritinib demonstrates spleen volume reduction in patients with myelofibrosis independent of JAK2V617F allele burden

AbstractMyelofibrosis (MF) has heterogeneous clinical manifestations, with some patients exhibiting a myelodepletive phenotype characterized by cytopenias and an absent or low JAK2V617F allele burden. Ruxolitinib may be less effective in these patients. We assessed the efficacy of pacritinib, a JAK2/IRAK1 inhibitor, in MF patients with low JAK2V617F allele burden. In this post hoc analysis of the PERSIST-1 and -2 trials, patients with MF randomized to pacritinib or best available therapy (BAT) were stratified by JAK2V617F allele burden quartile for spleen response of ≥35% and improvement in total symptom score of ≥50%. Five hundred thirty-six patients were included. Patients with lower JAK2V617F allele burden had smaller baseline spleens and lower hemoglobin and platelet counts as compared with higher allele burden patients. Among pacritinib-treated patients, spleen responses were observed across all JAK2V617F allele burden quartiles and in JAK2V617F− disease. No spleen responses were observed among BAT-treated patients with allele burden ≤50% or JAK2V617F− disease. The intention-to-treat response rate was significantly higher on the pacritinib arm for JAK2V617F− disease (23.0% vs 0%; P = .033), and for the lowest allele burden quartiles (0%-25%: 20.9% vs 0%, P < .001; 25%-50%: 15.4% vs 0%, P = .020). There were significantly more symptom responders with pacritinib vs BAT in the 0% to 25% and 25% to 50% cohorts. Pacritinib treatment led to superior spleen and symptom burden reduction compared with BAT in patients with absent or low JAK2V617F allele burden, suggesting that pacritinib may be uniquely suited for patients with myelodepletive MF.

The Addition of Navitoclax to Ruxolitinib Demonstrates Efficacy within Different High-Risk Populations in Patients with Relapsed/Refractory Myelofibrosis

The Addition of Navitoclax to Ruxolitinib Demonstrates Efficacy within Different High-Risk Populations in Patients with Relapsed/Refractory Myelofibrosis

Symptom Burden and Quality of Life in High-Risk Essential Thrombocythemia and Polycythemia Vera Patients Receiving Hydroxyurea or Pegylated Interferon Alfa-2a: Results of Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 Trials

Symptom Burden and Quality of Life in High-Risk Essential Thrombocythemia and Polycythemia Vera Patients Receiving Hydroxyurea or Pegylated Interferon Alfa-2a: Results of Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 Trials

Double-blinded randomized prospective trial of intranasal capsaicin treatment for nonallergic rhinitis.

Nonallergic rhinitis (NAR) is currently a diagnosis of exclusion with an unclear pathophysiologic mechanism and limited treatment options. In patients diagnosed with NAR based on symptoms, negative skin testing and positive optical rhinometry (ORM), the study's objective was to evaluate the therapeutic action of intranasal capsaicin in the management of rhinitic symptoms and the effect on ORM readings. Patients with a history of NAR underwent screening by a diagnostic intranasal capsaicin challenge with ORM and skin-prick testing. Twenty-two NAR patients were enrolled and randomized to either treatment with 0.1mM capsaicin (n = 11) or placebo (n = 11). Treatment consisted of 5 consecutive intranasal applications separated by 1 hour with follow-up at 4 and 12 weeks. At each visit, subjects underwent intranasal capsaicin challenge with ORM reading and a visual analog scale scoring of rhinitis symptoms. Treatment with intranasal capsaicin resulted in a median change with improvement in total symptom score (TSS) of -5 from baseline vs an increase of 2 with placebo at 4 weeks, which remained significantly different between the groups at 12 weeks (p = 0.03). At 12 weeks posttreatment, 60% of the intervention group vs 80% of placebo-treated patients still met objective criteria for NAR by ORM. Using ORM in the objective diagnosis of NAR, this trial showed that intranasal 0.1mM capsaicin not only improved rhinitic symptoms but also objectively reduced nasal reactivity and nasal congestion with a 40% responder rate at 12 weeks as noted by ORM.

Clinical efficacy of acupuncture in treatment of chronic urticaria and its ffects on the content of IgE and the imbalance of Th1/Th2 cell function

To observe the clinical efficacy of acupuncture in treatment of chronic urticaria and the change in the content of serum immunoglobulin E (IgE), and to discuss the effect of acupuncture on the imbalance of T helper (Th)1/Th2 cell function via observing the changes in the contents of interferon-γ (IFN-γ) and interleukin-4 (IL-4). Ninety patients meeting the inclusion criteria of chronic urticaria were randomized into an acupuncturemedication group, an acupuncture group and a Western medication group by the random number table method. The acupuncture-medication group was intervened by acupuncture, cupping, collateral-pricking bloodletting and oral administration of cetirizine hydrochloride tablets; the acupuncture group was treated with acupuncture, cupping and collateral-pricking bloodletting; the Western medication group only received oral administration of cetirizine hydrochloride tablets. Before treatment and after 6-week treatment, the changes in the symptom scores and the contents of serum IgE, IFN-γ and IL-4 in the three groups were observed. There were no significant differences in the total effective rate among the three groups (all P>0.05), but the cured and markedly effective rate was significantly higher in the acupuncture-medication group than that in the Western medication group (P<0.05). After treatment, the total symptom score decreased in the three groups (P<0.05), and the improvement of total symptom score in the acupuncture-medication group was more significant than that in the Western medication group (P<0.05). The component symptom scores all decreased after treatment in the three groups (all P<0.05); the improvements of the scores of itch intensity, and skin lesion size and number were more significant in the acupuncture-medication group than in the Western medication group (all P<0.05); the improvement of the skin lesion size score was more significant in the acupuncture group than in the Western medication group (P<0.01). The contents of IgE and IL-4 dropped (all P<0.05) and the content of IFN-γ increased (P<0.05) after treatment in the three groups; the post-treatment changes in the serum contents of IgE and IFN-γ were more significant in the acupuncture-medication group than in the Western medication group (both P<0.05). The incidence rate of adverse reactions was significantly lower in the acupuncture-medication group and acupuncture group than in the Western medication group (both P<0.05), and the relapse rate was significantly lower in the acupuncture-medication group than in the Western medication group (P<0.05). Combined acupuncture and medication can enhance the cured and markedly effective rate in treating chronic urticaria. Acupuncture is equivalent to cetirizine hydrochloride tablets comparing the clinical efficacy in treatment of chronic urticaria. Acupuncture plus medication and acupuncture alone both can effectively mitigate the clinical symptoms, with low incidence of adverse reactions. The relapse rate is low when using acupuncture together with medication. Acupuncture plus medication can work better in regulating the contents of IgE and IFN-γ and improving the imbalance of Th1/Th2 cell function.

Preliminary Report of MANIFEST, a Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), in Combination with Ruxolitinib, in JAK Inhibitor (JAKi) Treatment Naïve Myelofibrosis Patients

Preliminary Report of MANIFEST, a Phase 2 Study of CPI-0610, a Bromodomain and Extraterminal Domain Inhibitor (BETi), in Combination with Ruxolitinib, in JAK Inhibitor (JAKi) Treatment Naïve Myelofibrosis Patients