Efficacy Of Ruxolitinib Research Articles

Benefit of Early Ruxolitinib Initiation Regardless of Fibrosis Grade in Patients with Primary Myelofibrosis: A Post Hoc Analysis of the Single-Arm Phase 3b JUMP Study.

Bone marrow fibrosis (BMF) is an adverse prognostic factor for myelofibrosis (MF). The single-arm, open-label, phase 3b JUMP trial (NCT01493414) assessed the safety and efficacy of the JAK1/JAK2 inhibitor ruxolitinib in patients with symptomatic MF. This post hoc analysis investigated the impact of BMF grade on response and outcomes in patients with primary MF (PMF) from the JUMP study. BMF was assessed by biopsy and graded from 0 to 3; grades 0-1 were considered low-grade fibrosis (LGF) and grades 2-3 were considered high-grade fibrosis (HGF). Patients with LGF (n = 268) had lower rates of cytopenias at baseline but showed comparable disease burden vs. patients with HGF (n = 852). The proportion of patients achieving a spleen response was greater in the LGF group vs. the HGF group at Week 24 and at any time during the study, while overall survival estimates were improved in patients with LGF vs. patients with HGF. Early initiation of ruxolitinib therapy (within 2 years of diagnosis) was associated with increased response rates in all patients. These results highlight the efficacy of ruxolitinib in symptomatic patients with PMF, with the greatest clinical improvements observed in patients with LGF and in patients who received early treatment.

Efficacy of ruxolitinib for HAVCR2 mutation-associated hemophagocytic lymphohistiocytosis and panniculitis manifestations in children.

Frequent germline mutations of HAVCR2, recently identified in subcutaneous panniculitis-like T-cell lymphoma (SPTCL), are associated with an increased risk of hemophagocytic lymphohistiocytosis (HLH). However, SPTCL-HLH represents a challenge because of the difficulties in treatment with poor survival. Its malignant nature, specifically harbouring HAVCR2 mutations, has also been questioned. To better understand its pathology and treatment, we analysed the clinical data of six patients diagnosed at our centre. The median age at onset was 10.5 years (range, 0.8-12.4). Five patients presented with skin lesions of subcutaneous nodules/plaques and/or ulceration. All patients developed HLH; notably, one infant only had HLH without skin involvement. Histopathologically, only two patients were diagnosed with SPTCL and three were reported as panniculitis with no sufficient evidence of lymphoma. Genetically, germline homozygous mutation of HAVCR2 (p.Y82C) was identified in all patients, with a median diagnosis time of 4.6 months. All patients initially received corticosteroids, immunosuppressants or chemotherapy, achieving unfavourable responses. Strikingly, they responded well to ruxolitinib targeting inflammatory cytokines, allowing rapid disease resolution and/or long-term maintenance of remission. The excellent efficacy of ruxolitinib highlights this disease as an inflammatory condition instead of neoplastic nature and indicates novel agents targeting key inflammatory pathways as an encouraging approach for this disease entity.

A Multicenter, Retrospective Study Evaluating Clinical Outcomes of Ruxolitinib Therapy In Heavily Pretreated Chronic GVHD Patients With Steroid Failure

Although ruxolitinib is emerging as the treatment of choice for steroid-refractory or -dependent chronic graft versus host disease (cGVHD) based on randomized control trial data, there is relatively little real-world data published on ruxolitinib for this indication. We wanted to evaluate the real-world efficacy and safety of ruxolitinib in cGVHD patients who have failed any previous systemic therapy for cGVHD. We retrospectively evaluated the efficacy of ruxolitinib in 115 heavily pretreated patients with steroid-refractory or -dependent chronic GVHD across 5 transplantation centers. The majority of the study population had severe cGVHD (60%) and received ruxolitinib at the fourth treatment line or beyond (82%, n = 96). The median duration of follow-up in this study population was 13 months. The overall response rate (ORR) was 48.6%, 54.9%, and 48.5% at 3, 6, and 12 months, respectively. Clinical benefit (an outcome metric combining ORR with steroid reduction) was observed in 58.7%, 64.8%, and 60.6% of patients at 3, 6, and 12 months, respectively. Approximately one third of patients (37.9%) were able to discontinue prednisone at 12 months, and 63.8% were able to taper prednisone to a daily dose <0.1 mg/kg at 12 months. Failure-free survival at 12 months was 64.6% (54.1%-73.2%). Multivariate analysis identified that patients with severe cGVHD were at a higher risk of failure because of a therapy switch, whereas a pretransplantation hematopoietic stem cell transplantation–comorbidity index score ≥ 3 was associated with a high risk of failure because of increasing risk of non-relapse mortality. Overall, this study demonstrates the therapeutic efficacy of ruxolitinib for cGVHD in a heavily pretreated real-world population.

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.

Safety and Effectiveness of Ruxolitinib in Real-World Patients with Myelofibrosis: A 2-Year Observational Study from Taiwan

Introduction Ruxolitinib (RUX) is an approved JAK1/JAK2 inhibitor for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF), but real-world safety and efficacy of RUX in Taiwan are not well understood. This study was conducted to evaluate the safety and efficacy of treatment with RUX with intermediate-2 or high risk PMF, PPV-MF or PET-MF in routine clinical practice. Method This 2-year, single-arm, multicenter, post-marketing surveillance registry collected data on the safety, tolerability, efficacy, and other clinical information of adult patients (pts) aged ≥20 years with a confirmed diagnosis of intermediate-2 or high-risk PMF, PPV-MF, or PET-MF who either received RUX or starting RUX in accordance with the general clinical practice in Taiwan. Primary endpoint included collection of adverse events (AEs), AE of special interest (AESIs; anemia, thrombocytopenia, leukocytosis, hepatitis B virus (HBV) infection or reactivation, tuberculosis (TB) infection, and other infections), and serious adverse events (SAEs) throughout the study. Key secondary endpoints included treatment duration, discontinuation rates, dosage of prescribed RUX, Myeloproliferative Neoplasm symptom assessment form (MPN-10) score after study entry and change in spleen size, specifically in naïve patients who were eligible for spleen response evaluation. Results A total of 99 (51% PMF, 22.4% PPV-MF, and 26.5% PET-MF) pts were recruited, of which 38 (38.4%) pts discontinued due to consent withdrawal (n=11), death (n=10), discontinued prescription of RUX for 3 months (n=4), AEs (n = 2), unsatisfactory therapeutic effect (n=2), administrative problems (n=1), disease progression (n=1), required immediate stem cell transplantation (n=1), and others (n=6). Median age was 68.1 (range: 38.3-87.2) years and gender ratio was balanced, with 97 Taiwanese pts (98.0%). Median disease duration was 13.9 months (range: 0-967.6 months) and 70.7% and 28.3% of pts were identified with the risk of intermediate-2 or high using IPSS/DIPSS risk assessment, respectively. Majority of the recruited pts were RUX pre-treated (n=75; 75.8%) and 24.2% (n=24) pts were RUX-naïve at baseline. During the study, 88 pts (89.8%) had 673 AEs, and 44 (44.9%) experienced 159 SAEs. Half of the pts (55.1%) had moderate or severe SAEs and 39 pts recovered. Over 80% of SAEs (n=131) were not related to RUX. Major AESIs were anemia (29.6%) and thrombocytopenia (20.4%). There were no HBV infection or reactivation reported; 2% of pts had TB while 3% of pts had herpes zoster infections. The major reported infection was pneumonia (20.4%). Key safety data are summarized in Table 1. Most pts had their AEs resolved (77.6%), while 10 deaths occurred due to AEs (10.2%). Majority of the pts (41.8%) received a daily dose of RUX 20 mg at the enrolment, with an average mean daily dose of 22.7±9.2 mg (Figure 1). For naïve pts, mean initial dose was 18.8 ± 8.50 mg and gradually titrated up to 22.3 ± 8.69 mg at 3 months and to 24.0 ± 9.17 mg at 6 months. Among 98 pts, 13.3% pts whose platelet counts between 100-200×103/μL and 21.4% pts whose platelet counts were >200×103/μL were treated with RUX 5-10 mg twice daily. Among 27 RUX pre-treated patients (mean RUX duration before study entry: 17.0 ± 20.98 months), spleen size by palpation was relatively stable throughout the study period. For the 7 RUX naïve pts, the mean spleen size change from baseline was -15.9 %± 28.72 at 12 weeks, -30.8% ± 31.28 at 24 weeks, -54.2% ± 41.93 at 48 weeks and -52.0% ± 36.41 at 96 weeks. However, it should be interpreted with caution due to the small pt pool. A total of 65 pts (65.7%) had >50% improvement in the symptom response by MPN-10 during 2-year study period. . Conclusion This is the first real-world study in Taiwan to evaluate safety and efficacy with RUX in patients with MF. It was observed that physicians employed a conservative strategy for a lower starting dose with gradual titration resulting in comparable safety profile, but lower incidences of thrombocytopenia compared to published clinical trials. The majority of pts reported continuous symptomatic improvement and a small number of RUX naïve pts had pronounced spleen size reduction. Further investigations are required to evaluate whether optimal dose of RUX or titration speed would improve spleen response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Addition of Ruxolitinb to Corticosteroids As First-Line Therapy for High-Risk Acute Graft Versus Host Disease in Allogeneic Peripheral Blood Stem Cell Transplantation

PURPOSE Corticosteroids (2mg/kg/day) are commonly used as first-line treatment for acute graft versus host disease(aGVHD). However, steroid is effective in only about half of patients. Based on the promising efficacy of ruxolitinib as second-line therapy for aGVHD, we performed a randomized controlled study to assess the safety and efficacy of corticosteroids (2mg/kg/day) alone versus ruxolitinb combined with reduced dose of corticosteroids (1mg/kg/day) in patients with high-risk aGVHD after allogeneic peripheral blood stem cell transplantation. METHODS This multicenter, randomized, phase II controlled study (ClinicalTrials.gov, NCT04061876) enrolled patients with newly diagnosed aGVHD from 7 Chinese centers. Patients were randomly assigned at a ratio of 1:1 to methylprednisolone (2mg/kg/day) alone (steroids group) or ruxolitinib (5 mg/day) combined with methylprednisolone (1 mg/kg/day) (RUX/steroids combined group). The primary endpoint is the overall response rate on day 28, which is defined as an improvement of at least one stage in the severity of aGVHD in one organ without deterioration in any other organ or disappearance of any GVHD signs from all organs without requiring new systemic immunosuppressive treatment. The secondary objectives consist of response time, response duration, overall survival, disease-free survival, non-relapse mortality, failure-free survival. RESULTS From August 25 of 2019 to June 1 of 2022, 198 patients were enrolled and evaluated for response with a median follow-up of 601 days (Figure 1). The overall response rates at day 28 were 92.9% in the RUX/steroids combined group and 70.7% in the steroids group, respectively (P = 0.002; Figure 2A). Durable overall response at day 56 was significantly higher in the RUX/steroids combination group than in the steroids alone group (86% vs. 46%; odds ratio,7.69; P <0.001; Figure 2B) The incidences of adverse events were comparable between these two groups. For both groups, the most common grade 3 or worse adverse events were anaemia, thrombocytopenia and gamma-glutamyltransferase increased that were self-limiting. CONCLUSION Addition of ruxolitinb (5 mg/day) to methylprednisolone (1 mg/kg/day) represents an effective first-line therapy for newly diagnosed acute GVHD, which resulted in a high overall response rate and is well tolerated. These findings are an important contribution to the field, showing a safe strategy to incorporate ruxolitinb (5 mg/d) into the standard first line regimen for newly diagnosed acute GVHD internationally. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and safety of ruxolitinib for steroid-refractory graft-versus-host disease: Systematic review and meta-analysis of randomised and non-randomised studies.

BackgroundHematopoietic stem cell transplantation (HSCT) for haematological disorders. Graft-versus-host disease (GVHD), a cause of morbidity and mortality is treated with corticosteroids. However, patients with steroid-refractory GVHD after HSCT have a poor prognosis. Ruxolitinib, a selective Janus kinase inhibitor, is a novel treatment strategy for steroid-refractory GVHD.ObjectivesTo assess the efficacy of ruxolitinib for the treatment of steroid-refractory GVHD and analyse its adverse effects.Study designMeta-analysis.Search methodsRandomised controlled trials (RCTs) and non-RCTs of ruxolitinib-based therapy in patients with steroid-refractory GVHD were found in the Cochrane Central Register of Controlled Trials, EMBASE, PubMed, and Web of Science in March 2021. Outcomes included overall response rate, survival, and adverse effects. The Methodological Index for Non-randomised Studies (MINORS) and the Cochrane collaboration risk-of-bias tool were used to assess methodological quality. Funnel plots, Egger’s test, and the trim and fill method were used to assess publication bias.ResultsIn total, 1470 studies were identified; 19 studies (17 non-RCTs, 2 RCTs) involving 1358 patients met our inclusion criteria. Survival rates at the longest follow-up in non-RCTs, were 57.5% (95% CI 46.9–67.4) and 80.3% (95% CI 69.7–87.9) for acute GVHD (aGVHD) and chronic GVHD (cGVHD), respectively. In non-RCTs, the overall response was 74.9% (95% CI 66.6–81.8, I2 = 49%) in aGVHD and 73.1% (95% CI 62.5–81.6, I2 = 49%) in cGVHD. In aGVHD, the response rates were gastrointestinal, 61.4–90.2%; skin, 52.5–80.6%; and liver, 41.8–71.8%. In cGVHD, the response rates were gastrointestinal, 30.1–70.4%; skin, 30.1–84.4%; lung, 27.0–83.0%; and mouth 3.5–98.1%. In addition, a lower aGVHD grade and moderate cGVHD were associated with a better clinical response. Common adverse events were cytopenia and infectious complications.ConclusionsOur systematic review and meta-analysis indicated that ruxolitinib therapy could be a potentially effective and safe treatment for patients with steroid-refractory GVHD.

020 Topical ruxolitinib for the treatment of lupus-like skin disease in MRL/lpr mice

Cutaneous lupus erythematosus (CLE) is a difficult to treat autoimmune skin disease in need of new therapies. Interferons (IFN) are key inflammatory cytokines in CLE pathogenesis and signal through the JAK-STAT pathway. Oral ruxolitinib, a Janus kinase inhibitor, has been shown to be effective in preventing skin disease in the MRL/lpr mouse model of lupus. Topical ruxolitinib has not been studied in the MRL/lpr model or in human CLE, but has recently been approved for atopic dermatitis. In this study, we sought to determine the efficacy of ruxolitinib 1.5% cream for the prevention of MRL/lpr skin disease.

Real-World Outcomes of Ruxolitinib in Patients With Myelofibrosis Focusing on Red Blood Cell Transfusion: A Multicenter Study From the MPN Working Party of the Korean Society of Hematology

Introduction/BackgroundRuxolitinib is an established treatment for myelofibrosis (MF) that has demonstrated clinical benefit by reducing spleen size and debilitating MF-related symptoms. However, despite the efficacy of ruxolitinib, anemia remains a major adverse event that causes dose modification or discontinuation in real-world practice. Additionally, dependence on red blood cell (RBC) transfusion (TF) is common during treatment; therefore, we explored the outcome of ruxolitinib therapy with a primary focus on RBC TF. Patients/MethodsWe retrospectively reviewed the medical records of 123 MF patients treated with ruxolitinib between January 2012 and April 2020 at eight academic centers in Korea. ResultsAt ruxolitinib initiation, 38 patients (30.9%) underwent ≥ 2 units of RBC TF over 8 weeks. The most common reason for permanent discontinuation was intolerant anemia (10/63, 15.9%). The most common reasons for temporary interruption were nonhematologic toxicity (26/55, 21.1%), anemia (23/55, 18.7%) and thrombocytopenia (13/55, 10.6%). Among the 123 patients in the study, 57 (46.3%), 42 (34.1%), and 40 patients (32.5%) who were receiving or stopped ruxolitinib therapy had a status of RBC TF dependence, long-term RBC TF dependence, or severe RBC TF dependence, respectively. The presence of ≥ 2 units of RBC transfusion over 8 weeks at ruxolitinib initiation was an independent risk factor for persistent RBC TF dependence. ConclusionThe requirement for RBC TF is commonly encountered during treatment of MF with ruxolitinib, particularly among those with pre-existing ≥ 2 units of RBC TF over 8 weeks. For those patients, overcoming the barrier of maintenance TF is demanding.

PB2057: REAL -WORLD OVERALL SURVIVAL OF MYELOFIBROSIS PATIENTS ON RUXOLITINIB – A 6 YEAR ANALYSIS IN ALBANIAN POPULATION

Background: The survival and the outcome of the patients with Myelofibrosis has been prolonged with the use of Janus kinase inhibitors. The long term follow -up of the patients with primary /secondary Myelofibrosis treated with ruxolitinib demonstrated through several clinical trials an improvement in overall survival and in the quality of life of those patients. The use of IPSS risk classification in Myelofibrosis has played an important role in the prognostic stratification of the patients predictioning also the survival. Aims: Our study aims to evaluate the Overall Survival (OS) of all the patients diagnosed with Myelofibrosis and treated with Ruxolitinib from 2015 until january 2022. We also aimed to evaluate the role of IPSS risk group classification in the outcome and survival of MF patients in the Albanian population. Methods: We selected retrospectively all the patients diagnosed in our University Hospital Center “Mother Teresa” in Tirana, Albania with primary and secondary Mielofibrosis who started the treatment with ruxolitinib from 2015 until January 2022. We collected the data from the registries and database of Hematology Clinic based on the first availability of ruxolitinib in Albania since 2015. The data were analysed with SPSS Statistics 25.01. Results: From 2015 until January 2022 we have treated with Ruxolitinib 103 patients diagnosed with Myelofibrosis, 87 (84.5%) were primary MF and 16 (15.5%) were secondary MF. The median age resulted of 64 (range 31 – 88) years old. According to the IPSS risk group classification 1(!%) resulted IPSS Low risk, 21 (20.4%) were IPSS Int-1 risk, 49 (47.6%) resulted IPSS Int-2 risk, and 32(31.1%) were IPSS High risk. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of IPSS, we delineated 4 risk groups with no overlapping in their survival curves and the respective median survivals were 75, 40, 33, and 24 months We classified as IPSS Low risk all the patient with IPSS low and Int-1 risk, and as High risk all the patients with IPSS Int-2 and High risk. We identified 22 (21.4%) low risk patients and 81(78.7%) high risk patients. We compared the median overall survival between the Low risk and High risk MF groups and concluded that median OS in Low risk MF resulted 47 months (95% Confidence interval (CI): 11.2-82.7) and in High risk MF resulted of 32 months (95% Confidence interval (CI): 3,9 – 39,7) with P<0.01. Image:Summary/Conclusion: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm who can develop de novo (primary MF) or secondary in patients with antecedent polycythemia vera (PV) or essential thrombocythemia (ET). The mean age at the moment of diagnosis is 65 year old. In our study me median age at the moment of the diagnosis resulted 64 years old. In our study we compared the median overall survival between the Low risk and High risk MF groups and concluded that median OS in Low risk MF resulted 47 months (95% Confidence interval (CI): 11.2-82.7) and in High risk MF resulted of 32 months (95% Confidence interval (CI): 3,9 – 39,7) with P<0.01Despite the established fact on efficacy of Ruxolitinib in MF patients, real -world data still are limited. Our objective was to analyse the overall survival of our patients with Mielofibrosis under treatment with ruxolitinib, however additional data are needed.

Ruxolitinib combined with prednisone, thalidomide and danazol in patients with myelofibrosis: Results of a pilot study.

Ruxolitinib is a safe and effective therapy of myeloproliferative neoplasm-associated (MPN) myelofibrosis. However, often there are dose reductions and/or therapy interruptions because of therapy-related adverse events (AEs), especially anemia and thrombocytopenia. We previously reported combined therapy with prednisone, thalidomide and danazol (PTD) reversed anemia and thrombocytopenia in people with MPN-associated myelofibrosis. We wondered whether adding PTD to ruxolitinib might mitigate the hematologic AEs and thereby avoid the dose reduction of ruxolitinib and improve the efficacy. To test this hypothesis, we conducted a baseline hemoglobin and platelet concentration assignment prospective observational study in 72 patients comparing 3-month dose adjustment and efficacy of ruxolitinib with (N=53, the study group) or without (N=19, the control group) PTD. According to the platelet counts, the median daily ruxolitinib doses in the study group increased from 30 to 40mg by week 12, whereas in the control group it remained at 30mg (p=0.019). In the study group 35 patients had a hemoglobin increase ≥10g/L compared with no patient receiving ruxolitinib only (p<0.001). Platelet increases >100×10E+9/L were seen in 56.6% and 5.3% of patients in the two groups, respectively (p<0.001). In patients with anemia and thrombocytopenia, 18 patients in the study group had an anemia response at week 12 and 12 had a platelet increase of ≥50×10E+9/L. No patient in the control group achieved either response (p<0.001 and p=0.078). The study group had a more spleen response than the control group (p=0.046). Peripheral edema and transaminase elevation were the main nonhematologic AEs of PTD. These AEs can be alleviated by adjusting the danazol dose. In conclusion, adding PTD to ruxolitinib improved ruxolitinib-associated anemia and thrombocytopenia, and resulted in a higher ruxolitinib dose.

Ruxolitinib suppresses liver fibrosis progression and accelerates fibrosis reversal via selectively targeting Janus kinase 1/2

BackgroundJAK1 and JAK2 have been implicated in fibrosis and cancer as a fibroblast-related marker; however, their role in liver fibrosis has not been elucidated. Here, we aim to determine the effect and underlying mechanism of JAK1/2 inhibition on liver fibrosis and hepatic stellate cells (HSCs) and further explore the therapeutic efficacy of Ruxolitinib, a JAK1/2 selective inhibitor, on preventing and reversing liver fibrosis in mice.MethodsImmunohistochemistry staining of JAK1 and JAK2 were performed on liver tissue in mice with hepatic fibrosis and human liver tissue microarray of liver cirrhosis and liver cancer. LX-2 cells treated with specific siRNA of JAK1 and JAK2 were used to analysis activation, proliferation and migration of HSCs regulated by JAK1/2. The effects of Ruxolitinib (JAK1/2 inhibitor) on liver fibrosis were studied in LX-2 cells and two progressive and reversible fibrosis animal models (carbon tetrachloride (CCl4), Thioacetamide (TAA)).ResultsWe found that JAK1/2 expression was positively correlated with the progression of HCC in humans and the levels of liver fibrosis in mice. Silencing of JAK1/2 down-regulated their downstream signaling and inhibited proliferation, migration, and activation of HSCs in vitro, while Ruxolitinib had similar effects on HSCs. Importantly, Ruxolitinib significantly attenuated fibrosis progression, improved cell damage, and accelerated fibrosis reversal in the liver of mice treated with CCl4 or TAA.ConclusionsJAK1/2 regulates the function of HSCs and plays an essential role in liver fibrosis and HCC development. Its inhibitor, Ruxolitinib, may be an effective drug for preventing and treating liver fibrosis.

Analysis of the effect of gene mutations on the efficacy of ruxolitinib in patients with myelofibrosis based on second-generation sequencing technology

目的评估基因突变对芦可替尼治疗骨髓纤维化（MF）疗效的影响。方法回顾性分析2017年7月至2020年12月服用芦可替尼治疗并应用二代测序技术检测127个血液肿瘤相关基因突变的56例MF患者的临床资料，分析突变基因与芦可替尼疗效的关系。结果①56例患者中，原发性骨髓纤维化（PMF）36例、真性红细胞增多症（PV）后骨髓纤维化（PPV-MF）9例，原发性血小板增多症（ET）后骨髓纤维化（PET-MF）11例。②50例（89.29％）携带驱动基因突变，22例（39.29％）携带基因突变≥3个，29例（51.79％）检出高危基因突变（HMR）。③对于基因突变≥3个的MF患者，芦可替尼仍有较好的改善体质性症状及缩小脾脏的效果（P＝0.001，P<0.001）。与基因突变<3个组比较，基因突变≥3个组停药前持续用药时间（TTF）及无进展生存期（PFS）明显缩短［356（55～1061）d对471.5（50～1270）d，z＝−2.701，P＝0.007；444（91～4109）d对1248.5（91～7061）d，z＝−2.030，P＝0.042］。④与未检出HMR的患者比较，≥2个HMR患者的芦可替尼缩脾效果较差（t＝10.471，P＝0.034），TTF及PFS明显缩短（P<0.001，P＝0.001）。⑤在携带ASXL1、EZH2、SRSF2等附加基因突变患者中，芦可替尼缩脾、症状改善及稳定骨髓纤维化作用较差，携带ASXL1、EZH2突变患者TTF［ASXL1：360（55～1270）d对440（55～1268）d，z＝−3.115，P＝0.002；EZH2：327（55～975）d对404（50～1270）d，z＝−3.219，P＝0.001］及PFS较未携带者明显缩短（ASXL1：457（50～1331）d对574（55～1437）d，z＝−3.219，P＝0.001；EZH2：428（55～1331）d对505（55～1437）d，z＝−2.576，P＝0.008］。结论MF患者携带的基因突变类型、数量以及HMR对芦可替尼疗效有一定影响。

Efficacy and safety of ruxolitinib in patients with myelofibrosis and low platelet count (50 × 109/L to

Background:Thrombocytopenia is a common feature of myelofibrosis (MF), a myeloproliferative neoplasm driven by dysregulated JAK/STAT signaling; however, pivotal trials assessing the efficacy of ruxolitinib (a JAK1/2 inhibitor) excluded MF patients with low platelet counts (<100 × 109/L).Objectives:Determination of the maximum safe starting dose (MSSD) of ruxolitinib was the primary endpoint, with long-term safety and efficacy as secondary and exploratory endpoints, respectively.Design:EXPAND (NCT01317875) was a phase 1b, open-label, ruxolitinib dose-finding study in patients with MF and low platelet counts (50 to <100 × 109/L).Methods:Patients were stratified according to baseline platelet count into stratum 1 (S1, 75 to <100 × 109/L) or stratum 2 (S2, 50 to <75 × 109/L). Previous analyses established the MSSD at 10 mg twice daily (bid); long-term results are reported here.Results:Of 69 enrolled patients, 38 received ruxolitinib at the MSSD (S1, n = 20; S2, n = 18) and are the focus of this analysis. The incidence of adverse events was consistent with the known safety profile of ruxolitinib, with thrombocytopenia (S1, 50%; S2, 78%) and anemia (S1, 55%; S2, 44%) the most frequently reported adverse events and no new or unexpected safety signals. Substantial clinical benefits were observed for patients in both strata: 50% (10/20) and 67% (12/18) of patients in S1 and S2, respectively, achieved a spleen response (defined as ⩾50% reduction in spleen length from baseline) at any time during the study.Conclusion:The final safety and efficacy results from EXPAND support the use of a 10 mg bid starting dose of ruxolitinib in patients with MF and platelet counts 50 to <100 × 109/L.Registration:ClinicalTrials.gov NCT01317875.

Ruxolitinib Therapy during Hematopoietic Cell Transplantation for Myelofibrosis

Background :The beneficial effects of JAK 1/2 inhibitors (JAKi) ruxolitinib in MF patients have led to control of disease related symptoms,but ruxolitinib has been limited by their inability to deplete the malignant stem cell clones. Allogeneic hematopoietic cell transplantation (HCT) is currently the only treatment with proven curative potential for myelofibrosis (MF). Previous research suggested pre-HCT ruxolitinib may improve post-HCT outcome because of ruxolitinib accelerate engraftment, improve graft function, decrease the risk and severity of graft-versus-host disease (GVHD). However,HCT in PMF with higher non-relapse mortality (NRM),In the present study, we aimed to prospectively assess the effects of Rux therapy during HCT period(NCT04526223).Objective Preliminarily investigate the safety and efficacy of ruxolitinib in myelofibrosis patients during the peri-transplantation period.Method: To prospectively analyze the clinical data of 26 patients with myelofibrosis who were used DAC bridge BF as conditioning treatment and treated with ruxolitinib(5mg bid +6d to +60d) during the peri-transplantation period.Results: 26 patients were eligible if they had primary myelofibrosis (PMF) as defined by the 2008 World Health Organization classification or secondary MF as defined by the IWG for Myeloproliferative Neoplasms Research and Treatment criteria and met the criteria for Intermediate-1 (Int-1), Int-2, or high-risk disease by the DIPSS scoring system at the time of enrollment. Patients consenting to treatment with Rux for at least 8 weeks prior to HCT and could receive Rux (5mg bid +6d to +60d) during the peri-transplantation period. DAC bridge BF as Myeloablative regiment, There have been no episodes of cytokine release syndrome and all patients achieved sustained engraftment. Neutrophil reconstitution was obtained in 26 patients with a median time of 15 (10 to 31) d; platelet reconstitution was obtained in 26 patients with a median time of 26(12 to 68) d. Acute GVHD occurred in 26 patients (46.15%) , of which 1(3.8%) were ш°; chronic GVHD occurred in 9 patients (34.6%), 1 patients with extensive chronic GVHD. There patients relapsed and two patients died because of resistance to alvage treatment . With a median follow-up 336 (70-993) days，no patient died of non-relapse mortality (NRM)., overall survival is 92.3% (95% CI: 0.73, 0.97) and DFS is 88.5% (95% CI: 0.63, 0.96) at1 year post-HCT.Conclusion: This study demonstrates that Ruxolitinib therapy during HCT is well tolerated and suggests that during-HCT Rux may improve post-HCT outcome.Keywords: Ruxolitinib;Hematopoietic Cell Transplantation;Myelofibrosis DisclosuresNo relevant conflicts of interest to declare.

Peripheral Blasts Are Associated with Response to Ruxolitinib and Outcome in Patients with Chronic-Phase Myelofibrosis

Peripheral Blasts Are Associated with Response to Ruxolitinib and Outcome in Patients with Chronic-Phase Myelofibrosis

Clinical Efficacy of JAK Inhibitors in Patients with Vexas Syndrome: A Multicenter Retrospective Study

BackgroundVEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is due to a somatically acquired mutation of the E1-ubiquitin ligase UBA1, leading to the expression of a catalytically impaired isoform in myeloid cells. VEXAS syndrome combines severe auto-inflammatory manifestations and is frequently associated with myeloid neoplasia (MN). The outcome of VEXAS is poor, and most patients require high dose corticosteroids to reduce inflammation (Bourbon et al. Blood 2021). Therapeutic options besides steroids are currently limited in those patients. In this multicenter retrospective study, we report some clinical efficacy of JAK inhibitors (JAKi) in VEXAS patients.PatientsWe analyzed retrospectively 24 UBA1 mutated patients (Met41 or previously reported alternative splicing site) treated with JAKi (11 with ruxolitinib (RUXO), 11 with tofacitinib (TOFA), 1 with baricitinib, 1 with upadicitinib) in 7 French, 1 Portugese and 2 US centers. Complete clinical (CCR) and complete biological response (CBR) were defined as complete resolution of clinical symptoms and normalization of inflammation markers (C reactive protein, CRP) respectively. Partial clinical (PCR) and biological (PBR) response were defined by reduction of at least 50% of clinical or inflammation markers, respectively.ResultsAll 24 patients were males with a median age at VEXAS diagnosis of 72 years [range 54-89]. Thirteen had documented myeloid neoplasia (MN) (1 CMML-0, 1 other MDS/MPN, 10 MDS). Clinical manifestations at VEXAS diagnosis include skin involvement (87.5%), arthritis or arthralgia (83.3%), vasculitis (37.5%), fever (75%), ocular manifestations (29.2%) and pulmonary infiltrates (41.6%). IPSS-R was very low/low/intermediate in 8/3/2 cases respectively. Median time between first VEXAS related clinical manifestations and JAKi onset was 2.45 years [0.15-5.45]. Prior to JAKi onset, patients had received a median of 2.5 immunosuppressive/immunomodulatory treatments [range 0-9]. After 1 month, 12/24 (50%) patients had achieved clinical and/or biological response. CCR and CBR was achieved in 7/11 (64%) and 6/11 (54%) patients treated with RUXO, and in 3/13 (23%) and 2/13 (15%) patients treated with other JAKi (figure A). After 3 months, CCR and CBR was 100% and 80% (10 evaluable patients) in the RUXO group as compared to 25% and 25 % in patients treated with other JAKi (8 evaluable patients) (p=0.0036 et 0.0055 respectively, figure B). RUXO efficacy was similar in patients with (n=9) or without (n=2) associated MN. In RUXO treated patients, median CRP and steroid dose reduction was 72.5% [range 21.5- 99.5] and 66.25% [range 0-75] respectively at 3 months. With a median follow-up of 4 months [range 1.4-12], only 1 RUXO treated patient had lost response, whereas median time to next of treatment was 3.4 months with other JAKi (figure C).Of the 13 patients with MN, 7 were RBC transfusion dependent at JAKi onset (6 with RUXO, 1 with other JAKi). Four of 6 patients treated with RUXO achieved RBC transfusion independence at 3 months, but not the patient treated with other JAKi. Regarding safety, severe adverse events were reported in 6 patients: 3 deep vein thrombosis, (2 with TOFA/1 with RUXO), 1 pneumonia (RUXO), 1 enterohemorrhagic E. Coli infection (RUXO), and 1 lethal legionellosis (TOFA)).ConclusionRuxolitinib (and less often other JAK inhibitors used in this study) provides rapid response in most VEXAS patients, allowing in two third of the cases corticosteroid dose reduction/withdrawal and RBC transfusion independence in 4/6 patients with MN who were initially transfusion dependent. Those retrospective preliminary results, with limited follow up, must be interpreted with caution and will be updated at the meeting. The effect of RUXO on VEXAS patients with concomitant MN will soon be studied prospectively in a Groupe Francophone des Myélodysplasies (GFM) clinical study. [Display omitted] DisclosuresGalicier: Novartis Pharma Sas, Sanofi Aventis France: Consultancy; Lilly France, Baxalta France, Sanofi Aventis France Sas: Other: Payments as Speaker for Educational Program; Shire France SA, Janssen-Cilag, Pfizer Sas: Other: Invitation to Congress. Hirsch: Novartis Pharma: Consultancy; Daiichi Sankyo Oncology: Consultancy. Warrington: Eli Lilly: Research Funding; Kiniksa: Research Funding. Fenaux: Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

Ruxolitinib for Steroid-Refractory Acute Graft-Versus-Host Disease: A Single Centre Retrospective Study

BackgroundAcute graft-versus-host disease (aGVHD) is the major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation(allo-HSCT). But only 40% of the patients will respond to first-line therapies Corticosteroids. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, reduces the incidence and severity of GVHD while preserving graft-versus-leukemia effects in preclinical models. The retrospective study evaluated the efficacy of ruxolitinib compared with other second-line therapies for steroid-refractory aGVHD (SR-aGVHD) in a single-center.MethodsA total of 90 patients who developed SR-aGVHD after HSCT were evaluated in this retrospective study.They were treated with ruxolitinib (n=45) or other salvage-therapies (n=45) including MTX, basiliximab, etanercept and MSC at our institution. The primary endpoint was the overall response rate (ORR) at Day 28. Additional endpoints included overall survival (OS), cumulative incidence rates of failure-free survival (FFS), relapse, non-relapse mortality (NRM) and cGVHD. Treatment failure was defined as 1) addition of new systemic therapy for aGVHD, 2) NRM, 3) relapse, 4) progression of hematologic disease. FFS and OS were calculated from the day of starting the use of second-line treatments for aGVHD.ResultsThe median age was 34 years (range 14-69). At the time of enrollment 25 patients had grade Ⅱ disease, 39 with grade Ⅲ disease, 26 with grade IV disease. The skin was involved in 54.4%, lower gastrointestinal (GI) tract in 78.9% and liver in 20.2%. With a median follow-up of 1.33 years, the ORR at day 28 was higher in ruxolitinib group than non-ruxolitinib group (62.2% [95% CI, 47.5%-77.0%] vs. 26.7% [95% CI, 13.2%-40.1%], P=0.001) (Table 1). The 1-year OS was 64.4 % and 45.5% in the two groups, respectively (P=0.0382). Ruxolitinib treatment also improved the 1-year cumulative incidence of FFS (57.8% vs. 26.6%, P=0.002), while the 1-year cumulative incidence of relapse did not differ significantly (9.6% vs. 20.0%, P=0.195). The 1-year cumulative incidence of NRM was lower in the ruxolitinib group than the non-ruxolitinib group (24.4% vs. 45.3%, P=0.023). The 1-year and 3-year cumulative incidence of cGVHD were 17.8% vs. 33.3% and 26.8% vs. 44.4% between the ruxolitinib group and non-ruxolitinib group (P=0.10 and P=0.04).ConclusionsOur study demonstrated that ruxolitinib is effective than other second-line treatments in patients with SR-aGVHD due to the higher response rates and the improvement of prognosis. Furthermore, ruxolitinib could reduce the incidence and severity of chronic GVHD in aGVHD patients.Keywords: Ruxolitinib; Steroid-refractory; Acute graft-versus-host disease; Haploidentical hematopoietic stem cell transplantation [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Subgroup Analysis from a Phase 2 Study of the Efficacy and Safety of Parsaclisib, a Selective PI3Kδ Inhibitor, in Combination with Ruxolitinib in Patients with Myelofibrosis (MF)

Subgroup Analysis from a Phase 2 Study of the Efficacy and Safety of Parsaclisib, a Selective PI3Kδ Inhibitor, in Combination with Ruxolitinib in Patients with Myelofibrosis (MF)

Ruxolitinib for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Bronchiolitis obliterans syndrome (BOS) is an extremely unfavorable chronic GVHD manifestation with limited therapeutic options. Recent small retrospective series and the only prospective randomized trial have demonstrated different response rates (8.6 - 66.7%) in patients with BOS to JAK1/2 inhibitor ruxolitinib (Streiler C. et al. BMT 2020, Zhao Y. et al. Front. Pharmacol. 2021, Zeiser R. et al. NEJM 2021). Here we report a single-center study of the ruxolitinib efficacy for BOS in adults after HSCT.Methods: The study included 52 patients (median age 33 years (18-58), female 48%) diagnosed with BOS according to the NIH (2014) criteria between 2008 and 2020. The median %FEV1 at BOS diagnosis was 41.6% (20.0-74.1). Severe BOS was present in 44% patients. Due to the previous extrapulmonary cGVHD, the vast majority of patients (81%) had a history of various treatment options, including calcineurin inhibitors, systemic steroids, extracorporeal photopheresis (ECP), tyrosine kinase inhibitors (TKIs imatinib, dasatinib) and ruxolitinib. After BOS diagnosis the following treatments were administered: a FAM-like regimen (fluticasone, azithromycin and montelukast) (94%), CNIs (50%), mTOR inhibitor (35%), systemic corticosteroids (52%), ECP (25%) or low-dose rIL-2 (19%) as the first and subsequent lines of therapy. Seventeen patients (33%) received TKIs. A total of 20 BOS patients received ruxolitinib (median dose of 15 mg/day). The remaining 32 patients were included in the control group.The response was assessed by the dynamics of FEV1 according to the NIH scale (2014): partial response (PR, ≥10% increase in FEV1), stabilization (<10% change), progression (≥10% decrease) (n=45), as well as clinically by the degree of dyspnea according to the NIH symptom-based lung score and mMRC scale with PR defined as a decrease in dyspnea by at least 1 point (n=52). The overall survival (OS) was assessed with the Kaplan-Meier method from the moment of BOS diagnosis.Results: At a median follow up of 27 months (5-102) in the ruxolitinib group, 5 (26%) patients achieved PR criteria, while BOS stabilization and progression was observed in 7 (37%) cases each. In the control group, PR, stabilization and progression were documented in 3 (12%, p=0.253), 17 (65%) and 6 (23%) cases respectively (Fig.1). The clinical evaluation of dyspnea also did not reveal statistically significant differences in PR rate: 15% vs 19% according to NIH-CC and 30% vs 31% according to mMRC scale (p = 1.0). Systemic steroids were used less frequently in the ruxolitinib group (35% versus 63%, p = 0.049). As of July 1, 2021, 32 (62%) patients were alive. Twenty patients died due to cGVHD and infectious complications (n = 16, 80%) or underlying disease relapse (n = 4, 20%). As a result, the 5-year OS was 54.4% (95% CI, 36.7-69.1) with no statistically significant differences between ruxolitinib and control groups: 59.1% (95% CI, 25.6-81.6) vs 50.2 (95% CI, 29.5-67.7) (p=0.387).Conclusions: In comparison with the retrospective control group, ruxolitinib showed no significant benefit in FEV1-based and clinical response rate in patients with BOS after HSCT. However, ruxolitinib therapy provides a more frequent systemic steroid-free strategy. These data are consistent with the results of REACH3 (Zeiser R. et al. NEJM 2021). Despite very positive results of ruxolitinib in the general cGVHD population, BOS remains an unsolved problem. Novel approaches are required. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Ruxolitinib for BOS in the settings of cGVHD