Reduction In Total Symptom Score Research Articles

Head Injury Treatment With Healthy and Advanced Dietary Supplements: A Pilot Randomized Controlled Trial of the Tolerability, Safety, and Efficacy of Branched Chain Amino Acids in the Treatment of Concussion in Adolescents and Young Adults.

Concussion is a common injury in the adolescent and young adult populations. Although branched chain amino acid (BCAA) supplementation has shown improvements in neurocognitive and sleep function in pre-clinical animal models of mild-to-moderate traumatic brain injury (TBI), to date, no studies have been performed evaluating the efficacy of BCAAs in concussed adolescents and young adults. The goal of this pilot trial was to determine the efficacy, tolerability, and safety of varied doses of oral BCAA supplementation in a group of concussed adolescents and young adults. The study was conducted as a pilot, double-blind, randomized controlled trial of participants ages 11-34 presenting with concussion to outpatient clinics (sports medicine and primary care), urgent care, and emergency departments of a tertiary care pediatric children's hospital and an urban tertiary care adult hospital, between June 24, 2014 and December 5, 2020. Participants were randomized to one of five study arms (placebo and 15 g, 30 g, 45 g, and 54 g BCAA treatment daily) and followed for 21 days after enrollment. Outcome measures included daily computerized neurocognitive tests (processing speed, the a priori primary outcome; and attention, visual learning, and working memory), symptom score, physical and cognitive activity, sleep/wake alterations, treatment compliance, and adverse events. In total, 42 participants were randomized, 38 of whom provided analyzable data. We found no difference in our primary outcome of processing speed between the arms; however, there was a significant reduction in total symptom score (decrease of 4.4 points on a 0-54 scale for every 500 g of study drug consumed, p value for trend = 0.0036, [uncorrected]) and return to physical activity (increase of 0.503 points on a 0-5 scale for every 500 g of study drug consumed, p value for trend = 0.005 [uncorrected]). There were no serious adverse events. Eight of 38 participants reported a mild (not interfering with daily activity) or moderate (limitation of daily activity) adverse event; there were no differences in adverse events by arm, with only two reported mild adverse events (both gastrointestinal) in the highest (45 g and 54 g) BCAA arms. Although limited by slow enrollment, small sample size, and missing data, this study provides the first demonstration of efficacy, as well as safety and tolerability, of BCAAs in concussed adolescents and young adults; specifically, a dose-response effect in reducing concussion symptoms and a return to baseline physical activity in those treated with higher total doses of BCAAs. These findings provide important preliminary data to inform a larger trial of BCAA therapy to expedite concussion recovery.

A Real-World Observational Study to Evaluate the Safety and Effectiveness of Fluticasone Furoate-Oxymetazoline Fixed Dose Combination Nasal Spray in Patients with Allergic Rhinitis.

Allergic rhinitis (AR) has shown an increasing prevalence leading to a considerable medical and social burden. Nasal congestion is the cardinal symptom of AR, and the upper respiratory tract is most affected by this long-lasting ailment. Intranasal corticosteroids alleviate nasal congestion, along with other symptoms of AR, but their effect is not evident immediately. Oxymetazoline has a rapid onset of action, but its use should be limited to 3-5days. The study aimed to evaluate the safety and effectiveness of the fixed-dose combination nasal spray containing fluticasone furoate and oxymetazoline hydrochloride (FF+OXY) 27.5/50mcg once daily in patients with AR in a real-world clinical setting. The study was a prospective, open-label, single-arm, multicenter, real-world observational study conducted in patients with AR for a period of 28days. Patients (n=388) with a diagnosis of AR were treated with a combination of FF+OXY nasal spray. Total nasal symptom score (TNSS), total ocular symptom score (TOSS) and total symptom score (TSS) were documented at baseline and at the end of study period. The overall effectiveness of treatment with FF + OXY was rated by the investigators as very good/good/satisfactory/poor (4-point Likert scale) for each patient. Treatment with FF+OXY resulted in significant reduction in the TNSS, TOSS and TSS, from 7.18±3.38 at baseline to 0.20±0.84 (p<0.001), from 2.34±2.29 at baseline to 0.09±0.53 (p<0.001), from 9.51±4.94 at baseline to0.29±1.32 (p<0.001) at 28days respectively. With respect to effectiveness, the investigators reported very good effectiveness in 52.12% of patients. No serious adverse events were reported. The fixed-dose combination of once-daily fluticasone furoate and oxymetazoline hydrochloride nasal spray 27.5/50mcg was effective in relieving the nasal congestion and reduction of TNSS, TOSS and TSS in patients suffering from AR. The combination was safe and well tolerated with no rebound congestion throughout the treatment period.

Individual wearable air purifier protects against pollen, house dust mite, and cat allergens: Report from anallergen exposure chamber.

Evaluation of a new individual wearable air purifier (Respiray Wear A+) for birch pollen, house dust mite (HDM), and cat-allergic rhinoconjunctivitis (ARC) patients in a standardized allergen exposure chamber (AEC). Eligible allergic patients were exposed to birch pollen, HDM raw material, and cat allergen in an AEC for 60 minutes without (V1) and with (V3) the use of the Respiray device. Nasal, ocular, bronchial, and other symptoms were rated by the patients every 10 minutes, and their wellbeing, peak nasal inspiratory flow (PNIF), and lung function parameters were assessed every 30 minutes. The primary endpoint was the change in the median of the total symptom score (TSS) at V3 compared to V1 at 60 minutes of exposure. The secondary endpoints consisted of the total nasal symptom score (TNSS) and total eye symptom score (TESS). 23 patients with birch pollen allergy, 37 patients with HDM allergy, and 41 patients with cat allergy were included in the analysis. Significant reduced symptom scores of ~49% were observed when using Respiray Wea A+ under birch pollen exposure (p<0.05) in the primary endpoint TSS (V3 2.43 compared to V1 4.78). An 48% reduction of symptoms was seen in TSS in case of HDM exposure (V3 3.59; V1 6.92, (t-test: p<0.01)) and the highest reduction of TSS (60%) under Respiray A+ using cat allergens (V3 2.95, V1 7.44, (t-test p<0.01) after 60 minutes of exposure. The personal wellbeing revealed clinically meaningful improvements over time in all three studies which manifested in a lower symptom increase during the final allergen exposures. The individual wearable air purifier Respiray Wear A+ protects significantly against airborne pollen, HDM, and cat allergens and may be a very useful device for avoiding indoor allergens in a new way.

Assessment of Minimal Clinically Important Difference in Patient-Reported Myelofibrosis-Associated Symptoms Using an Anchor-Based Analysis Based on MANIFEST Arm 3 Data

Background Myelofibrosis (MF) is a life-threatening hematologic neoplasm that can arise as a primary condition or as a progression from polycythemia vera or essential thrombocythemia. The MF Symptom Assessment Form (MFSAF) v4.0 is a seven-item questionnaire that assesses symptom severity from the patients' (pts) perspective. Each item is rated on a scale from 0 (Absent) to 10 (Worst Imaginable). The MFSAF Total Symptom Score (TSS) ranges from 0 to 70, with higher scores indicating worse symptoms. A ≥50% reduction in TSS (TSS50) is a commonly used binary endpoint in clinical trials. However, the clinical meaningfulness of the dichotomization of response at 50% cutoff across the spectrum of responses remains uncertain. The relevance of considering TSS as a continuous endpoint in MF studies is assessed here to capture the full spectrum of symptom changes, enabling a potentially more accurate assessment of treatment effects. Pelabresib (CPI-0610) is an investigational oral small-molecule BET inhibitor, while the Janus kinase inhibitors (JAKis) ruxolitinib or fedratinib are the current standard of care for intermediate- or high-risk pts with MF.InArm 3 of the Phase 2 MANIFEST trial of JAKi treatment-naïve pts with MF treated with pelabresib and ruxolitinib, 56% achieved TSS50 response at Week (Wk) 24. Aims This anchor-based analysis aims to determine the minimal clinically important difference (MCID) of change in TSS as a continuous endpoint, based on data from JAKi treatment-naïve pts with MF treated with pelabresib and ruxolitinib, to better evaluate the incremental clinical benefit of treatment effects. Methods Data from Arm 3 of the MANIFEST Phase 2 study of treatment-naïve pts with MF treated with pelabresib combined with ruxolitinib were used (July 29, 2022 data cut). Anchor-based methods compare the change in a scale-based outcome measure with that of an established patient-reported outcome (PRO). These methods are commonly used to establish the MCID, defined as the smallest difference in score that pts consider beneficial. In this analysis, the Patient Global Impression of Change (PGIC), a seven-point scale reflecting overall improvement compared with baseline (BL), was used as the anchor PRO. On the PGIC, pts rated their change from ‘very much improved’ to ‘very much worse’ (Table 1). The relationship between TSS changes (percentage and absolute) at Wk 24 and PGIC categories was examined using correlation and graphical analyses. Linear and quantile regressions were applied to assess the impact of a one-point difference in PGIC score on TSS change at Wk 24, adjusting for BL TSS score. Only pts with available TSS and PGIC data at Wk 24 were included, with no imputation for missing values. Results In Arm 3 of the MANIFEST trial, 78 of 84 pts treated with pelabresib and ruxolitinib had complete TSS data and PGIC at Wk 24. At BL, mean TSS was 16.4 (SD=8.4), and median TSS was 15.5 (range 2.0-38.3). A -58.8% and -7.7 median percentage and absolute reduction in TSS at Wk 24 was observed, respectively. For PGIC at Wk 24 (Table 1), only six pts (7.7%) scored in the three worsening PGIC categories. Percentage and absolute changes in TSS, and the percentage TSS50 responders for each PGIC category are shown in Table 1. Linear regression demonstrated that a one-category increase in PGIC (indicating worsening) corresponded to an 11.89% increase (95% CI 3.12-20.65) in TSS (indicating worsening) at Wk 24. The quantile regression estimate for this relationship was 11.36% (3.53-19.19). For absolute change at Wk 24, a one-category increase in PGIC resulted in a 1.67 (range 0.74-2.60) increase in mean TSS, with a 1.87 (range 0.62-3.12) increase in median TSS. Conclusion Assuming a one-category change in the seven-category PGIC represents a clinically meaningful difference, the analyses suggest that the MCID in TSS for JAKi treatment-naïve pts with MF could be approximately 11-12% for percentage change from BL and approximately 1.5-2 points for absolute change from BL. These findings provide valuable guidance for assessing treatment outcomes and evaluating symptom improvements' clinical significance in this patient population. Further exploration of these findings requires larger data sets, which will be addressed in the forthcoming Phase 3 MANIFEST-2 study evaluating pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve pts with MF.

A Phase 2 Study to Evaluate the Efficacy and Safety of Selinexor Monotherapy in Patients with JAK Inhibitor-Naïve Myelofibrosis and Moderate Thrombocytopenia (XPORT-MF-044)

Background and Significance: Myelofibrosis (MF) is one of several myeloproliferative neoplasms (MPN) associated with somatic mutations in JAK2, CALR, or MPL. Thrombocytopenia is a common occurrence in patients with MF and associated with poor outcomes; the rate of moderate thrombocytopenia (platelet counts of &amp;lt;100 x 10 9 /L) in patients with JAK inhibitor (JAKi)-naïve MF is approximately 25%. While multiple JAKi therapies have been approved for MF, thrombocytopenia is an on-target side effect and suboptimal doses are often used in thrombocytopenic patients leading to suboptimal symptom and/or spleen response. Selinexor is an investigational oral XPO1 inhibitor that may inhibit MF-relevant pathways including STAT, extracellular signal-regulated kinase (ERK), and protein kinase B (AKT). Previously we reported that in a Phase 1 study of selinexor (using two different doses) and the JAKi ruxolitinib, the combination was generally tolerable and manageable in JAKi-naïve patients with MF (NCT04562389). In the cohort receiving 60 mg selinexor weekly in combination with ruxolitinib, 79% of the intent-to-treat (ITT) population achieved a ≥35% reduction in spleen volume from baseline (SVR35) at Week 24; SVR35 rates were consistent across subgroups, including gender and regardless of ruxolitinib starting dose (this includes patients treated with ruxolitinib 5mg BID, a dose associated with limited SVR and TSS responses). Robust symptom improvement was also observed with 58% of the ITT achieving a ≥50% reduction in total symptom score from baseline (TSS50) at Week 24. Additionally, a Phase 1 study of selinexor monotherapy in patients with MF refractory or intolerant to JAKi therapy (NCT03627403; ESSENTIAL) has reported a generally tolerable and manageable safety profile with improvements in SVR35. Single agent selinexor resulted in a robust rate of SVR35, achieved by 4 of 10 patients (40%) at ≥24 weeks; responses were durable with long term therapy beyond 2 years. Positive results of this monotherapy study provide rationale to further explore selinexor as a monotherapy in subpopulations with MF with high unmet need such as those with thrombocytopenia. XPORT-MF-044 will therefore evaluate the efficacy and safety of selinexor monotherapy (40 mg and 60 mg QW) in patients with JAKi-naïve MF and moderate thrombocytopenia in addition to assessing the performance of JAKi add-on treatments in those patients who achieve suboptimal response to selinexor monotherapy. Study Design and Methods: The XPORT-MF-044 trial is a two arm, sequential, multicenter, open-label, Phase 2 study with corresponding optional expansion to evaluate the efficacy of selinexor for up to 118 patients with JAKi-naïve MF and moderate thrombocytopenia ( Figure 1). Patients in Arm 1 will receive 60 mg of selinexor and those in Arm 2 will receive 40 mg of selinexor. Both arms will be able to enroll an additional 30 patients independently for the optional expansion arms after reaching 29 patients. Optional treatment of ruxolitinib or pacritinib, may be added for patients whose SVR is &amp;lt;10% at week 12 or &amp;lt;35% at week 24 when compared to baseline; and the choice of ruxolitinib or pacritinib will be considered based on platelet count. Select inclusion criteria are patients ≥18 years of age, measurable splenomegaly as demonstrated by spleen volume of ≥450 cm 3 by MRI or CT scan, dynamic international prognostic scoring system (DIPSS) of intermediate-1 with symptoms, intermediate-2, or high-risk, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, platelet counts of 50 - 100 x 10 9 /L, and not eligible for stem cell transplantation. Major exclusion criteria are &amp;gt;10% blast in peripheral blood or bone marrow and previous treatment with JAKi for MF. The primary endpoint is SVR35 at week 24. Primary secondary endpoints are safety, TSS50 at week 24, anemia response at week 24, overall survival, and overall response rate. Efficacy and safety assessments will also be performed on patients who receive optional add-on treatment.

A Global, Phase 3, Randomized, Double-Blind Study to Evaluate Safety and Efficacy of Selinexor, an XPO-1 Inhibitor, in Combination with Ruxolitinib in JAK Inhibitor-Naïve Myelofibrosis (XPORT-MF-034)

Background and Significance: Myelofibrosis (MF) is a myeloproliferative neoplasm that commonly harbors somatic gene driver mutations in Janus kinase 2 ( JAK2), calreticulin ( CALR), and myeloproliferative leukemia virus ( MPL) genes. Selinexor is an investigational oral XPO1 inhibitor that may inhibit MF-relevant pathways including STAT, extracellular signal-regulated kinase (ERK), protein kinase B (AKT) and p53. Furthermore, in vivo preclinical studies have shown potential synergy between selinexor and ruxolitinib treatment. The Phase 3 trial was initiated based on data from the Phase 1 portion of XPORT-MF-034 evaluating the combination of selinexor and ruxolitinib in JAKi-naïve patients with MF. Previously we reported that the combination of selinexor and ruxolitinib was generally tolerable and manageable and that the 60 mg selinexor dose cohort showed 71% and 79% of the intent-to-treat (ITT) population achieving a ≥35% reduction in spleen volume from baseline (SVR35) at Week 12 and Week 24, respectively; SVR35 rates were consistent across subgroups, including gender and regardless of ruxolitinib starting dose. Robust symptom improvement was also observed with 58% of the ITT achieving a ≥50% reduction in total symptom score from baseline (TSS50) at Week 24 (Ali et al., ASCO 2023; Ali et al., AACR 2023). These data provided strong support to further evaluate selinexor (60 mg) and ruxolitinib in patients with JAKi-naïve MF. Study Design and Methods: The XPORT-MF-034 (NCT04562389) trial includes a global, Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate the combination of 60 mg selinexor and ruxolitinib. Patients will be randomized 2:1 to receive oral selinexor 60 mg or placebo once weekly (28-day cycle) and twice daily ruxolitinib. Select eligibility criteria include patients ≥18 years of age, with a spleen volume of ≥450 cm 3 by MRI or CT, dynamic international prognostic scoring system (DIPSS) of intermediate-1, intermediate-2, or high-risk, active symptoms of MF as determined by presence of at least 2 symptoms with a score ≥3 or total score of ≥10 at screening using the MFSAF v4.0, currently not eligible for stem cell transplantation, ECOG PS ≤2, platelet count ≥100 x 10 9/L, and creatinine clearance &amp;gt;15mL/min. Patients will be excluded if more than 10% blasts are present in peripheral blood or bone marrow; received previous treatment with JAK inhibitors for MF, or previous treatment with selinexor or other XPO1 inhibitors. The co-primary study endpoints are SVR35 at Week 24 as measured by MRI or CT scan and TSS50 at Week 24 as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) V4.0. The key secondary endpoint is anemia response as per the International Working Group Myeloproliferative Neoplasms Research and Treatment and European Leukemia Network (IWG-MRT and ELN) criteria at Week 24. Results: TheXPORT-MF-034 Phase 3 trial is currently open for enrollment; a total of 306 JAKi-naïve MF patients will be enrolled and the study was initiated on June 28, 2023.

Efficacy and Safety of Fedratinib in Patients with Myelofibrosis Previously Treated with Ruxolitinib: Results from the Phase 3 Randomized FREEDOM2 Study

Introduction Patients (pts) with myelofibrosis (MF) treated with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) show spleen volume reduction (SVR) and symptom reduction. However, most develop RUX intolerance or relapsed/refractory (R/R) disease and survival rates after RUX discontinuation are poor. Fedratinib (FEDR) delivered SVR and symptom reduction in the JAKARTA2 and FREEDOM studies (C Harrison et al. Am J Hematol 2020; V Gupta et al. Blood 2022). FREEDOM2 (NCT03952039) was a phase 3, open-label, randomized study to evaluate the safety and efficacy of FEDR compared with best available therapy (BAT) in pts with MF previously treated with RUX. Methods Pts aged ≥ 18 years with primary, post-polycythemia vera, or post-essential thrombocythemia MF with Dynamic International Prognostic Scoring System (DIPSS) score ≥ intermediate-2, splenomegaly (≥ 450 cm 3), platelets ≥ 50 x 10 9/L, peripheral blood myeloblasts &amp;lt; 5%, and normal baseline thiamine, R/R or intolerant to RUX, were randomized 2:1 to FEDR 400 mg/day or BAT in 28-day cycles, with stratification by spleen size, platelet count, and RUX R/R vs intolerant. Crossover to FEDR was permitted for progressive disease or after cycle 6 (EOC6) response assessment. Pts were treated until intolerance or lack of efficacy and followed-up every 3 months until death, withdrawal of consent, or study closure. The primary endpoint was SVR ≥ 35% (SVR35) at EOC6; secondary endpoints included symptom response (≥ 50% reduction in total symptom score measured by Myelofibrosis Symptom Assessment Form), SVR ≥ 25% (SVR25), durability of SVR and symptom response, and safety. Results Overall, 201 pts were initially randomized and treated, 134 and 67 pts in the FEDR and BAT arms, respectively; subsequently, 46 (68.7%) pts from the BAT arm crossed over to FEDR. Median (interquartile range) age was 70 (64-74) years, 52.2% were male, and most had primary MF (54.7%) and intermediate-2 DIPSS risk (76.1%). Assessed by aggregated group, most pts in the BAT arm received RUX (70.1%), hydroxyurea (10.4%), or RUX plus hydroxyurea (7.5%). At the data cutoff of December 27, 2022 (median follow-up, 15 months), pts receiving FEDR had significantly higher rates of SVR35 at EOC6 compared with BAT (35.8% vs 6.0%; P &amp;lt; 0.0001), as well as superior SVR25 at EOC6 and SVR35 during the full treatment course ( Table, Figure). SVR35 benefit with FEDR was observed across subgroups. The FEDR arm also showed higher rates of symptom response at EOC6 compared with BAT (34.1% vs 16.9%; P = 0.0033; Table). Median treatment duration was 43 weeks of FEDR and 24.7 weeks of BAT. During the first 6 cycles in the safety population: 70 (52.2%) pts on FEDR and 20 (29.9%) pts on BAT had dose interruption/reduction; median time to first reduction/interruption was 44.0 days for FEDR and 56.5 days for BAT. Treatment-emergent adverse events (TEAEs) leading to permanent treatment discontinuation occurred in 13 (9.7%) and 4 (6.0%) pts in the FEDR and BAT arms, respectively, during the first 6 cycles. During the first 6 cycles, 132 (98.5%) pts on FEDR and 65 (97.0%) pts on BAT had ≥ 1 TEAE; treatment-related AEs (TRAEs) occurred in 109 (81.3%) and 23 (34.3%) pts in the FEDR and BAT arms, respectively. The most frequently occurring TRAEs with FEDR were diarrhea (38.1% FEDR vs 0.0% BAT) and nausea (32.1% FEDR vs 1.5% BAT); most cases were grade 1/2. Grade 3/4 TRAEs occurred in 52 (38.8%) pts in FEDR and 8 (11.9%) pts in BAT arms, most frequently thrombocytopenia (11.9% FEDR vs 3.0% BAT) and anemia (9.0% FEDR vs 9.0% BAT). In the FEDR arm, 22 (16.4%) pts had thiamine levels below normal range, compared with 2 (3.0%) pts receiving BAT; most cases occurred prior to the study amendment of prophylactic thiamine supplementation. There was a single grade 1 case of suspected Wernicke's encephalopathy in the FEDR arm during cycle 3, which resolved fully 24 hours after thiamine supplementation (0 cases in BAT arm). Two pts each in FEDR and BAT arms had TRAEs of infection. Conclusions In this phase 3 randomized study in pts with MF and prior RUX treatment, FEDR demonstrated superior SVR and symptom response rates compared with BAT. Most pts on BAT received RUX, highlighting a clinical need for an alternative JAKi. Differences in AE and discontinuation rates in the first 6 cycles are consistent with other studies comparing JAKi with BAT. AE mitigation strategies were effective and no new safety concerns for FEDR were identified. Study support Bristol Myers Squibb

Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Patients with Myelofibrosis: Results of the MANIFEST-2 Randomized, Double-Blind, Phase 3 Study

Background Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and MF-associated symptoms. These hallmarks result from dysregulation of the JAK/STAT pathway and BET-mediated MF target gene modulation. Pelabresib (CPI-0610; pela) is an investigational oral small-molecule drug designed to inhibit BET-mediated gene transcription involved in MF pathogenesis. Preclinical data support the potential of combining pela with therapiesthat target overlapping pathways, such as JAK/STAT, to improve response by inhibiting the molecular drivers of MF. The Phase 3 MANIFEST-2 trial was initiated based on compelling data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pela and ruxolitinib (rux) in JAK inhibitor (JAKi) treatment-naïve patients (pts) with MF. In Arm 3 of MANIFEST, primary endpoint analyses at 24 Weeks (Wks) for the 84 pts enrolled reported SVR35 (≥35% reduction in spleen volume from baseline) in 68% of pts and TSS50 (≥50% reduction in Total Symptom Score [TSS] from baseline) in 56% of pts (Mascarenhas, et al. 2023). Aims MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pela + rux versus placebo + rux in JAKi treatment-naïve pts with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pela + rux. Here we present the study design and baseline patient stratification for MANIFEST-2. Results from the primary analysis of MANIFEST-2 will be presented at the ASH Annual Meeting 2023. Methods The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a DIPSS score of Intermediate-1 (Int-1) or higher, platelet count ≥100 × 10 9/L, spleen volume ≥450 cm 3 by CT or MRI, ≥2 symptoms with an average score ≥3 or a TSS of ≥10 using the MFSAF v4.0, peripheral blast count &amp;lt;5% and an ECOG performance status ≤2. Patient randomization was stratified by DIPSS risk category (Int-1 vs Int-2 vs High), platelet count (&amp;gt;200 × 10 9/L vs 100-200 × 10 9/L) and spleen volume (≥1800 cm 3 vs &amp;lt;1800 cm 3). Double-blind treatment of pela (125-175 mg) or placebo was administered once daily for 14 consecutive days, followed by a 7-day break, which is considered one cycle of treatment. Rux (5-25 mg) was administered twice daily based on platelet counts and spleen response for all 21 days of the cycle. The primary endpoint is SVR35 response at Wk 24. Secondary endpoints include TSS50, percentage change in TSS, safety, pharmacokinetics, changes in bone marrow fibrosis, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 wks. Results A total of 591 pts were screened at 138 sites. Following the screening process, 431 pts from North America, Europe, Asia and Australia were randomized. The number of pts assigned to each randomization stratum are presented in Table 1; the majority of pts presented with DIPSS Int-1 or -2, had a platelet count above 200 × 10 9/L and spleen volume below 1800 cm 3. The study opened for enrolment in November 2020; the first patient received their initial treatment on April 22, 2021, and the last patient received their first treatment on March 2, 2023. The last patient is expected to reach the 24-wk primary endpoint on August 31, 2023, following which a primary analysis will occur. As of June 27, 2023 there were 383 pts ongoing in the study. Conclusion The Phase 3 MANIFEST-2 study was initiated based on compelling data from the ongoing Phase 2 MANIFEST study, in which the combination of pela and rux in Arm 3 demonstrated significant clinical activity and disease-modifying potential without clinically relevant treatment-limiting toxicity. MANIFEST-2 has completed recruitment and will provide definitive efficacy results of combination therapy in JAKi treatment-naïve pts with MF. As DIPSS Int-1 pts have been excluded or underrepresented in prior randomized trials in MF, MANIFEST-2 will also provide important insights in assessing the benefits of starting treatment at an earlier stage of the disease. Primary results from the pivotal Phase 3 MANIFEST-2 trial of pela and rux versus placebo and rux in JAKi treatment-naïve pts may have the potential to influence the MF treatment paradigm and will be presented at the ASH Annual Meeting 2023.

Elenestinib, an Investigational, Next Generation KIT D816V Inhibitor, Reduces Mast Cell Burden, Improves Symptoms, and Has a Favorable Safety Profile in Patients with Indolent Systemic Mastocytosis: Analysis of the Harbor Trial

Introduction Indolent systemic mastocytosis (ISM) is a rare clonal mast cell disease driven by the KIT D816V mutation in nearly all patients. Patients with ISM can present with debilitating acute and chronic cutaneous, gastrointestinal, neurocognitive, and systemic symptoms caused by the release of inflammatory mediators from abnormal mast cells. In some patients, symptoms are not adequately controlled with best supportive care (BSC) medications. Elenestinib (BLU-263) is a novel, investigational, oral, next-generation tyrosine kinase inhibitor that potently and selectively inhibits KIT D816V with limited central nervous system penetration and pharmacokinetics (PK) that support once daily dosing. HARBOR (NCT04910685) is a randomized, double-blind, placebo-controlled, phase 2/3 study assessing efficacy and safety of elenestinib in patients with ISM. Methods Eligible adult patients with ISM, confirmed following central review of bone marrow (BM) pathology, clinical, and laboratory findings per World Health Organization criteria and a moderate-to-severe symptom score based on minimum mean total symptom score (TSS) of the ISM-Symptom Assessment Form (ISM-SAF©2018), were stratified by baseline serum tryptase (&amp;lt;20 ng/mL vs ≥20 ng/mL) and randomly assigned 3:1 to elenestinib 25 mg, 50 mg, or 100 mg once daily + BSC (“elenestinib”) or placebo + BSC (“placebo”). The primary objective of Part 1 was to determine the recommended dose based on safety, PK, and pharmacodynamics. Secondary endpoints included changes in biomarkers of disease burden (serum tryptase, KIT D816V variant allele fraction [VAF], and BM mast cells) and ISM-SAF TSS. Three additional open-label PK groups enrolled patients at 50 mg, 75 mg, and 100 mg to further characterize PK and safety. Results As of data cutoff on July 3, 2023, a total of 122 patients with ISM have received their assigned treatment in Part 1 of the study; 39 were blinded and randomized to elenestinib or placebo, and 83 were treated with open-label elenestinib in the PK groups (21 patients at 50 mg, 34 patients at 75 mg, and 28 patients at 100 mg). Baseline demographics were similar to those reported for the general ISM population. After 12 weeks of therapy, symptom improvement was observed for all dose cohorts, and symptom reduction by TSS was greater for patients on elenestinib versus placebo in the blinded portion of Part 1. Patients receiving elenestinib at 25 mg, 50 mg, and 100 mg doses showed reduction (mean percent) from baseline for tryptase (-15.4%, -50.9%, and -68.4% vs 3.3%, respectively) and KIT D816VVAF (-37.5%, -70.3%, and -77.0% vs -2.5%, respectively) as compared to placebo. Similar reductions in TSS and disease-related biomarkers were observed in the open-label PK cohorts. After a median treatment duration of 35.3 weeks, elenestinib was well-tolerated at all dose levels. There were no treatment-related serious adverse events and no treatment-related adverse events that led to drug discontinuation. Conclusion Elenestinib at all tested doses demonstrated beneficial effects on disease-related symptoms and biomarkers of mast cell burden in this large and maturing cohort of patients with ISM with a moderate-to-severe symptom burden. Elenestinib was well tolerated across all dose levels with a promising early benefit-risk profile in ISM. These preliminary findings will inform dosing for the planned Part 2 of HARBOR, which will examine elenestinib versus placebo in a randomized, blinded, placebo-controlled setting.

Selinexor Plus Ruxolitinib in JAK Inhibitor (JAKi)-Naïve Patients with Myelofibrosis: Long Term Follow up from XPORT-MF-034 Suggestive of Disease Modification

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, and inflammation due to unregulated, clonal proliferation of hematopoietic stem cells in the bone marrow. Common genetic drivers include JAK2, CALR, and MPL. Although improvements in splenomegaly and symptoms occur with the current approved therapies, additional assessments are needed to understand the impact of therapies on disease modification. Increased burden of variant allele frequency (VAF) of driver mutations is associated with poor disease outcomes, and increased expression of pro-inflammatory cytokines is implicated in disease pathophysiology and symptoms burden. Selinexor (SEL) is an investigational oral XPO1 inhibitor that may inhibit multiple MF-relevant pathways including STAT, ERK, and AKT. Preclinical studies have shown potential synergy between SEL and ruxolitinib (RUX) treatment in vivo. Safety and efficacy analysis of SEL plus RUX in JAKi treatment-naïve MF in a Phase 1 study supported a 60 mg SEL dose as the recommended dose in a Phase 3 study. Here we include exploratory analyses of a range of biomarkers in the Phase 1 study of SEL and RUX in JAKi-naïve myelofibrosis. Methods: Phase 1 of XPORT-MF-034 (NCT04562389) is an open-label study evaluating the safety and efficacy of SEL at 40mg and 60mg once weekly plus RUX with JAKi-naïve MF. Assessments included safety and rates of spleen volume reduction of ≥35% (SVR35) and total symptom score reduction of ≥50% (TSS50). Platelet and hemoglobin levels were also assessed. Longitudinal clinical biomarker assessments included %VAF change at week 24 for driver genes and plasma cytokine levels at week 4 (Cycle 2 Day 1). Bone marrow (BM) biopsies were obtained at screening and week 24, then evaluated for bone marrow fibrosis (BMF) and other BM cellular markers (CD61, CD71). Results: As of April 10, 2023, a total of 24 patients (pts) received at least one dose of SEL (40 mg: n=10; 60 mg n=14). The most common adverse events (AEs) overall of any grade were nausea (75% majority grade 1-2), fatigue (58%), anemia (54%), and thrombocytopenia (54%). Those receiving a prophylactic anti-emetic reported lower incidence and severity of nausea AEs compared to those that did not; pts experienced a median weight increase of 3.3 kg at week 24. Two pts discontinued treatment due to treatment-related AEs (thrombocytopenia and neuropathy). Generally stable hemoglobin levels were observed in 48% of transfusion-independent pts. Median hemoglobin levels were 10.1 g/dL at baseline, 9.3 g/dL at week 12, and 10.2 g/dL at week 24. Median platelet counts remained generally stable with median values of 258 k/uL at baseline, 164 k/uL at week 12, and 193 k/uL at week 24. SVR35 at week 24 in the intent-to-treat (ITT) population was achieved by 40% of the 40 mg cohort and 79% of the 60 mg cohort and TSS50 was achieved by 10% and 58%, respectively. Mutation analysis showed no pts were triple negative, with 18 harboring JAK2 mutations, 5 with CALR, and 1 with MPL. Of 13 pts with available data at week 24, 5 pts (38%) had a reduction of VAF that was ≥20%, and 3/5 of these pts had high VAF (&amp;gt;50%) driver mutations at baseline and were also characterized as HMR. A panel of 74 cytokines was evaluated in 21 MF pts with baseline and week 2 samples (including 10 with end-of-treatment [EOT] samples), and in 10 healthy donors. Comparing baseline MF to healthy samples, 50% of the analyzed cytokines were elevated. A rapid and durable decrease of pro-inflammatory MF-relevant cytokines including TGF-β1, IFNɣ, TNF-α, IL-7, IL-1Ra, and IL-16 was observed in the majority of pts at week 2 and continued into EOT. Notably, the reduction in IL-18 correlated to SVR and TSS response at week 24, with R 2 values of 0.29 and 0.28, respectively. BM analysis at week 24 showed an increased number of erythroid CD71+ elements in 3/14 pts. Conclusions: SEL plus RUX was generally well tolerated and manageable.Evidence of potential disease modification in pts with JAKi-naïve MF patients was seen via rapid stabilization of platelets and maintaining hemoglobin levels, VAF reduction, and pro-inflammatory cytokine reduction. Promising biomarker and efficacy data suggests that SEL in combination with RUX has the potential to become a novel, first-line treatment for pts with MF. Updated clinical data with longer follow-ups and additional subgroup analyses will be available at the time of presentation.

Momelotinib in Myelofibrosis Patients With Thrombocytopenia: Post Hoc Analysis From Three Randomized Phase 3 Trials

The oral activin A receptor type I, Janus kinase 1 (JAK1), and JAK2 inhibitor momelotinib demonstrated symptom, spleen, and anemia benefits in intermediate- and high-risk myelofibrosis (MF). Post hoc analyses herein evaluated the efficacy and safety of momelotinib in patients with MF and thrombocytopenia (platelet counts &lt;100 × 109/L) from randomized phase 3 studies: MOMENTUM (momelotinib versus danazol; JAK inhibitor experienced); SIMPLIFY-1 (momelotinib versus ruxolitinib; JAK inhibitor naïve); and SIMPLIFY-2 (momelotinib versus best available therapy; JAK inhibitor experienced); these studies were not statistically powered to assess differences in thrombocytopenic subgroups, and these analyses are descriptive. The treatment effect of momelotinib versus ruxolitinib on week 24 response rates (spleen volume reduction ≥35%/Total Symptom Score reduction ≥50%/transfusion independence) was numerically comparable or better in thrombocytopenic patients versus the overall JAK inhibitor naive population; rates were preserved with momelotinib in thrombocytopenic patients but attenuated with ruxolitinib (momelotinib: 27%/28%/67% overall versus 39%/35%/61% in thrombocytopenic group; ruxolitinib: 29%/42%/49% overall versus 0%/22%/39% in thrombocytopenic group, respectively). In contrast to ruxolitinib, momelotinib maintained high dose intensity throughout the treatment. In the JAK inhibitor experienced population, thrombocytopenic patients had the following: (1) numerically higher symptom and transfusion independence response rates with momelotinib than in control arms; and (2) preserved spleen, symptom, and transfusion independence response rates with momelotinib relative to the overall study populations. The safety profile of momelotinib in thrombocytopenic patients was also consistent with the overall study population. In summary, momelotinib represents a safe and effective treatment option for patients with MF and moderate-to-severe thrombocytopenia.

Matching-adjusted indirect comparison of the pelabresib-ruxolitinib combination vs JAKi monotherapy in myelofibrosis

AbstractJanus kinase inhibitors (JAKis) ruxolitinib, fedratinib, and pacritinib are the current standard of care in symptomatic myelofibrosis (MF). However, progressive disease and toxicities frequently lead to JAKi discontinuation. Preclinical data indicate that combining JAK and bromodomain and extraterminal (BET) domain inhibition leads to overlapping effects in MF. Pelabresib (CPI-0610), an oral, small-molecule BET1,2 inhibitor (BETi), in combination with ruxolitinib showed improvements in spleen volume reduction (SVR35) and total symptom score reduction (TSS50) from baseline in the phase 2 MANIFEST study (NCT02158858) in patients with MF. Given the absence of a head-to-head clinical comparison between JAKi monotherapy and JAKi with BETi combination therapy, we performed an unanchored matching-adjusted indirect comparison analysis to adjust for differences between studies and allow for the comparison of SVR35, TSS50, and TSS measured at several timepoints in arm 3 of MANIFEST (pelabresib with ruxolitinib in JAKi treatment–naive patients with MF), with data from the following JAKi monotherapy studies in JAKi treatment–naive patients: COMFORT-I and COMFORT-II (ruxolitinib), SIMPLIFY-1 (ruxolitinib and momelotinib), and JAKARTA (fedratinib). Response rate ratios >1 were observed for pelabresib with ruxolitinib vs all comparators for SVR35 and TSS50 at week 24. Improvements in TSS were observed as early as week 12 and were durable. These results indicate that pelabresib with ruxolitinib may have a potentially higher efficacy than JAKi monotherapy in JAKi treatment–naive MF.

A randomized, double-blind, phase 3 study of jaktinib versus hydroxyurea (HU) in patients (pts) with intermediate-2 or high-risk myelofibrosis (MF).

7015 Background: Ruxolitinib and HU are recommended by Chinese MF guideline for splenomegaly. There is an unmet need for new treatments. Jaktinib, a novel JAK and AVCR1 inhibitor, showed promising activity on splenomegaly, anemia, and MF symptoms in a phase 2 study (NCT03886415). Here we present the interim results of a phase 3 study, which assessed the efficacy and safety of jaktinib compared to HU. Methods: Pts aged ≥ 18 with primary or post-ET/PV MF, DIPSS Int-2 or high risk, and no prior or ≤10 days’ treatment with a JAK inhibitor were enrolled and randomly assigned (2:1) to receive jaktinib 100 mg bid plus HU placebo or HU 0.5g bid plus jaktinib placebo, stratified by DIPSS risk status (Int-2 or high risk). One interim analysis was pre-specified to be conducted when 70 pts completed the week (wk) 24 visit or met the criteria for treatment termination before wk 24. The primary endpoint was the proportion of pts with a spleen volume reduction of ≥ 35% from baseline (SVR35) at wk 24, measured by MRI/CT images and assessed centrally. Secondary endpoints included the best spleen response rate (defined as achieving SVR35 at any time), the proportion of pts with a ≥ 50% reduction in Total Symptom Score (TSS50), improvement of anemia, safety, etc. Results: This interim analysis (cut-off: April 8, 2022) included 47 pts receiving jaktinib and 23 receiving HU. 66.0% (jaktinib) and 69.6% (HU) had a baseline hemoglobin (Hb) &lt; 100 g/L. 59.6% (jaktinib) and 69.6% (HU) were JAK2V617F positive. The SVR35 rates at wk 24 were 72.3% for jaktinib vs. 17.4% for HU ( p≤0.0001). The best spleen response rates were 80.9% of jaktinib-treat pts vs. 26.1% of HU-treated pts ( p≤0.0001). The median maximum percentage change from baseline in spleen volume were -46.59% vs. -18.50%. The TSS50 rates at wk 24 were 63.8% for jaktinib vs. 43.5% for HU ( p = 0.1163). 5 of 7 jaktinib-treated and two of 5 HU-treated pts who required RBC transfusion at baseline achieved a ≥50% decrease in RBC transfusion by wk 24. In transfusion-independent pts with baseline Hb ≤100 g/L, 39.3% for jaktinib and 15.4% for HU had a ≥20 g/L Hb increase. The most common grade ≥3 hematological treatment emergent adverse events (TEAEs) (jaktinib vs. HU) were anemia (25.5% vs. 43.5%), thrombocytopenia (17.0% vs. 39.1%), leukopenia (2.1% vs. 21.7%), neutropenia (2.1% vs. 21.7%) and decreased lymphocyte count (2.1% vs. 13.0%). Most common non-hematological TEAEs were upper respiratory tract infection (21.3% vs. 21.7%), elevated bilirubin (12.8% vs. 26.1%), fever (12.8% vs. 21.7%) and diarrhea (10.6% vs. 21.7%), predominantly of grade 1 or 2. TEAEs leading to treatment discontinuation occurred in 8.5% of jaktinib and 17.4% of HU. Conclusions: Jaktinib demonstrated significant clinical benefits over HU in MF pts for spleen response with improved symptom response and less cytopenias. Jaktinib may be a new treatment option for MF pts, especially for those with anemia. Clinical trial information: NCT04617028 .

Selinexor (SEL) plus ruxolitinib (RUX) in JAK inhibitor (JAKi) treatment-naïve patients with myelofibrosis: Updated results from XPORT-MF-034.

7063 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, high symptom burden, and poor prognosis. Activity has been shown with the combination of SEL + the JAKi RUX in preclinical studies. Specific subgroups with lower response rates to RUX monotherapy, such as males vs females (25% vs 59%) and those with a lower (≤15 mg vs 20 mg) RUX starting dose (22-27% vs 43%), highlight unmet need in specific groups (grps). Methods: XPORT-MF-034 is a Phase 1/2, open-label study evaluating safety and efficacy of SEL at 40 mg and 60 mg once-weekly plus RUX per standard of care in 28-day cycles. Assessments included safety, spleen/symptom response, survival, and hemoglobin levels. The primary analysis population included those who had baseline assessment and were treated to at least Week 24 (W24) or discontinued before W24. Two pts with baseline total symptom score (TSS) = 0 were excluded from analysis of TSS reduction of ≥50% (TSS50). Results: As of Dec 21, 2022, 10 participants received 40 mg and 14 participants received 60 mg SEL; 22 of the 24 pts enrolled had reached at least W24 and were included in the efficacy analysis. The median duration of treatment was 28 wks overall, 33 wks for 60 mg and 22.5 wks for 40 mg grps. Most common adverse events (AEs) by dose (60/40 mg) were nausea (79%/70%; majority grade 1-2), anemia (79%/50%), and fatigue (57%/60%). Most common Grade ≥3 AEs were anemia (50%/40%), thrombocytopenia (29%/10%), and neutropenia (7%/20%). AEs were reversible with dose modifications. Two patients discontinued treatment due to treatment-related AEs (thrombocytopenia and neuropathy); 3 deaths have occurred in the study, none related to SEL. Overall, 64% (14/22) achieved SVR35 at W24, with 79% [11/14] vs 38% [3/8], in the 60 mg vs 40 mg grp, respectively. The 60 mg grp achieved a deeper median SVR response vs the 40 mg grp at W24 (49% vs 31%). At W24, TSS50 was achieved by 45% (9/20) overall, 58% [7/12] of the 60 mg, and 25% [2/8] of the 40 mg grp. Among 11 pts with baseline hemoglobin &lt; 10 g/dL, median hemoglobin decreased by 0.5 g/dL from baseline to W12 and increased by 0.8 g/dL from baseline to W24. Similar efficacy was observed across all subgrps with 60 mg. Reduction of variant allele frequency from baseline to W24 was &gt; 10% in 50% (4/8) and &gt; 20% in 25% (2/8) of evaluable pts for 60 mg grp. Conclusions: Encouraging activity with 60mg SEL + RUX combination were observed in TSS50, SVR and hemoglobin levels overall, as well as in key subgroups including males, in pts started on low dose RUX (≤15 mg), and pts with larger baselines spleen size. Updated data will be available for presentation. Clinical trial information: NCT04562389 . [Table: see text]

The Impact of Momelotinib on Patient Reported Quality of Life for Symptomatic and Anemic Patients with Myelofibrosis: Results from the Phase 3 Momentum Study

Introduction Disease-related inflammation, anemia and splenomegaly contribute to a host of burdensome symptoms in patients with myelofibrosis (MF), including fatigue, bone pain, night sweats, and others, which can negatively impact health-related quality of life (HRQoL). There are no approved treatments for patients with intermediate- and high-risk MF that specifically target anemia, and approved MF therapies for splenomegaly and symptoms often exacerbate anemia. Momelotinib (MMB) is a Janus kinase (JAK) 1, JAK2, and activin A receptor type 1 (ACVR1) inhibitor with demonstrated symptom, spleen, and anemia benefits in patients with MF. MOMENTUM, a phase 3 study in symptomatic, anemic patients with MF who were previously treated with a JAKi, showed that MMB significantly improved disease-related symptoms compared to danazol (DAN) (24.6% vs 9.2%) as measured by achieving at least a 50% reduction in total symptom score (TSS50) at week 24 compared to baseline. Herein we report the results of patient-reported health status and HRQoL analyses, including impact on fatigue and physical function, for patients treated with MMB compared to DAN in the MOMENTUM study. Methods Patient-reported outcome (PRO) analyses were performed for the following assessments in the intent-to-treat (ITT) population: Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 TSS and individual items, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)-derived scales and items, and Patient-Reported Outcomes Measurement Information System (PROMIS) short form physical function total score 10b and additional PROMIS bank items. Analyses of PRO response were summarized by corresponding meaningful change threshold (MCT) for each PRO. Longitudinal change from baseline scores were analyzed using mixed model for repeated measures (MMRM). Longitudinal responder analyses were performed by generalized estimating equation (GEE) after multiple imputation for missing scores. Odds ratio (OR) for response, 95% confidence interval (CI), and p-value were presented as the treatment effect (MMB vs DAN). Time to first response was analyzed using the Kaplan-Meier method. A stratified log-rank test was performed to compare treatment arms, and hazard ratios (HR) were estimated from a stratified Cox regression model. Results Proportionally greater improvements in MF-related symptoms, physical function, and global quality of life were observed with MMB versus DAN as measured at week 24 by the MFSAF, PROMIS, and EORTC QLQ-C30 questionnaires, respectively. Improvements in all MFSAF individual item scores from baseline at week 24 were greater in the MMB group than in the DAN group based on median scores (Figure 1) and MMRM analysis (Table 1), with the greatest treatment differences noted for night sweats, abdominal discomfort, bone pain, and rib pain, favoring MMB. Longitudinal MFSAF TSS response analysis indicated a higher likelihood of response for patients in the MMB group: an overall OR of 2.50 throughout the 24-week randomized treatment period. HRs for response were greater than 1 (ranging from 1.47 - 3.82) in the time to first response analysis for MFSAF TSS and individual items, excluding itching (0.77), indicating a faster symptom response for more patients in the MMB group for TSS and 6 of 7 individual items. Responder analyses showed that the proportion improved for fatigue was greater in the MMB group based on MFSAF fatigue (18.5% MMB, 9.2% DAN) and EORTC QLQ-C30 fatigue (41.5% MMB, 21.5% DAN), where missing data was considered nonresponse. Consistent with these results, responder analysis using the PROMIS assessments related to physical function also favored MMB (17.7% MMB, 4.6% DAN). This trend was supported by shorter times to first response for physical function in more patients in the MMB group versus the DAN group (HR = 1.93, 95% CI 0.95, 3.91). Improvement in global quality of life as measured by EORTC QLQ-C30 was also greater in the MMB group with a proportion difference of 14.6% between MMB and DAN (95% CI: 1.5-27.7%; p = 0.04). Conclusions Consistent with the positive primary endpoint (TSS50) result of the MOMENTUM study, these responder, longitudinal, and time-to-event analyses demonstrate that MMB provides comprehensive improvements in disease-related symptoms with associated improvement in physical function and overall HRQoL compared with DAN in patients with MF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Preliminary Data from the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients with Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy

Introduction: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, ineffective hematopoiesis, splenomegaly, and debilitating symptoms. Expression of PIM-1 is significantly upregulated in MF hematopoietic cells, supporting exploration of PIM-1 as a potential therapeutic target in MF. TP-3654 is a highly selective oral investigational PIM-1 kinase inhibitor. When administered alone and in combination with ruxolitinib, TP-3654 reduced spleen size and BM fibrosis in JAK2V617F and MPLW515L murine MF models (Dutta, 2021). In addition, TP-3654 decreased cytokine response genes and serum TGF-b in progenitor cells and JAK2V617F mice, respectively. TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation. Methods: This Phase I/II study evaluates the safety and efficacy of TP-3654 monotherapy in patients with MF (NCT04176198). Key eligibility criteria include primary or secondary MF; intermediate or high-risk MF per DIPSS; previously treated with or ineligible for JAK inhibitor treatment; grade ≥2 BM fibrosis; platelet count ≥25x109/L; absolute neutrophil count ≥1x109/L; splenomegaly; and ≥2 measurable symptoms. The study aims to identify the maximum tolerated dose and/or recommended Phase II dose using a Bayesian logistic regression model (BLRM) with overdose control, and to assess clinical activity (spleen volume reduction [SVR], total symptom score [TSS] improvement, and BM fibrosis reduction), safety, pharmacokinetic, and pharmacodynamic markers in peripheral blood and BM biopsies. Results: As of 11 July 2022, 8 patients were enrolled across 5 dose levels in the dose escalation phase. At baseline, median age was 70 years (range, 61 to 77), median spleen volume was 2370 cm3 (range, 1189 to 4407), median total symptom score was 19 (range, 4 to 62), median platelet count was 120 x109/L (range 68 to 237), median hemoglobin was 10.1 g/dL (range, 5.9 to 13.7), and two patients were transfusion-dependent. All patients had received prior treatment with at least one JAK inhibitor. Median duration of prior JAK inhibitor treatment was 35 weeks (range, 13 to 269). Six patients had JAK2V16F mutation, 2 patients had CALR mutation. The median duration of TP-3654 treatment was 21 weeks (range, 1 to 45). No dose-limiting toxicities occurred. Treatment-related adverse events (TRAEs) occurring in >20% of patients included mild to moderate nausea, vomiting, and diarrhea. Grade ≥ 3 TRAEs included only 1 case of vomiting. No hematological TRAEs were reported. No discontinuation due to AE occurred. SVR was observed in 5 out of 6 evaluable patients (median best change -14%, range -3.2% to -35%) (Figure 1). Symptom improvement was observed in 5 out of 6 evaluable patients (median best change -70%, range -32 to -100%). A panel of cytokines were evaluated in plasma samples obtained at baseline and during TP-3654 treatment. Reductions in cytokines (TGF-b, IL-18, VEGF, RANTES, MMP-9, and TIMP-1) were observed after TP-3654 treatment (Figure 2). Patients with higher cytokine reductions correlated with higher reduction in total symptom score. Enrollment is ongoing, updated data will be presented. Conclusions: The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Efficacy of Fedratinib in Patients with Primary (P), Post-Polycythemia Vera (Post-PV), and Post-Essential Thrombocythemia (Post-ET) Myelofibrosis (MF) Previously Treated with Ruxolitinib: Primary Analysis of the FREEDOM Trial

Introduction: Fedratinib is an oral selective Janus kinase (JAK) 2 inhibitor approved for treatment (tx) of patients (pts) with MF, including those previously treated with ruxolitinib (RUX). In the single-arm phase 2 JAKARTA2 trial (NCT01523171), fedratinib 400 mg once daily improved spleen volume and MF symptom burden in pts with MF resistant/intolerant to prior RUX (Harrison et al. Am J Hematol 2020). Long-term data are lacking due to early termination. The ongoing, single-arm, phase 3b FREEDOM trial (NCT03755518) further evaluates the safety and efficacy of fedratinib in pts with MF previously treated with RUX and includes proactive strategies to mitigate gastrointestinal (GI) adverse events (AEs), thiamine level decreases, and potential encephalopathy (including Wernicke's encephalopathy [WE]). Methods: Eligible pts aged ≥ 18 years with PMF, post-PV MF, or post-ET MF with ≥ 3 months prior tx with RUX were enrolled in the study. Pts were required to have Dynamic International Prognostic Scoring System (DIPSS) intermediate- or high-risk MF, Eastern Cooperative Oncology Group performance status ≤ 2 and baseline platelet count ≥ 50 x 109/L. Pts were treated with fedratinib 400 mg once daily in continuous 28-day cycles until lack of efficacy, intolerance, or disease progression, and followed for 12 months after end of tx (EOT). AE mitigation strategies included prophylactic use of antiemetics and symptomatic use of antidiarrheals, thiamine supplementation, surveillance for encephalopathy, and adjusting preferred time of day for fedratinib administration. Results: Thirty-eight pts were enrolled and treated. Due to accrual challenges during the COVID-19 pandemic, the study was capped early, and data lost statistical power due to reduced sample size. At the database cutoff (November 29, 2021), median tx duration was 38 weeks, 13 pts had tx ongoing, and 25 pts had discontinued tx. At baseline, median age was 68.5 years, 23 (60.5%) pts had a diagnosis of PMF, 9 (23.7%) post-PV MF, and 6 (15.8%) post-ET MF, with DIPSS assessment of intermediate-1 risk in 13 (34.2%) pts, intermediate-2 risk in 18 (47.4%) pts, and high risk in 7 (18.4%) pts. Baseline median spleen volume was 1831.6 mL. A total of 9/35 (25.7%) evaluable pts met the primary endpoint of ≥ 35% spleen volume reduction (SVR) by magnetic resonance imaging/computed tomography at end of cycle (EOC) 6; 13 (37.1%) pts had ≥ 35% SVR when missing EOC6 assessments were imputed with last observation carried forward (LOCF) method (Table). In addition, 9 (25.7%) pts achieved a ≥ 35% SVR before or after EOC6, for a best overall response of ≥ 35% SVR in 22 (62.9%) pts up to end of tx. With a ≥ 25% SVR threshold, 24 (68.6%) pts had a response with LOCF at EOC6. Of ≥ 35% SVR responders, 19/22 (86.4%) maintained durable response at data cutoff (Figure). In secondary endpoints, 21/36 (58.3%) and 16/36 (44.4%) evaluable pts showed ≥ 50% reduction in total symptom score (TSS) at EOC3 and EOC6, respectively. A total of 34/38 (89.5%) pts had 1 tx-emergent AE related to study medication; 3 (7.9%) were serious AEs. Anemia and thrombocytopenia were reported in 23 (60.5%) and 13 (34.2%) pts, respectively. GI AEs were reported in 34 (89.5%) pts, with nausea, vomiting, and diarrhea reported in 15 (39.5%), 7 (18.4%), and 15 (39.5%) pts, respectively. Most GI AEs were grade 1/2 and occurred during cycle 1, and decreased in the subsequent cycles. Grade 1/2 decreases in thiamine levels were reported in 6 pts after initial tx; all instances were treated and resolved at next assessment. No pts required tx discontinuation due to low thiamine levels. There were no cases of WE reported. There were 2 deaths during tx and 7 during follow-up; none were related to study medication. Conclusions: Clinically relevant and durable spleen and symptom responses were observed in FREEDOM study participants, with a majority of responders showing durable SVR at data cutoff. This supports the use of fedratinib in pts with MF previously treated with RUX. One limitation of the study was small pt sample size. In this first fedratinib study proactively assessing a GI mitigation strategy and thiamine monitoring, results showed GI AEs were easily mitigated and no WE was reported. Study support: This study was supported by Bristol Myers Squibb. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pelabresib (CPI-0610) As Add-on to Ruxolitinib in Myelofibrosis: Durability of Response and Safety Beyond Week 24 in the Phase 2 MANIFEST Study

Background: Myelofibrosis (MF) is largely characterized by bone marrow (BM) fibrosis, splenomegaly and cytopenias. Progressive BM fibrosis results from aberrant megakaryopoiesis and proinflammatory cytokine expression, two processes that are tightly regulated by bromodomain and extraterminal domain (BET) protein-mediated expression of genes (eg NF-κB target genes, MYC and BCL-2) and often lead to myeloproliferation and cytopenias. Although the current standard of care for MF is treatment with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX), many patients (pts) experience a suboptimal response to RUX monotherapy or must discontinue treatment due to cytopenias and therefore there is a significant unmet need for new therapies in this population. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100). Aims: In the ongoing, open-label Phase 2 MANIFEST study (NCT02158858), PELA is under investigation as monotherapy and in combination with RUX in pts with MF. In Arm 2 of MANIFEST, pts with suboptimal/lost response to RUX are treated with PELA as 'add-on’ to RUX. In this abstract we will discuss results from the September 2021 data cut; updated data with longer follow-up on efficacy (≥35% reduction in spleen volume from baseline [BL; SVR35], ≥50% total symptom score reduction from BL [TSS50], duration of response and BM fibrosis improvement) and safety data from the planned July 2022 data cut will be presented. Methods: Pts in Arm 2 are stratified as transfusion dependent (TD; Arm 2A) and nontransfusion dependent (non-TD; Arm 2B). The primary endpoints are conversion from TD to transfusion independence (TI) in Arm 2A (TD cohort) and SVR35 at Week (Wk) 24 for Arm 2B (non-TD cohort). The secondary endpoints include TSS50 per MF Symptom Assessment Form v4.0 at Wk 24 and SVR35 at Wk 24 in Arm 2A (TD cohort). BM biopsies to assess BM fibrosis, durability of responses and safety data are evaluated. Data reported here are from the September 2021 data cut. Results: At Wk 24 in Arm 2 (N=86), 20% (16/81) of pts achieved SVR35 (Figures 1 and 2); 17% for Arm 2A (TD cohort) and 26% for Arm 2B (non-TD cohort). SVR35 at any time was achieved by 30% (24/81) of pts. At Wk 24, 27% (22/81) pts achieved ≥25% reduction in spleen volume from BL (SVR25); 26% (14/54) pts in Arm 2A (TD cohort) and 30% (8/27) pts in Arm 2B (non-TD cohort). Median spleen volume reduction for the full Arm 2 cohort was -18% at Wk 24. Durable (up to Wk 60) spleen volume reductions were observed as depicted in mean spleen volume change over time, and spleen volume reduction deepened over time (Figure 1). Twenty percent (16/80) pts had SVR35 response at Wk 48. In Arm 2A (TD cohort), the TD to TI rate was 16% (6/38). TSS50 at Wk 24 was 37% (30/81); 36% for Arm 2A (TD cohort) and 39% for Arm 2B (non-TD cohort). A total of 54% (46/86) of pts achieved TSS50 at any time. Median total symptom score reduction was -47% at Wk 24. As of data cut off, the median follow-up time was 24.4 (23.0-30.7) months and median treatment duration was 14.0 (8.4-20.6) months. After 24 wks of treatment, BM fibrosis improvement by ≥1 grade was achieved in 26% of evaluable pts by central pathology review; 50% of pts maintained the improvement at the next available assessment or longer. A total of 39% of pts achieved ≥1 grade improvement at any time (best response). The two most common hematologic treatment-emergent adverse events (TEAEs) of any grade were thrombocytopenia, reported in 52% (Grade ≥ 3: 33%) pts, and anemia, reported in 27% (Grade ≥ 3: 19%) pts. Low-grade gastrointestinal TEAEs and respiratory infections were observed but rarely a reason for treatment discontinuation. A total of 20 pts (23%) reported TEAEs that led to PELA discontinuation. Serious adverse events reported in ≥3 pts were anemia (6 pts), respiratory tract infections (4 pts) and urinary tract infections (3 pts). Conclusions: Based on these preliminary Phase 2 data, PELA as 'add-on’ to RUX in pts with a suboptimal/lost response to RUX monotherapy resulted in durable splenic and symptom responses, deepening of spleen responses over time, and was generally well tolerated. Additionally, improvement in BM fibrosis, as a marker of disease modification, was observed in 39% of treated pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pelabresib (CPI-0610) Combined with Ruxolitinib for JAK Inhibitor Treatment-Naïve Patients with Myelofibrosis: Durability of Response and Safety Beyond Week 24

Background: Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis, splenomegaly and cytopenias resulting from aberrant megakaryopoiesis and proinflammatory cytokine expression. These processes are heavily regulated by bromodomain and extraterminal domain (BET) protein-mediated gene expression (eg NF-κB target genes, MYC and BCL-2) and lead to myeloproliferation and cytopenias. The current standard of care for patients (pts) with MF is the Janus kinase inhibitor (JAKi) ruxolitinib (RUX); however, the depth and durability of responses, along with the percentage of pts that achieve ≥35% spleen volume reduction from baseline (BL; SVR35) and ≥50% total symptom score reduction (TSS) from BL (TSS50) with RUX monotherapy are limited. Pelabresib (CPI-0610; PELA) is an oral, small-molecule, investigational BET inhibitor that downregulates NF-κB signaling and other relevant genes involved in MF disease pathways (Mascarenhas J, et al. HemaSphere 2022;6:99-100). In the ongoing Phase 2 MANIFEST study (NCT02158858), PELA is under investigation as monotherapy and in combination with RUX in pts with MF. Here, we present results from Arm 3 of MANIFEST (in which JAKi-naïve pts with MF receive PELA in combination with RUX). Aims: The primary endpoint of MANIFEST Arm 3 is SVR35 after 24 weeks (wks) of treatment. Secondary endpoints include TSS50, duration of splenic response, pharmacokinetics and safety. Exploratory endpoints include transfusion independence and changes from BL in BM fibrosis. In this abstract we will discuss results from the September 2021 data cut; longer-term data from the July 2022 data cut will be presented. Methods: Spleen volume was assessed by computed tomography or magnetic resonance imaging every 12 wks; TSS per Myelofibrosis Symptom Assessment Form v4.0; and BM fibrosis by biopsies at Wk 24 and Wk 48. Duration of splenic response and safety data are also evaluated. Data presented are from the September 2021 data cut; a more mature data set will be presented at the conference. Results: Eighty-four pts received ≥1 dose of PELA and RUX. Median age was 68 years (range 37-85); 24%, 61% and 16% had Dynamic International Prognostic Scoring System intermediate-1, intermediate-2 or high risk, respectively. Pts who did not reach Wk 24 were counted as nonresponders. At Wk 24 and Wk 48, 68% (57/84) and 60% (47/79) of pts, respectively, achieved SVR35. SVR35 at any time was achieved by 80% pts (67/84), and 87% (58/67) pts with SVR35 maintained response at the time of data cutoff. Median spleen volume change was -50% (range -84.4% to 27.9%) at Wk 24. Median time to SVR35 response was 12 wks (first on-treatment assessment of splenic response); durable spleen volume reductions were observed as depicted in mean spleen volume change over time in Figure 1. TSS50 was achieved by 56% (46/82) pts at Wk 24 and 43% (34/79) at Wk 48. TSS50 at any time was achieved by 81% pts (68/84). The median change in TSS was −59% (range −100% to 225%) at Wk 24. Mean TSS change over time is shown in Figure 2, indicating sustained reduction in symptom burden. Median follow up for Arm 3 was 21.8 (range 21.2-22.5) months; median treatment duration was not reached as of data cutoff. BM fibrosis improved by ≥1 grade in 28% (16/57) of evaluable pts at Wk 24 as assessed by central pathology review; 56% maintained the improvement at the next available assessment (Wk 48 or beyond) or longer; and 40% achieved ≥1 grade improvement at any time (best response). The most common hematologic treatment-emergent adverse event (TEAE) of any grade was thrombocytopenia, reported in 52% (Grade ≥3: 12%) of pts. Anemia was reported in 42% (Grade ≥3: 34%). Serious adverse events reported in ≥2 pts were respiratory tract infections (6 pts), pyrexia (3 pts) and anemia, multiorgan failure, fall and pelvic fracture (2 pts each). TEAEs that led to PELA discontinuation occurred in 7 pts (8%). Updated data with longer follow-up, including durability of splenic response and safety data from a more mature data set, will be available for presentation at the conference. Conclusions: The combination of PELA and RUX in JAKi-naïve pts with MF showed durable improvements in spleen volume, total symptom score and BM fibrosis, and was generally well tolerated. The randomized, double-blind, active-controlled Phase 3 MANIFEST-2 study is open for enrollment and evaluating the safety and efficacy of PELA in combination with RUX in JAKi treatment-naïve pts with MF (NCT04603495). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal