Ruxolitinib Group Research Articles

Hemostasis in patients with primary myelofibrosis treated with ruxolitinib

Aim. To evaluate the effect of ruxolitinib therapy on hemostasis in patients with primary myelofibrosis (PMF).Materials and methods. 30 patients with PMF were examined, 16 of them received ruxolitinib (group 1) at the time of examination and 14 were untreated (group 2). The control group consisted of 30 healthy individuals. A complete blood count was performed, the platelets aggregation, the activity of Willebrand factor, factor VIII and natural anticoagulants were evaluated. In the thrombin generation test, the endogenous thrombin potential (ETP, nM×min) was determined; sensitivity to thrombomodulin and coagulation index were calculated. Kruskal-Wallis test with post hoc Dunn test was used to compare groups.Results. Hemoglobin and platelet count were lower in group 1 compared to group 2 and control. Platelet aggregation with collagen was lower in patients with PMF than in the control group, and lower in group 1 than in group 2: 2.2 (1.6; 5.7) % vs 41.6 (3.4; 64.8) %, p < 0.05. In patients in group 1, the activity of Willebrand factor – 150.0 (122.5; 195) % and factor VIII – 173 (148.5; 200) % was higher (p < 0.05) than in the control: 97 (84.8; 110) % and 104 (85; 130) % respectively. Antithrombin did not differ in the PMF and control group. Protein S was reduced in both groups with PMF: group 1 – 70 (58; 86,6) %, group 2 – 65 (43,6; 107,5) %, control – 102 (86; 109,0) %, p < 0.001. ETP and sensitivity to thrombomodulin in groups 1 and 2 were low, p < 0.001. The coagulation index tended to higher values than in the control: 5.3 (3.0; 11.4) – group 1; 3.2 (2.4; 7.3) – group 2; control – 1.9 (1.6; 2.2), p = 0.073.Conclusion. Ruxolitinib therapy leads to the failure of the platelet hemostasis, the procoagulant activity of plasma with an increase in the activity of Willebrand factor and factor VIII and a decrease in the activity of protein S.

Periostin regulates the activity of keloid fibroblasts by activating the JAK/STAT signaling pathway

A keloid is secondary to skin trauma or has spontaneously manifested as an overgrowth and occurs when the skin heals abnormally after an injury. The main pathological manifestations are abnormal proliferation of keloid fibroblasts (KEL-FIB). This study researched periostin (POSTN) on keloid fibroblasts (KEL-FIB) and the associated mechanism, aiming to provide a reference for the targeted therapy of keloid. We got tissues from Second People’s Hospital of Guangxi Zhuang Autonomous Region between June 2022 and March 2023. POSTN expression was increased in keloid skin tissue and KEL-FIB than normal skin tissue and normal fibroblasts. We collected and inoculated KEL-FIB cells, transfection of si-NC (Silencing of POSTN negative control), si-POSTN (Silencing of POSTN), pcDNA-NC (Overexpression of POSTN negative control), and POSTN (Overexpression of POSTN) (Thermo Fisher Scientific) used Lipofectamine 2000 transfection reagent. Wound closure, cell proliferation viability, migrated cell numbers, and POSTN, p-JAK2, p-STAT3 protein levels were reduced in the si-POSTN group. Wound closure, cell proliferation viability, migrated cell numbers, and POSTN, p-JAK2, p-STAT3 protein levels were elevated in the POSTN group. POSTN protein levels did not changed and wound closure, cell proliferation viability, migrated cell numbers, were reduced in the POSTN+S-Ruxolitinib group. The study results indicated that POSTN promotes cell migration and proliferation by activating the JAK/STAT pathway, promoting KEL-FIB development.

Ruxolitinib in steroid-refractory acute graft-vs-host disease: Japanese subgroup analysis of the randomized REACH2 trial

Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6 months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25 months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results.

ECP versus ruxolitinib in steroid-refractory chronic GVHD – a retrospective study by the EBMT transplant complications working party

Ruxolitinib has become the new standard of care for steroid-refractory and steroid-dependent chronic GVHD (SR-cGVHD). Our aim was to collect comparative data between ruxolitinib and extracorporeal photophoresis (ECP). We asked EBMT centers if they were willing to provide detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. 31 centers responded positively and we included all patients between 1/2017-7/2019 treated with ECP or ruxolitinib for moderate or severe SR-cGVHD. We identified 84 and 57 patients with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-cGVHD (steroid dependent vs. refractory vs. intolerant to steroids). At day+180 after initiation of treatment for SR-cGVHD the odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.35 (95% CI = [0.64; 2.91], p = 0.43). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. The clinical significance is limited by the retrospective study design and the current data can’t replace prospective studies on ECP in SR-cGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-cGVHD.

ECP versus ruxolitinib in steroid-refractory acute GVHD - a retrospective study by the EBMT transplant complications working party.

Extracorporal Photophoresis (ECP) is in clinical use for steroid-refractory and steroid-dependent acute GVHD (SR-aGVHD). Based on recent Phase-III study results, ruxolitinib has become the new standard of care for SR-aGVHD. Our aim was to collect comparative data between ruxolitinib and ECP in SR-aGVHD in order to improve the evidence base for clinical decision making. We asked EBMT centers if they were willing to participate in this study by completing a data form (Med-C) with detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. 31 centers responded positively (14%) and we included all patients receiving alloSCT between 1/2017-7/2019 and treated with ECP or ruxolitinib for SR-aGVHD grades II-IV from these centers. We identified 53 and 40 patients with grades II-IV SR-aGVHD who were treated with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-aGVHD (steroid dependent vs. refractory). At day+90 after initiation of treatment for SR-aGVHD we found no statistically significant differences in overall response. The odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.13 (95% CI = [0.41; 3.22], p = 0.81). In line, we detected no statistically significant differences in overall survival, progression-free survival, non-relapse mortality and relapse incidence. The clinical significance is limited by the retrospective study design and the current data can't replace prospective studies on ECP in SR-aGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-aGVHD.

Ruxolitinib Versus Best Available Therapy for Polycythemia Vera: A Systematic Review and Meta-Analysis

Background: Polycythemia vera (PV) is characterized by dysregulated Janus kinase (JAK) activation, leading to excessive production of blood cells, increased risk of thrombotic and hemorrhagic events, and an impairment on the quality of life of patients. Ruxolitinib, a JAK1/JAK2 inhibitor, has shown promising results in recent trials, but its comparative efficacy to best available therapy (BAT) remains unclear. We aimed to perform a systematic review and meta-analysis comparing the efficacy and safety of Ruxolitinib versus BAT for patients with PV. Methods: We systematically searched PubMed, Embase, and Cochrane Central for clinical studies published up to July 1st comparing Ruxolitinib to BAT. BAT was defined as hydroxyurea, interferon or pegylated interferon, pipobroman and anagrelide. Efficacy outcomes assessed were complete response to therapy and reduction in the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) score; safety outcomes were thromboembolism, anemia, and herpes. We pooled outcomes as risk ratios (RR) with 95% confidence intervals (CI). Statistical analysis was performed with Review Manager version 5.4.1. Heterogeneity was assessed with I² statistics. The protocol was registered in PROSPERO (ID: CRD42023427977). Results: A total of five studies met our inclusion criteria, of which four were randomized trials. Our analysis encompassed a population of 684 patients, including 336(49%) allocated to the Ruxolitinib group, and 348(51%) allocated to the BAT group. Ruxolitinib had a significantly greater response to treatment compared to BAT (RR 1.97; 95% CI 1.03 -3.77; p=0.04; I²=60%; Fig 1A) and significantly reduced MPN-SAF score by at least 50% (RR 2.50; 95% CI 1.29-4.86; p=0.007; I²=76%; Fig 1B). Additionally, use of Ruxolitinib showed a significantly higher incidence of herpes infection (RR 3.57; 95% CI 1.27 -10.04; p=0.02; I²=0%; Fig 1C) and anemia (RR 1.97; 95% CI 1.15-3.37; p=0.01; I²=50%; Fig 1D). There were no significant differences between the two treatment groups regarding thromboembolic events (p=0.07; Fig 1E). Conclusion: Our meta-analysis reveals that Ruxolitinib exhibits superior efficacy in achieving a complete response for PV patients compared to BAT and in reducing MPN-SAF score by ≥50%. While no significant difference was observed in thromboembolic events, Ruxolitinib demonstrated significant risk of anemia and herpes infection.

Ruxolitinib or Interferon-α Treatment As a Protective Strategy for Patients with Philadelphia-Negative Myeloproliferative Neoplasms (MPN) during the COVID-19 Pandemic

Background: Both myeloproliferative neoplasms (MPNs) and coronavirus disease 2019 (COVID-19) are characterized by systemic inflammation and with intrinsic thrombotic risk. Series of studies found that ruxolitinib treatment was efficacy for COVID-19 in patients with hyperinflammation, and interferon-α as the innate immune system rapidly to combat viral infections, has been considered a potential therapeutic strategy to treat COVID-19 disease. However, ruxolitinib or interferon-α treatment with response outcomes for MPN patients were still unidentified. Patients and methods : We prospectively analyzed the outcome of ruxolitinib (n=175) or interferon-α (n=165) treatment group versus other available therapy (n=478) group for MPN patients during the COVID-19 Pandemic (from May, 2020, to December, 2022). Outcomes were the rate of thrombosis, bleeding, acute respiratory distress syndrome (ARDS) and death. Results: There were no difference between ruxolitinib and interferon-α treatment group in thrombosis rate, bleeding, the rate of ARDS and death. Thrombosis occurred lower frequently in patients treated with ruxolitinib or interferon-α than other available therapy group (1.1% vs 1.8% vs 5.6%, p = 0.004), rates of bleeding (1.7% vs 1.8% vs 2.0%, p = 0.93), rates of ARDS (1.1% vs 1.8% vs 4.2%, p = 0.048), and death (6.8% vs 3.0% vs 6.9%, p = 0.22) of COVID-19 disease were similar. Conclusion: Ruxolitinib or interferon-α therapy was associated with lower thrombosis event and lower rate of ARDS for MPN patients in COVID-19 Pandemic. Keywords: MPN, Ruxolitinib, thrombosis event, interferon-α

A Single-center, Real-world Experience of Chronic GVHD Treatment Using Ibrutinib, Imatinib, and Ruxolitinib and its Treatment Outcomes.

Chronic graft-versus-host disease (cGVHD) is a common cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Tyrosine kinase inhibitors (TKIs), including ruxolitinib, imatinib, and ibrutinib, have shown promising efficacy in cGVHD treatment. A total of 43 patients who developed cGVHD and received at least one line of TKI therapy for cGVHD treatment were evaluated retrospectively. The overall response, clinical benefit (CB), corticosteroid dose reduction, failure-free survival (FFS), and overall survival (OS) were assessed. A total of 62 lines of TKI therapy were evaluated, including ruxolitinib (n = 18), ibrutinib (n = 13), and imatinib (n = 31). With a 12-month median follow-up duration, 19/58 (32.8%), 20/41 (48.7%), and 17/29 (58.6%) responded to TKI therapy at 3, 6, and 12 months, respectively. The CB was observed in 80% of patients over time, allowing prednisone dose reduction in all 3 TKIs. The FFS rate at 12 months was higher in the imatinib (71%) and ruxolitinib groups (67%) than in the ibrutinib group (46%), while the OS rate at 12 months was similar among the three groups at 96%-100% in patients. In the sclerotic GVHD patient subgroup (n = 39), the overall response rate gradually increased over time. Ruxolitinib appeared to be as effective as imatinib and gradually improved the photographic range of motion score in sclerotic GVHD patients. TKI drugs ruxolitinib, imatinib, and Ibrutinib are effective and feasible for cGVHD treatment. Ruxolitinib is as effective as imatinib for sclerotic GVHD.

Ruxolitinib versus basiliximab for steroid-refractory acute graft-versus-host disease: a retrospective study.

Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic hematopoietic stem cell transplantation; not all patients respond to standard glucocorticoids treatment. This study retrospectively evaluated the effects of ruxolitinib compared with basiliximab for steroid-refractory aGVHD (SR-aGVHD). One hundred and twenty-nine patients were enrolled, 81 in ruxolitinib and 48 in basiliximab group. The overall response (OR) at day 28 was higher in ruxolitinib group (72.8% vs. 54.2%, P = 0.031), as with complete response (CR) (58.0% vs. 35.4%, P = 0.013). Ruxolitinib led to significantly lower 1-year cumulative incidence of chronic GVHD (cGVHD) (29.6% vs. 43.8%, P = 0.021). Besides, ruxolitinib showed higher 1-year overall survival (OS) and 1-year cumulative incidence of failure-free survival (FFS) (OS: 72.8% vs. 50.0%, P = 0.008; FFS: 58.9% vs. 39.6%, P = 0.014). The 1-year cumulative incidence of non-relapse mortality (NRM) was lower in ruxolitinib group (16.1% vs. 37.5%, P = 0.005), and the 1-year relapse was not different. The 1-year cumulative incidence of cytomegalovirus (CMV) viremia, CMV-associated diseases and Epstein-Barr virus (EBV)-associated diseases was similar between the two groups, but EBV viremia was significantly lower in ruxolitinib group (6.2% vs. 29.2%, P < 0.001). Subgroup analyses revealed that OR and survival were similar in ruxolitinib 5mg twice daily (bid) and 10mg bid groups. However, ruxolitinib 10mg bid treatment markedly reduced 1-year cumulative incidence of cGVHD compared with 5mg bid (21.1% vs. 50.0%, P = 0.016). Our study demonstrated that ruxolitinib was superior to basiliximab in SR-aGVHD treatment and cGVHD prophylaxis, therefore should be recommended.

Propensity score matching analysis comparing the efficacy of Ruxolitinib to historical controls in second-line or beyond treatment for chronic GvHD after steroid failure.

Established first-line therapy for chronic graft-versus-host disease (cGvHD) comprises corticosteroids with/without calcineurin inhibitors, but about half of cGvHD patients are refractory to corticosteroid therapy. The present study retrospectively analyzed treatment outcomes in 426 patients and undertook a propensity-score matching (PSM) analysis between ruxolitinib (RUX) treated group and a historical group of cGvHD patients treated with best available treatment (BAT). PSM process adjusted unbalanced risk factors between the 2 groups, including GvHD severity, HCT-CI score, and treatment line, extracting 88 patients (44 in BAT/RUX groups each) for final analysis. In PSM subgroup, RUX group showed 74.7% 12 months' FFS rate vs 19.1% for BAT group (p < 0.001), whereas 12 months' OS rates were 89.2% and 77.7%, respectively. Multivariate analysis for FFS confirmed RUX superiority over BAT together with HCT-CI score 0-2 vs ≥3. For OS, RUX was superior to BAT, while age ≥60 years and severe grade cGvHD adversely impacted OS. In PSM subgroup, at months 0, 3, and 6, 4.5%, 12.2% and 22.2% more patients in RUX group could discontinue prednisone compared to BAT group, respectively. In conclusion, the current study showed that for FFS, RUX was superior to BAT as second-line therapy or beyond in cGvHD patients after therapy failure.

Addition of ruxolitinib in Graft-versus-Host disease prophylaxis for pediatric β-Thalassemia major patients after allogeneic stem cell transplantation: A retrospective cohort study.

To evaluate the effect of addition of ruxolitinib in Graft-versus-Host Disease (GVHD) prophylaxis on pediatric patients with β-thalassemia major after allogeneic hematopoietic stem cell transplantation(HSCT). This retrospective study reviewed 49 consecutive β-thalassemia major pediatric patients who underwent HSCT from unrelated or haploidentical donors from February 2018 to October 2022. All transplantation recipients received cyclosporine A (CsA), mycophenolate mofetil (MMF), and short-term methotrexate (MTX) as GVHD prophylaxis; while 27 of them in the ruxolitinib group had added ruxolitinib oral to GVHD prophylaxis regimen at 2.5mg twice daily once successful engraftment after January 2020. The outcome showed that the ruxolitinib group had a lower cumulative incidence than the control group regardless of acute GVHD (22.2% vs.40.9%; p=.153) or chronic GVHD (18.5% vs.40.9%; p=.072); especially, the incidence of grade III-IV acute GVHD was reported significantly less frequently in ruxolitinib group than that of the control group (0 vs. 27.3%, p=.005). No significant difference was detected between the two groups in EBV (Epstein-Barr virus)/CMV (cytomegalovirus) reactivation and BKV (BK virus) infection (p=.703, 1.000, and .436, respectively). Twenty-six patients (96.3%) in the ruxolitinib group were alive, while two patients (9.1%) in the control group died of intestinal acute GVHD. The 2-year overall survival (OS) and thalassemia-free survival (TFS) were both 96.296% in the ruxolitinib group, while both 90.909% in the control group. This study reveals that ruxolitinib prophylaxis is a promising option to decrease the incidence of grade III-IV acute GVHD in pediatric patients with β-thalassemia major.

Proactive anti-inflammatory therapy in the advanced stages of a new coronavirus infection. Main results of the inpatient phase of the COLORIT study (Colchicin vs. Ruxolitinib and secukinumab in an open, prospective, randomized trial in patients with novel coronavirus infection COVID-19).

Aim To evaluate clinical efficacy of the proactive anti-inflammatory therapy in patients hospitalized for COVID-19 with pneumonia and a risk of "cytokine storm".Material and methods The COLORIT study was a comparative study with randomization into 4 groups: colchicine (n=21) 1 mg for the first 3 days followed by 0.5 mg/day through day 12 or discharge from the hospital; secukinumab 300 mg/day, s.c., as a single dose (n=20); ruxolitinib 5 mg, twice a day (n=10); and a control group with no anti-inflammatory therapy (n=22). The effect was evaluated after 12±2 days of inpatient treatment or upon discharge, what comes first. For ethical reasons, completely randomized recruitment to the control group was not possible. Thus, for data analysis, 17 patients who did not receive any anti-inflammatory therapy for various reasons not related with inclusion into the study were added to the control group of 5 randomized patients. Inclusion criteria: presence of coronavirus pneumonia (positive PCR test for SARS-CoV-2 RNA or specific clinical presentation of pneumonia; IDC-10 codes U07.1 and U07.2); C-reactive protein (CRP) concentration &gt;60 mg/l or its threefold increase from baseline; at least 2 of 4 symptoms (fever &gt;37.5 °C, persistent cough, shortness of breath with inspiratory rate &gt;20 per min or blood saturation with oxygen &lt;94 % by the 7th-9th day of disease. The study primary endpoint was changes in COVID Clinical Condition Scale (CCS-COVID) score. The secondary endpoints were the dynamics of CRP and changes in the area of lung lesion according to data of computed tomography (CT) of the lungs from the date of randomization to 12±2 days.Results All three drugs significantly reduced inflammation, improved the clinical course of the disease, and decreased the disease severity as evaluated by the CCS score: in the ruxolitinib group, by 5.5 (p=0.004); in the secukinumab group, by 4 (p=0.096); in the colchicine group, by 4 (p=0.017), and in the control group, by 2 (р=0.329). In all three groups, the CCS-COVID score was 2-3 by the end of observation period, which corresponded to a mild process, while in the control group, the score was 7 (р=0.005). Time-related changes in CRP were significant in all three anti-inflammatory treatment groups with no statistical difference between the groups. By the end of the study, changes in CT of the lungs were nonsignificant.Conclusion In severe СOVID-19 with a risk of "cytokine storm", the proactive therapy with ruxolitinib, colchicine, and secukinumab significantly reduces the inflammation severity, prevents the disease progression, and results in clinical improvement.

Inhibition of JAK1,2 Prevents Fibrotic Remodeling of Pulmonary Vascular Bed and Improves Outcomes in the Rat Model of Chronic Thromboembolic Pulmonary Hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism with poor clinical outcomes. Therapeutic approaches to prevention of fibrotic remodeling of the pulmonary vascular bed in CTEPH are limited. In this work, we tested the hypothesis that Janus kinase 1/2 (JAK1/2) inhibition with ruxolitinib might prevent and attenuate CTEPH in a rat model. CTEPH was induced by repeated embolization of the pulmonary artery with partially biodegradable 180 ± 30 μm alginate microspheres. Two weeks after the last injection of microspheres, ruxolitinib was administered orally at doses of 0.86, 2.58, and 4.28 mg/kg per day for 4 weeks. Prednisolone (1.475 mg/kg, i.m.) was used as a reference drug. Ruxolitinib in all doses as well as prednisolone reduced pulmonary vascular wall hypertrophy. Ruxolitinib at a dose of 2.58 mg/kg and prednisolone reduced vascular wall fibrosis. Prednisolone treatment resulted in decreased right ventricular systolic pressure. Pulmonary vascular resistance was lower in the prednisolone and ruxolitinib (4.28 mg/kg) groups in comparison with the placebo group. The plasma level of brain natriuretic peptide was lower in groups receiving ruxolitinib at doses of 2.58 and 4.28 mg/kg versus placebo. This study demonstrated that JAK1/2 inhibitor ruxolitinib dose-dependently reduced pulmonary vascular remodeling, thereby preventing CTEPH formation in rats.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

Immunomodulators in Mechanically Ventilated Patients With COVID-19: Lessons Learned From Underpowered Trials.

BMS-986158, a Potent BET Inhibitor, As Monotherapy and in Combination with Ruxolitinib or Fedratinib in Intermediate- or High-Risk Myelofibrosis: First Results from a Phase 1/2 Study

Background Bromodomain and extraterminal (BET) proteins play a role in cancer-cell proliferation, survival, and oncogenic progression, providing a rationale for using inhibitors of BET as anticancer drugs. BET inhibitors (BETi) alone and in combination with Janus kinase (JAK) inhibitors have been demonstrated to reduce inflammatory signals and disease burden in mouse myelofibrosis (MF) models, and combined inhibition of BET-mediated pathways and the JAK-STAT pathway has shown additional benefits for patients (pts) with MF. BMS-986158 is an orally bioavailable, potent, and selective small-molecule BETi that has demonstrated a dose-proportional pharmacokinetic profile with linear increases in exposure, as well as time- and dose-dependent modulation of BET target gene expression (Hilton J et al. Ann Oncol 2018;29(suppl 8):1429). BMS-986158 is being evaluated in pts with MF, alone and in combination with the JAK inhibitors ruxolitinib (RUX) or fedratinib (FED), in the CA011-023 study (NCT04817007). Here, we present initial safety and efficacy data from the dose-escalation parts (1A and 1B) of this study. Methods CA011-023 comprises a dose-escalation phase with BMS-986158 + RUX in RUX-naive pts (Part 1A) or BMS-986158 + FED in pts with previous RUX treatment (Part 1B), and a dose-expansion phase at the Recommended Phase 2 Dose (RP2D) evaluating BMS-986158 + RUX (Part 2A) or BMS-986158 ± FED (Part 2B). Eligible pts had primary or secondary MF, splenomegaly (spleen volume ≥ 450 cm3), ECOG performance status ≤ 2, and Dynamic International Prognostic Scoring System risk scores of intermediate-1 with symptoms, intermediate-2, or high. Planned dose levels for pts in Part 1A are BMS-986158 2.0 mg, 3.0 mg, and 4.5 mg once daily (QD) 5 days on/2 days off and RUX 15 mg twice daily. For pts in Part 1B, planned dose levels are BMS-986158 0.5 mg, 0.75 mg, 1.25 mg, and 2.0 mg QD 5 days on/2 days off and FED 400 mg QD. Primary objectives in the dose-escalation phase are assessment of safety and tolerability and determination of the maximum tolerated dose and/or RP2D of BMS-986158 in combination with RUX or FED. Secondary objectives include spleen volume reduction (SVR) from baseline. Assessment of pharmacodynamic markers, such as JAK2 variant allele, is an exploratory objective. Results As of May 31, 2022, 13 pts were treated, 6 with BMS-986158 + RUX (median 66 years [range, 36-81]; 100% male) and 7 with BMS-986158 + FED (median 62 years [range, 37-77]; 57% male). Grade 1/2 treatment-related adverse events (TRAEs) were reported in 3 (50%) pts in the BMS-986158 + RUX group and in 2 (29%) pts in the BMS-986158 + FED group. Grade 3 TRAEs considered to be related to the combination treatment reported in the BMS-986158 + RUX group were thrombocytopenia (2 pts [33%]), and neutropenia and hypertension (1 pt each [17%]). Grade 3 TRAEs considered to be related to the combination treatment in the BMS-986158 + FED group were anemia (2 pts [29%]) and thrombocytopenia (1 pt [14%]). No grade 4/5 TRAEs were reported for either combination. One dose-limiting toxicity (DLT; grade 3 thrombocytopenia leading to dose reduction of BMS-986158) was reported at the 2.0 mg dose level of BMS-986158 + RUX on cycle 1 day 19. No DLTs have been reported in pts treated with BMS-986158 + FED. No serious TRAEs or TRAEs leading to treatment discontinuation have been reported. Importantly, SVR was observed at Week 12 in all evaluable pts across both treatment groups and continued to deepen at Week 24 in evaluable pts. In the BMS-986158 + RUX group, 4/5 (80%) pts met SVR35 at week 12, and 2/2 (100%) pts met SVR35 at week 24. In the BMS-986158 + FED group 0/3 (0%) pts met SVR35 at week 12, and 1/2 (50%) pts met SVR35 at week 24 (Table 1). Pts with post-baseline spleen volume by MRI in Part 1B were treated at lower BMS-986158 dose levels (0.5 mg and 0.75 mg 5 days on/2 days off) compared to Part 1A (2 mg 5 days on/2 days off). Analysis of JAK2 variant allele frequency and determination of RP2D are ongoing. Conclusions Most TRAEs were grade 1/2 in severity, while grade 3 TRAEs were successfully managed with dose delays or modifications without leading to treatment discontinuation. Initial results demonstrate that BMS-986158 in combination with RUX or FED produced robust SVR in pts with MF, with responses that deepened beyond Week 12 under continued treatment. Enrollment is continuing in the dose-escalation cohorts to establish RP2D for both combinations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Quantitative MRI Identifies Heterogeneous Bone Marrow Treatment Responses in a Mouse Model of Myelofibrosis

Myeloproliferative neoplasms (MPNs), a class of blood cancers, typically arise from mutations in the thrombopoietin receptor (MPL), JAK2, or calreticulin that constitutively activate JAK/STAT signaling in hematopoietic stem and progenitor cells. Myelofibrosis (MF), the most aggressive of the MPNs, can arise as a primary neoplasm or secondary to other MPNs. MF is characterized by progressive fibrosis of bone marrow (BM), destruction of the hematopoietic niche, and eventual BM failure. Recently, the focus of treatment in MF has shifted toward restoration of healthy BM architecture and a functional hematopoietic niche rather than focusing solely on alleviating symptoms. Accomplishing this paradigm shift in drug development and therapy requires new approaches to monitor spatial and temporal changes in BM in patients during treatment. We present a quantitative magnetic resonance imaging (MRI) approach to analyze key pathologic changes in BM in a mouse model of MPN driven by MPLW515L. To evaluate disease extent, progression, and response to therapy in mice, we use anatomical MRI for spleen volume and three quantitative MRI metrics for BM: 1) apparent diffusion coefficient (ADC), 2) proton density fat fraction (PDFF), and 3) magnetization transfer ratio (MTR). PDFF and ADC assess the fat content and water movement of the BM and are useful in identifying cellularity changes such as hypercellularity in MPNs and MF. MTR probes changes in macromolecular structure, such as those observed with increasing fibrosis in MF. We used quantitative MRI to measure response to treatment in BM and change in spleen volume in response to three drugs: ruxolitinib (JAK1/2 inhibitor), fedratinib (JAK2 inhibitor), and navitoclax (BCL-2/BCL-xL inhibitor). Within 10 days after starting treatment, diseased spleen volumes in the ruxolitinib group (~3.5x healthy volume) had the greatest average reduction in spleen volume measured by MRI (-73.5% ± 11.4%) followed by the fedratinib group (-52.7% ± 16.7%). Interestingly, the spleens of every ruxolitinib-treated mouse displayed consistent and prolonged spleen volume reductions, while only a subset of mice in the other treatment groups (~70% fedratinib mice; ~33% navitoclax mice) demonstrated reductions in spleen volume. Despite the robust spleen response in ruxolitinib-treated mice, only some of the mice (~60%) exhibited sustained changes in BM ADC, MTR, and PDFF signals expected with reversion to healthy BM (decreased ADC, decreased MTR, and increased PDFF). In mice treated with fedratinib or navitoclax, even fewer mice (~40% and ~33% respectively) showed reversion toward healthy BM. Importantly, we observed spatial heterogeneity of BM response within the tibia of single mice, where proximal and distal tibia regions often responded disparately (~49% of cases). Because improving BM cellularity and fibrosis is increasingly the target of therapy in MPNs and in MF specifically, there is a distinct need for better techniques for longitudinally evaluating variations in treatment efficacy in living subjects. In this study, we demonstrate that the combination of three quantitative MRI metrics (ADC, PDFF, and MTR) can detect the impact of therapy on the BM in a preclinical mouse model of MPN/MF. Interestingly, we identified pronounced heterogeneity at multiple levels during treatment: 1) differences in changes in spleen volume versus BM; 2) disparate treatment responses of mice within a treatment group; and 3) contrasting regional treatment responses of the BM within a single mouse. Because these quantitative MRI metrics are directly translatable to clinical medicine and can identify variations in treatment efficacy in BM, both between and within subjects, this study sets the stage for future drug development and analysis of therapeutic interventions on the BM of patients with MF.

Analysis of US Registry Data on Patient Characteristics, Treatment Patterns and Outcomes of Patients Receiving Extracorporeal Photopheresis with or without Ruxolitinib

Background Chronic Graft vs. Host Disease (cGvHD) occurs in up to 60% of long-term survivors of allogeneic hematopoietic cell transplantation (alloHCT) and is associated with substantial morbidity and mortality. 1 Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used in the treatment of cGvHD, often in combination with steroids or other established immunosuppressants. The purpose of this retrospective analysis of a registry database is to understand how ECP is being used within the real-world setting especially with introduction of newer immunosuppressants in particular ruxolitinib (RUX). Methodology Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry was used. Inclusion criteria were patients in the United States who received an alloHCT during 2017 to 2019, were diagnosed with cGvHD within twelve months following alloHCT and received ECP for the treatment of cGvHD. Only data from centres who completed the Comprehensive Report Forms were included. For the analysis pre-specified end points were: Overall survival (OS) from date of first ECP±RUX treatment, and 'GvHD presence’ and 'GvHD still being treated with steroids or Immunosuppressants’ at last contact. Data was analysed by recipient, disease, transplant and post-transplant variables. OS survival was estimated by the Kaplan-Meier method. Results Of 2,435 patients who developed cGvHD within one year of alloHCT, 200 patients (8.2%) from 69 centres were eligible for the analysis. Median follow-up among all survivors was 35 months. The median age was 56 years (including 20 paediatric patients with median age of 11 years), 57% were males, and 70% White (Table). The majority of patients had prior aGvHD (79%), extensive cGVHD (95%) and were transplanted for a malignant disease (91%). Approximately 48% (n=96) of study patients had ECP in combination with ruxolitinib (ECP +RUX), either simultaneously, overlapping or sequential, with slightly younger age (55 vs 57 years) and higher percent of Caucasians (77% vs 63%) than ECP patients (n=104) without RUX (ECP-RUX)). The median time from cGVHD onset to ECP± RUX was 3 overall (range 0-43), 2 months for the ECP+RUX group and 3 months for ECP-RUX. For the ECP+RUX group, 52 (54%) patients had ECP treatment first and 38 (40%) had RUX treatment first (4 were same day and 2 unreported). Median time to switch or add in either ECP or RUX was 3 months and for 35% (33/96) of patients this occurred <1 month. The overall survival at year 1 and 2 following ECP+RUX or ECP-RUX treatment, were 77.4% vs 69.6% and 64.7% vs 52.9% (p=0.110), . Overall cGvHD presence at last contact was still high at 88% (n=176/200) and 53% (105) of patients were still taking steroids, while 63 patients (37%) stopped after ECP± RUX were initiated (10 patients stopped prior to initiation and for 12, the stop date was not reported) . In the ECP -RUX group 57% (19 /33) of patients stopped steroids < 6 months, compared to 30% (9/30) in ECP+RUX. Overall, 70% (139) were still taking an immunosuppressant agent (other than steroids), 74% and 65% in RUX+ECP and RUX-ECP, respectively. Conclusion Results from this CIBMTR study using recent data show that ECP is used to primarily treat patients with extensive cGvHD. In nearly half the patients RUX was used in combination with ECP. Some differences were observed in characteristics and outcomes in the ECP group with and without RUX. Not all clinical outcomes and measures (in particular cGVHD response rates) were reported by centers or were only available at baseline, and data on all agents used to treat GvHD was not analysed. Despite these limitations, while cGvHD still persists in most patients, over a third of patients in our analyses were able to stop steroids . References 1 Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol. Blood Marrow Transplant. 2003;9(4):215-233 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1037: DOES EARLY INTERVENTION IN MYELOFIBROSIS IMPACT OUTCOMES? A POOLED ANALYSIS OF THE COMFORT I AND II STUDIES

Background: Myelofibrosis (MF) is characterized by cytopenias, splenomegaly, burdensome symptoms, and poor overall survival (OS). Few studies have investigated if earlier intervention with targeted MF therapies affects response and OS. In a pooled analysis of the COMFORT I and II trials of ruxolitinib (RUX), patients (pts) who received RUX at randomization or after crossover from placebo (PBO) or best available therapy (BAT) had improved OS. Aims: To assess the association of MF disease duration before treatment with disease outcomes using pooled COMFORT data Methods: COMFORT I (NCT00952289) and COMFORT II (NCT00934544) were phase 3 trials of RUX vs PBO or BAT, respectively, in pts with intermediate-2 or high-risk MF who provided written informed consent. In this post hoc analysis, data from RUX-treated pts in both studies were combined (RUX group), and data from the PBO/BAT arms were pooled (control group). Pt subgroups were defined based on disease duration before treatment initiation (≤12 mo or >12 mo from diagnosis). Assessments included frequency of thrombocytopenia (platelets [PLT] <100 Gi/L or PLT transfusion) and anemia (hemoglobin <100 g/L or red blood cell transfusion) events, spleen volume response (SVR; spleen volume reduction ≥35% from baseline [SVR35]), symptom response (MF-Symptom Assessment Form total symptom score [TSS] reduction ≥50% from baseline [TSS50]; available in COMFORT I only), and OS. OS was assessed using the Kaplan-Meier method; pts randomized to PBO/BAT were included in the PBO/BAT group regardless of crossover. A multivariable analysis (MVA) using a logistic regression model was used to examine factors associated with SVR. Results: There were 525 pts in the analysis (RUX: ≤12 mo, n=84; >12 mo, n=216; PBO/BAT: ≤12 mo, n=66; >12 mo, n=159). Median age across groups ranged from 65 to 70 y. Baseline clinical characteristics were generally similar across subgroups, but pts with shorter vs longer disease duration were slightly younger with higher blood counts. Among pts who received RUX, fewer thrombocytopenia events were observed among those treated earlier (≤12 mo vs >12 mo), with differences seen as early as Wk 4–8 on treatment (18% vs 33%) and sustained over time; a similar trend was observed for anemia events (Wk 4–8, 59% vs 72%). The proportion of pts with SVR35 was greater among those who initiated RUX earlier (≤12 mo vs >12 mo) at Wk 24 (48% vs 33%; P=0.0610) and 48 (44% vs 27%; P=0.0149; Table). A numerically greater proportion of pts who initiated RUX at ≤12 mo vs >12 mo achieved TSS50 at Wk 24 (56% vs 40%; P=0.0829; Table). OS at Wk 240 was improved among pts who initiated RUX at ≤12 mo vs >12 mo (63% [95% CI, 51%–73%] vs 57% [95% CI, 49%–64%]; P=0.0430; Table). Comparatively, OS was longer with RUX vs PBO/BAT regardless of disease duration. A sensitivity analysis using a 24-mo cutoff was also conducted but yielded weaker associations between disease duration and SVR, TSS, and OS. In the MVA, a significantly greater binary SVR was seen among pts with shorter (≤12 mo) vs longer (>12 mo) MF disease duration (odds ratio, 2.1; P=0.022). Image:Summary/Conclusion: These findings suggest that earlier RUX initiation in MF may improve clinical outcomes, including cytopenias, SVR, symptom burden, and OS. While “watch and wait” remains a common treatment approach for newly diagnosed patients, these data suggest that pts with MF may benefit from earlier intervention. Additional studies to further evaluate the impact of early intervention are warranted.

Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study

The phase 3b, randomised, open-label RESPONSE-2 study in patients with inadequately controlled polycythaemia vera without splenomegaly showed superiority of the Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib versus best available therapy for the primary endpoint of haematocrit control at week 28. Here, we present secondary endpoints of the RESPONSE-2 study after 5 years of follow-up. RESPONSE-2 was an open-label, randomised, phase 3b study done at 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and Canada. Patients (aged ≥18 years) with polycythaemia vera without splenomegaly, who were intolerant of, or resistant to hydroxyurea, with an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) to receive ruxolitinib or best available therapy for up to 80 weeks. Patients received oral ruxolitinib at a starting dose of 10 mg twice a day or best available therapy. Patients assigned to best available therapy could cross over to ruxolitinib at week 28 if the primary endpoint was not met, or after week 28 and up to week 80 if best available therapy was ineffective or not tolerated. Patients receiving ruxolitinib at week 80, including crossover patients, could continue ruxolitinib treatment up to week 260. We assessed secondary endpoints at week 260, including durable haematocrit control, median duration of haematocrit control, median haematocrit level over time, number of phlebotomies, and overall survival. Analyses were based on the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT02038036 and was completed on April 7, 2020. Patients were enrolled between March 25, 2014 and Feb 11, 2015. 149 patients were randomly assigned to ruxolitinib (n=74) or best available therapy (n=75). The median follow-up was 67 months (IQR 65-70). At randomisation, best available therapy regimens included hydroxyurea (n=38), interferon or pegylated interferon (n=9), pipobroman (n=5), lenalidomide (n=1), or no treatment (n=22). Between weeks 28 and 80, 58 (77%) of 75 patients in the best available therapy group crossed over to ruxolitinib; no patients continued best available therapy after week 80 per protocol. 97 patients received ruxolitinib until week 260, including 59 (80%) of 74 patients in the ruxolitinib group and 38 (66%) of 58 patients in the crossover groups. At week 260, 16 (22%; 95% CI 13-33) of 74 patients in the ruxolitinib group had achieved durable haematocrit control, with estimated median duration not reached (NR; 95% CI 144 to NR). Median duration of haematocrit control was not reported for patients in the best available therapy group due to the small number of responders by week 80. During the 5-year follow-up, median haematocrit level among patients in the ruxolitinib group remained below 45%. 60 phlebotomies were required among 74 patients in the ruxolitinib group in 260 weeks, and 106 phlebotomies among 75 patients in the best available therapy group in 80 weeks. 5-year overall survival was 96% (95% CI 87-99) in the ruxolitinib group and 91% (80-96) in the best available therapy group. The most common grade 3-4 adverse events (exposure-adjusted per 100 patient-years) in the ruxolitinib group (n=74) and best available therapy group (n=75) were hypertension (eight [2·4%] vs three [5·6%]), thrombocytopenia (one [0·3%] vs three [5·6%]), and thrombocytosis (0 vs four [7·5%]). Exposure-adjusted rates of any-grade thromboembolic events were 1·5% per 100 person-years (five of 74 patients) in the ruxolitinib group and 3·7% per 100 person-years (two of 75 patients) in the best available therapy group. No treatment-related deaths occurred during the study. 5-year results from the RESPONSE-2 study support the use of ruxolitinib as a second-line therapy of choice for patients with inadequately controlled polycythaemia vera without splenomegaly. Novartis.

Ruxolitinib versus dexamethasone in hospitalized adults with COVID-19: multicenter matched cohort study

BackgroundSeveral anti-cytokine therapies were tested in the randomized trials in hospitalized patients with severe acute respiratory syndrome coronavirus 2 infection (COVID-19). Previously, dexamethasone demonstrated a reduction of case-fatality rate in hospitalized patients with respiratory failure. In this matched control study we compared dexamethasone to a Janus kinase inhibitor, ruxolitinib.MethodsThe matched cohort study included 146 hospitalized patients with COVID-19 and oxygen support requirement. The control group was selected 1:1 from 1355 dexamethasone-treated patients and was matched by main clinical and laboratory parameters predicting survival. Recruitment period was April 7, 2020 through September 9, 2020.ResultsRuxolitinib treatment in the general cohort of patients was associated with case-fatality rate similar to dexamethasone treatment: 9.6% (95% CI [4.6–14.6%]) vs 13.0% (95% CI [7.5–18.5%]) respectively (p = 0.35, OR = 0.71, 95% CI [0.31–1.57]). Median time to discharge without oxygen support requirement was also not different between these groups: 13 vs. 11 days (p = 0.13). Subgroup analysis without adjustment for multiple comparisons demonstrated a reduced case-fatality rate in ruxolitnib-treated patients with a high fever (≥ 38.5 °C) (OR 0.33, 95% CI [0.11–1.00]). Except higher incidence of grade 1 thrombocytopenia (37% vs 23%, p = 0.042), ruxolitinib therapy was associated with a better safety profile due to a reduced rate of severe cardiovascular adverse events (6.8% vs 15%, p = 0.025). For 32 patients from ruxolitinib group (21.9%) with ongoing progression of respiratory failure after 72 h of treatment, additional anti-cytokine therapy was prescribed (8–16 mg dexamethasone).ConclusionsRuxolitinib may be an alternative initial anti-cytokine therapy with comparable effectiveness in patients with potential risks of steroid administration. Patients with a high fever (≥ 38.5 °C) at admission may potentially benefit from ruxolitinib administration.Trial registration The Ruxolitinib Managed Access Program (MAP) for Patients Diagnosed With Severe/Very Severe COVID-19 Illness NCT04337359, CINC424A2001M, registered April, 7, 2020. First participant was recruited after registration date