Ruxolitinib In Patients Research Articles

S197: NAVITOCLAX PLUS RUXOLITINIB IN JAK INHIBITOR-NAÏVE PATIENTS WITH MYELOFIBROSIS: PRELIMINARY SAFETY AND EFFICACY IN A MULTICENTER, OPEN-LABEL PHASE 2 STUDY

Background: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients with myelofibrosis (MF) that improves disease symptoms in approximately 40% of patients with limited impact on disease biology. Many patients lose response over time, highlighting an unmet need for novel therapies. Navitoclax is a first-in-class, oral, small molecule that binds with high affinity to BCL-XL and BCL-2, key pro-survival proteins in the apoptotic pathway, and has a synergistic effect when used in combination with JAK inhibitors to enhance malignant cell death in MF. This ongoing, open-label, multicenter, phase II trial (NCT03222609) is evaluating the efficacy and safety of navitoclax with or without ruxolitinib in patients with MF and previously published data suggest clinically meaningful activity of the combination in patients with prior ruxolitinib failure (Pemmaraju et al., ASH 2020). Here, we report results from patients who were JAK inhibitor-naïve and treated with navitoclax and ruxolitinib combination therapy. Aims: N/A Methods: Enrolled patients had primary or secondary MF with splenomegaly (DIPSS ≥ Intermediate-1) and did not receive prior therapy with JAK-2 or bromodomain and extraterminal motif (BET) inhibitors. Patients initiated navitoclax at 100 mg once per day (QD) or 200 mg QD if baseline platelet count was ≤150 × 109/L or >150 × 109/L, respectively. Ruxolitinib was orally administered twice daily at a starting dose based on baseline platelet count as per the local ruxolitinib label. The primary endpoint was spleen volume reduction of ≥35% (SVR35) from baseline at week 24. SVR35 was assessed at weeks 12, 24, and once every 24 weeks thereafter. Key secondary endpoints were ≥50% reduction in total symptom score (TSS50), bone marrow fibrosis reduction, and anemia response (per International Working Group criteria). Adverse events (AEs) were monitored throughout the study. Results: As of Oct 04, 2021, 32 patients received navitoclax plus ruxolitinib. The median duration of follow-up was 6.1 (range, 1.9 to 18.6) months. Twenty-eight (88%) patients received a navitoclax dose of 200 mg, and 4 (13%) received 100 mg OD. The median age was 69 years (range, 44 to 83), median spleen volume was 1889.08 cm3 (range, 645.6 to 7339.6), and 38% had at least 1 prior line of therapy. The median navitoclax and ruxolitinib exposures were 24.1 (range, 5.1 to 80.9) and 24.1 (5.1 to 80.9) weeks, respectively. Thirty-one (97%) patients experienced ≥1 AE, 25 (78%) had Grade ≥3 AEs, and 6 (19%) had serious AEs. The most frequent Grade ≥3 AEs were anemia (34%), thrombocytopenia (31%), and neutropenia (19%). Three (9%) and 2 (6%) patients experienced an AE that led to navitoclax and ruxolitinib discontinuation, respectively, and 2 (6%; 1 progressive disease, 1 cardiac disorder unrelated to navitoclax) AEs led to death ≤30 days after the last dose of navitoclax. SVR35 was achieved by 52% of evaluable patients at week 24 (SVR35 in DIPSS Intermediate-2, 50%; High-risk, 33%) and by 76% at any time on the study (Table). The median time to first SVR35 was 12.1 (range, 11 to 47) weeks. Image:Summary/Conclusion: The combination of navitoclax and ruxolitinib was well tolerated and demonstrated early and robust reductions in spleen volume, anemia, and BM fibrosis in patients without prior JAK-2 inhibitor exposure. SVR35, anemia, and bone marrow fibrosis improved over time.

Ruxolitinib in patients with polycythemia vera with hydroxyurea resistance or intolerance

The clinical triumvirate of polycythemia vera include disease-related symptoms, vascular events, and transformation to myelofibrosis or blast phase. However, regulatory approval for polycythemia vera directed therapy is dependent on the achievement of a complete hematological response or phlebotomy associated goals (short-term clinical trial endpoints) that might not affect the most clinically relevant outcome measures of thrombosis, progression, and overall survival due to longer time to event, and lower incidence, which make polycythemia vera a challenging disease to evaluate in prospective trials.

Making a case for disease-modifying agents in myelofibrosis

JAK inhibitors are currently the cornerstone of non-transplantation treatment strategies in intermediate and high-risk myelofibrosis. 1 National Comprehensive Cancer NetworkNCCN clinical practice guidelines in oncology — myeloproliferative neoplasms, version 2. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdfDate: 2022 Date accessed: May 9, 2022 Google Scholar Ruxolitinib, the first approved JAK inhibitor in this setting, rapidly reduces splenomegaly and controls symptoms in a substantial proportion of patients, 2 Harrison C Kiladjian J-J Al-Ali HK et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012; 366: 787-798 Crossref PubMed Scopus (1280) Google Scholar , 3 Verstovsek S Mesa RA Gotlib J et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012; 366: 799-807 Crossref PubMed Scopus (1407) Google Scholar alongside conferring a survival benefit that seems to occur in the absence of a consistent disease-modifying ability. 4 Harrison CN Vannucchi AM Kiladjian JJ et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016; 30: 1701-1707 Crossref PubMed Scopus (284) Google Scholar However, high discontinuation rates by the third year of treatment and dismal outcomes of patients after stopping ruxolitinib 5 Newberry KJ Patel K Masarova L et al. Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation. Blood. 2017; 130: 1125-1131 Crossref PubMed Scopus (135) Google Scholar underline the need for effective second-line treatments and, ideally, for improved front-line options. Fedratinib and pacritinib, two JAK inhibitors recently approved by the US Food and Drug Administration (FDA) for the treatment of myelofibrosis regardless of previous JAK inhibitor exposure, will probably only partially fill the second-line therapeutic gap. 6 Harrison CN Schaap N Vannucchi AM et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017; 4: e317-e324 Summary Full Text Full Text PDF PubMed Scopus (168) Google Scholar , 7 Mascarenhas J Hoffman R Talpaz M et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018; 4: 652-659 Crossref PubMed Scopus (140) Google Scholar Multiple molecules are currently being tested, either alone or in combination, in patients with previous exposure to JAK inhibitors, and some of these experimental drugs are in more advanced phases of development. The appendix describes selected (ie, non-JAK inhibitor monotherapy), ongoing second-line phase 3 trials in patients with myelofibrosis, and highlights the heterogeneity of inclusion criteria with respect to previous JAK inhibitor exposure, deriving from the absence of both reliable predictive biomarkers and of well-defined response criteria to JAK inhibitors associated with clinically relevant endpoints. The recent “Response to Ruxolitinib After 6 Months” model 8 Maffioli M Mora B Ball S et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022; 6: 1855-1864 Crossref PubMed Scopus (8) Google Scholar identifies predictors of survival after 6 months of ruxolitinib treatment, including spleen length reduction, red blood cell transfusion requirement, and ruxolitinib dose intensity, and will hopefully facilitate the harmonisation of second-line trial inclusion criteria. Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 studyThese biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy. Full-Text PDF

Addition of navitoclax to ongoing ruxolitinib treatment in patients with myelofibrosis (REFINE): a post-hoc analysis of molecular biomarkers in a phase 2 study

Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVR35) and reduced symptoms in patients with myelofibrosis no longer benefiting from ruxolitinib. Here, we report the exploratory post-hoc biomarker analyses from cohort 1a. REFINE is a phase 2, multicentre, open-label trial designed to assess the activity and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Cohort 1a of the study included patients who had disease progression or suboptimal response on stable ruxolitinib monotherapy. Patients in cohort 1a, who had previously received ruxolitinib for 12 weeks or more, continued their current stable dose, and navitoclax was orally administered at 50 mg per day and escalated weekly to a maximum of 300 mg per day, based on tolerability. The primary activity endpoint was SVR35 at week 24 from baseline. Secondary endpoints were a 50% or greater reduction in total symptom score (TSS50) at week 24 from baseline as measured by the Myelofibrosis Symptom Assessment Form (version 4.0), anaemia response assessed according to International Working Group-Myeloproliferative Neoplasms Research and European LeukemiaNet criteria, and change in grade of bone marrow fibrosis according to the European consensus grading system; and exploratory endpoints included overall survival and changes in inflammatory cytokines. Exploratory analyses investigated potential prognostic biomarkers of the benefit of navitoclax-based combination treatment, including bone marrow fibrosis and variant allele frequency, in patients with a suboptimal response to ruxolitinib. This study is registered with ClinicalTrials.gov (NCT03222609) and is ongoing. Between Nov 14, 2017, and April 10, 2019, 34 patients in cohort 1a received at least one dose of navitoclax plus ruxolitinib. 23 (68%) patients were male, with 32 (94%) being White. At data cutoff (May 6, 2021), the median follow-up for survivors was 26·2 months (IQR 21·9-32·3). 33 patients were evaluable for biomarker analyses; 19 (58%) had high molecular risk mutations. Five (31%) of 16 patients had SVR35 at week 24 in the high molecular risk group, as did four (31%) of 13 in the non-high molecular risk group. Four (36%) of 11 patients in the high molecular risk group had TSS50 at week 24 compared with two (25%) of eight in the non-high molecular risk group; seven (39%) of 18 in the high molecular risk group had an improvement in fibrosis by at least one grade compared with five (36%) of 14 in the non-high molecular risk group; and four (28%) of 14 had reductions in variant allele frequency of 20% or greater in the high molecular risk group compared with two (17%) of 12 in the non-high molecular risk group. Patients with improvements in fibrosis of one grade or more and a reduction of 20% of more in variant allele frequency had improved overall survival (median overall survival not reached) compared with those who did not achieve fibrosis improvement or a reduction in variant allele frequency (median overall survival 28·5 months [95% CI 19·6-not estimable] for both), suggesting potential disease modification. Additionally, changes in concentrations of β-2-microglobulin (week 12: r=0·57; week 24: r=0·57), TIMP metallopeptidase inhibitor 1 (week 12: r=0·47; week 24: r=0·54), TNF receptor type II (r=0·55; week 24: r=0·40), and vascular cell adhesion molecule-1 (r=0·58; week 24: r=0·50) were positively associated with changes in spleen volume. These biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy. AbbVie.

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。

A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis

AbstractRuxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose <20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P = .03), (2) palpable spleen length reduction from baseline ≤30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P = .0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P = .07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P = .02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.

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.

Addition of Navitoclax to Ongoing Ruxolitinib for Patients with Myelofibrosis: Subgroup Analysis of Molecular Biomarkers in the Phase 2 Study (REFINE)

Addition of Navitoclax to Ongoing Ruxolitinib for Patients with Myelofibrosis: Subgroup Analysis of Molecular Biomarkers in the Phase 2 Study (REFINE)

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)

A Retrospective Head-to-Head Comparison between Pacritinib and Ruxolitinib in Patients with Myelofibrosis and Moderate to Severe Thrombocytopenia

A Retrospective Head-to-Head Comparison between Pacritinib and Ruxolitinib in Patients with Myelofibrosis and Moderate to Severe Thrombocytopenia

Indirect Treatment Comparisons of the Effect of Fedratinib Versus Navitoclax Plus Ruxolitinib on Spleen Volume and Symptoms in Patients with Myelofibrosis and Prior Ruxolitinib Treatment

▪Introduction: Myelofibrosis (MF) is a serious and life-threatening myeloproliferative neoplasm that is characterized by stem cell-derived clonal myeloproliferation, bone marrow fibrosis, anemia and splenomegaly. The Janus kinase (JAK) pathway is the critical pathway in its pathogenesis. Ruxolitinib, a JAK1/2 inhibitor, was the first US Food and Drug Administration (FDA)-approved therapy for intermediate- and high-risk MF. However, there remains a high unmet need for alternative treatment options for patients who discontinue (41.1%-60.9% of patients discontinue after 3 months and 48.4%-73.0% after 6 months) (Fonseca E, et al. Blood 2013;122. Abstract 2833) or are no longer responding to ruxolitinib therapy (Bose P, Verstovsek S. Leuk Lymphoma 2020;61:1797-1809). The efficacy and safety of fedratinib, a JAK2 inhibitor approved by the FDA in 2019, was investigated post ruxolitinib in the single-arm trial JAKARTA-2 (NCT01523171) (Harrison CN, et al. Lancet Haematol 2017;4:e317-324; Harrison CN, et al. Am J Hematol 2020;95:594-603). New clinical evidence for treating a similar population with navitoclax plus ruxolitinib was presented at the American Society of Hematology Annual Meeting in 2020 (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50). The efficacy of fedratinib relative to navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib has not yet been evaluated.Objective: To explore the comparative efficacy of fedratinib versus navitoclax plus ruxolitinib in patients with MF previously treated with ruxolitinib for the 2 binary endpoints of ≥ 35% spleen volume reduction (SVR) from baseline to the end of cycle 6 (EOC6; 24 weeks) and ≥ 50% reduction in total symptom score (TSS) from baseline to the EOC6.Methods: Evidence for fedratinib was informed by JAKARTA-2 patient-level data, and evidence for navitoclax plus ruxolitinib was informed by known reported evidence from the REFINE study (NCT03222609) (Pemmaraju N, et al. Blood 2020;136(suppl 1):49-50; Harrison CN, et al. J Clin Oncol 2019;37 (suppl 15). Abstract 7057). The suitability of these studies for indirect treatment comparison (ITC) was assessed by considering the comparability of study design, population, intervention, and outcomes. Given the lack of a common comparator in the identified studies, unanchored ITCs were performed for SVR using matching-adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) methods. Univariable and multivariable regression models were used to identify potential prognostic factors to adjust for in the ITCs. Additionally, all reported Dynamic International Prognostic Scoring System (DIPSS)-Plus criteria were considered. Where sample size was too small, response rates (number of responders divided by total number of patients) were compared naively.Results: A subgroup of 58 JAKARTA-2 patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 and intermediate-2 or high-risk disease most closely aligned with the REFINE population was used in the analyses. Baseline mean platelet count was similar between subgroups. Across the analyses performed, results suggested fedratinib consistently increased the odds/risk of a spleen response compared with navitoclax plus ruxolitinib (Table). The MAIC, matching on ECOG PS, suggested that the odds of having an SVR for patients in the fedratinib group was 2.19 times (95% confidence interval [CI], 1.26 to 3.66) that of the navitoclax plus ruxolitinib group, and the risk of having an SVR for patients in the fedratinib group was 17.59% higher (95% CI, −2.14 to 36.97). The results from the MAIC that additionally matched on all possible DIPSS-Plus criteria (age, hemoglobin, and platelet count) were consistent. Results from the 2 methods (MAIC and STC) were also consistent. For TSS reduction, the sample size (N = 20) in REFINE was considered too small to perform a meaningful ITC; however, the absolute response rates for TSS reduction were similar across the 2 groups (29% [16/56] in the fedratinib group and 30% [6/20] in the navitoclax plus ruxolitinib group).Conclusion: In the population of patients with MF previously treated with ruxolitinib, these analyses suggest treatment with fedratinib was associated with a greater proportion of patients achieving a spleen response compared with navitoclax plus ruxolitinib. Limited data were available for comparison of TSS. [Display omitted] DisclosuresAbraham: Bristol Myers Squibb: Current Employment. Liao: BMS: Consultancy. Chevli: Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Smith: Sarah Smith is an employee of BresMed. BresMed received consultancy fees from BMS/Celgene for the reasearch in this abstract. She did not receive direct payment as a result of this work outside of her normal salary payments.: Consultancy.

Precision Co-Targeting of the Thymic Stromal Lymphopoietin Receptor in Childhood CRLF2-Rearranged Acute Lymphoblastic Leukemia

Introduction : Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is associated with high rates of chemoresistance and relapse. CRLF2 (cytokine receptor-like factor 2) rearrangements occur in 50% of Ph-like and 60% of Down Syndrome (DS)-associated ALL and induce constitutive JAK/STAT and other kinase signaling. Current clinical trials are studying chemotherapy with the JAK inhibitor ruxolitinib in patients with CRLF2-rearranged Ph-like ALL, but results are not yet known. While chimeric antigen receptor T-cell (CART) immunotherapies have induced remarkable remissions in children with relapsed/refractory B-ALL, approximately 50% of CD19CART-treated patients will relapse again, many with CD19 antigen loss. New therapies are needed to prevent relapse and overcome immunotherapeutic resistance.Methods : We previously developed CAR T cells targeting the thymic stromal lymphopoietin receptor (TSLPR; encoded by CRLF2) and demonstrated potent preclinical activity in Ph-like ALL models (Qin Blood 2015), which has led to a soon-to-open phase 1 clinical trial for patients with relapsed/refractory CRLF2-overexpressing ALL. In the current preclinical studies, we hypothesized that combinatorial targeting with bispecific TSLPRxCD19CART or TSLPRxCD22CART (Ross Cancer Res 2020) or with TSLPRCART + ruxolitinib will have superior activity against CRLF2-rearranged Ph-like and DS-ALL.Results : TSLPRCART treatment of CRLF2-rearranged ALL cell line (n=1) and patient-derived xenograft (PDX) models potently inhibited leukemia proliferation in vitro and in vivo and induced long-term ‘cure’ of xenograft mice. However, co-administration of TSLPRCART + ruxolitinib markedly diminished in vivo T cell numbers, blunted cytokine production, and facilitated leukemia relapse, which could be abrogated by delaying ruxolitinib. Importantly, ruxolitinib co-treatment prevented severe TSLPRCART-induced cytokine release syndrome (CRS) and animal death. Interestingly, ruxolitinib withdrawal led to return of T-cell functionality with re-detection of TSLPRCART in peripheral blood, induction of IFN-γ production, and leukemia clearance upon CRLF2+ ALL rechallenge (Figure 1).Conclusions: In these preclinical studies, we report potent activity of TSLPRCART in cell line (n=1) and PDX models of childhood CRLF2-rearranged Ph-like ALL (n=2) and DS-ALL (n=2) and, interestingly, deleterious effects of concomitant JAK inhibition upon CAR T cell functionality. We demonstrated that ruxolitinib co-administration impaired in vivo TSLPRCART-induced ALL cell killing but was also beneficial in protection against life-threatening cytokine release syndrome in co-treated animals. Importantly, TSLPRCART was not eliminated, only suppressed, by JAKi co-treatment with restoration of T cell functionality upon ruxolitinib removal and/or leukemia relapse/rechallenge studies. Ongoing studies are defining optimal TSLPRCART + ruxolitinib sequence(s) to maximize both anti-leukemia efficacy and potential CRS mitigation, as well as assessing in vivo efficacy of bispecific TSLPRCARTs in CRLF2-R Ph-like ALL and DS-ALL PDX models for future translation and clinical evaluation in next-generation trials. [Display omitted] DisclosuresFry: ElevateBio: Research Funding; Sana Biotechnology: Current Employment, Current equity holder in publicly-traded company. Tasian: Aleta Biotherapeutics: Consultancy; Kura Oncology: Consultancy; Gilead Sciences: Research Funding; Incyte Corporation: Research Funding.

Baseline Serum Ferritin Differentially Predicts W24 Transfusion Independence Response for Momelotinib and Ruxolitinib in Patients with Myelofibrosis

Baseline Serum Ferritin Differentially Predicts W24 Transfusion Independence Response for Momelotinib and Ruxolitinib in Patients with Myelofibrosis

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

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

Clinical Efficacy of Ruxolitinib in Patients with Myelofibrosis: A Nationwide Population-Based Study in Korea.

Previous studies have reported the survival benefit after ruxolitinib treatment in patients with myelofibrosis (MF). However, population-based data of its efficacy are limited. We analyzed the effects of ruxolitinib in MF patients with data from the Korean National Health Insurance Database. In total, 1199 patients diagnosed with MF from January 2011 to December 2017 were identified, of which 731 were included in this study. Patients who received ruxolitinib (n = 224) were matched with those who did not receive the drug (n = 507) using the 1:1 greedy algorithm. Propensity scores were formulated using five variables: age, sex, previous history of arterial/venous thrombosis, and red blood cell (RBC) or platelet (PLT) transfusion dependence at the time of diagnosis. Cox regression analysis for overall survival (OS) revealed that ruxolitinib treatment (hazard ratio (HR), 0.67; p = 0.017) was significantly related to superior survival. In the multivariable analysis for OS, older age (HR, 1.07; p < 0.001), male sex (HR, 1.94; p = 0.021), and RBC (HR, 3.72; p < 0.001) or PLT (HR, 9.58; p = 0.001) transfusion dependence were significantly associated with poor survival, although type of MF did not significantly affect survival. Considering evidence supporting these results remains weak, further studies on the efficacy of ruxolitinib in other populations are needed.

A 10-year retrospective cohort study of ruxolitinib and association with nonmelanoma skin cancer in patients with polycythemia vera and myelofibrosis

Clinical trials report occurrence of nonmelanoma skin cancers (NMSCs) with ruxolitinib in patients with polycythemia vera (PV) or myelofibrosis (MF); however, the level of risk and effect of covariates are not known in the real-world setting. To systematically assess the risk of developing NMSC after ruxolitinib exposure in patients with PV or MF. A 10-year retrospective cohort of patients with PV or MF at Stanford Medical Center was identified and matched according to age, gender, race, Charlson Comorbidity Index, disease diagnosis, and follow-up time. The main outcome measure was hazard ratio (HR) for NMSC (comprised of basal cell carcinoma and squamous cell carcinoma [SCC]) after ruxolitinib exposure, adjusted for covariates. The study cohort consisted of 564 patients (188 exposed to ruxolitinib for at least 4weeks, 376 unexposed). Ruxolitinib-exposed patients with PV or MF had an adjusted NMSC HR of 2.69 (95% CI, 1.03-7.02). In particular, ruxolitinib exposure was associated with SCC (HR, 3.24; 95% CI, 1.45-7.22), with non-Janus kinase 2-mutated patients showing even higher SCC risk (HR, 7.40; 95% CI, 2.54-21.63). Retrospective design. Our real-world results indicate that SCC risk is increased in patients with PV or MF taking ruxolitinib and support consideration of skin cancer monitoring.

JAK Inhibition with Ruxolitinib in Patients with COVID-19 and Severe Pneumonia: Multicenter Clinical Experience from a Compassionate Use Program in Italy.

Jak inhibitors are potent anti-inflammatory drugs that have the potential to dampen the hyperactive inflammatory response associated with severe COVID-19. We reviewed the clinical outcomes of 218 patients with COVID-19 hospitalized for severe pneumonia and treated with ruxolitinib through a compassionate use program. Data on the duration of treatment; outcomes at 4, 7, 14, and 28 days; oxygen support requirements; clinical status; and laboratory parameters were retrospectively collected. Overall, according to the physician evaluation, 66.5% of patients showed improvement at follow-up; of these, 83.5% showed improvement by day 7. Oxygen support status also showed improvement, and by day 7, 21.6% of patients were on ambient air, compared with 1.4% at baseline, which increased to 48.2% by day 28. Significant decreases in C-reactive protein and increases in the lymphocyte total count were already observed by day 4, which seemed to correlate with a positive outcome. At the end of the observation period, 87.2% of patients were alive. No unexpected safety findings were observed, and grade 3/4 adverse events were reported in 6.9% of patients.

Ruxolitinib in severe COVID-19 Results of a multicenter, prospective, single arm, open-label clinical study to investigate the efficacy and safety of ruxolitinib in patients with COVID-19 and severe acute respiratory syndrome

Ruxolitinib in severe COVID-19 Results of a multicenter, prospective, single arm, open-label clinical study to investigate the efficacy and safety of ruxolitinib in patients with COVID-19 and severe acute respiratory syndrome

Hypoxemic Respiratory Failure Following Ruxolitinib Discontinuation in Allogeneic Hematopoietic Cell Transplantation Recipients.

Ruxolitinib, a selective inhibitor of Janus kinases 1 and 2, is increasingly being used in allogeneic hematopoietic cell transplantation (HCT) recipients following its approval by the U.S. Food and Drug Administration for the treatment of steroid-refractory acute graft-versus-host disease. Although there is extensive experience using ruxolitinib for patients with myeloproliferative neoplasms, the biologic effects and clinical implications of its dosing, tapering, and discontinuation for allogeneic HCT recipients are incompletely characterized. We describe three allogeneic HCT recipients who developed acute hypoxemic respiratory failure within 3 months of ruxolitinib discontinuation. Radiographic findings included marked bilateral ground-glass opacities. Systemic corticosteroids and reinitiation of ruxolitinib resulted in rapid clinical improvement in all three patients. All three patients achieved a significant clinical response, with decrease in oxygen requirement and improvement in radiographic changes. Given the increasing use of ruxolitinib in allogeneic HCT recipients, there is significant impetus to characterize the biologic and clinical effects resulting from discontinuation of ruxolitinib, to better tailor treatment plans and prevent potential adverse effects.

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

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