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Suliman Al-Fayoumi,1 Taishi Hashiguchi,2 Yuka Shirakata,2 John Mascarenhas,3 Jack W Singer1 1CTI BioPharma, Seattle, WA, USA; 2SMC Laboratories, Tokyo, Japan; 3Tish Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA Background: Fibrotic diseases result from an exuberant response to chronic inflammation. Myelofibrosis is the end result of inflammation in bone, caused by an inflammatory process triggered by production of abnormal myeloid cells driven by mutations affecting the JAK–STAT pathway. Inflammatory cytokine overproduction leads to increased mesenchymal cell proliferation, culminating in fibrosis. Although JAK2 inhibitors, such as the JAK1/2 inhibitor ruxolitinib and the JAK2/FLT3/CSF1R/IRAK1 inhibitor pacritinib suppress abnormal clone expansion in myelofibrosis, ruxolitinib does not appear to prevent or reverse bone-marrow fibrosis in most patients. In two Phase III clinical trials, pacritinib, however, demonstrated improvements in platelet counts and hemoglobin and reductions in transfusion burden in some patients with baseline cytopenias, suggesting it may improve bone-marrow function. Unlike ruxolitinib, pacritinib suppresses signaling through IRAK1, a key control point for inflammatory and fibrotic signaling. Purpose: To investigate potential antifibrotic effects of pacritinib in an animal model of liver fibrosis relevant to the observed course of human disease.Methods: Pacritinib, negative control (vehicle), and positive control (the angiotensin 2-receptor antagonist and PPARγ partial agonist telmisartan) were assessed in the murine Stelic animal model, which mimics the clinically observed progression from hepatic steatosis to nonalcoholic steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Histopathological analysis used hematoxylin and eosin staining. Body and liver weight changes, nonalcoholic fatty-liver disease activity scores, and plasma cytokeratin 18 fragment levels (a biomarker of hepatic necrosis) were measured.Results: Pacritinib-treated mice had significantly (P

BACKGROUND: Pixantrone dimaleate (pixantrone)-a novel aza-anthracenedione-was synthesised to reduce anthracycline-related cardiotoxicity without compromising antitumour efficacy. We aimed to assess the efficacy and safety of pixantrone versus an investigator's choice of a single-agent therapy in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin lymphoma. METHODS: In this phase 3, multicentre, open-label, randomised trial at 66 hospitals in Europe, India, Russia, South America, the UK, and the USA, patients with histologically confirmed aggressive non-Hodgkin lymphoma who had relapsed after two or more previous chemotherapy regimens were randomly assigned (1:1) by an interactive voice response system to treatment with pixantrone dimaleate (85 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle, for up to six cycles) or to a comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, or gemcitabine) given at prespecified standard doses and schedules. Patients were stratified by region, International Prognostic Index score, and previous stem-cell transplantation. Patients and investigators were not masked to treatment assignment; however, an independent assessment panel was masked. The primary endpoint was the proportion of patients with a complete or unconfirmed complete response in the intention-to-treat (ITT) population at the end of treatment. Primary analyses of efficacy were based on the independent assessment panel's data review. The study is registered at ClinicalTrials.gov, number NCT00088530. FINDINGS: The ITT population comprised 70 patients randomly assigned to the pixantrone group and 70 to the comparator. Five patients (two in the pixantrone group and three in the comparator group) dropped out before receiving their study drug. 14 patients (20·0% [95% CI 11·4-31·3]) who received pixantrone achieved a complete or unconfirmed complete response at end of treatment compared with four patients (5·7% [1·6-14·0]) in the comparator group (p = 0·021). The most common grade 3 or 4 adverse events in patients given pixantrone were uncomplicated, non-cumulative neutropenia (28 [41·2%] of 68 patients vs 13 [19·4%] of 67 patients in the comparator group), leucopenia (16 [23·5%] vs five [7·5%]), and thrombocytopenia (eight [11·8%] vs seven [10·4%]). INTERPRETATION: Pixantrone, given as a single-agent salvage therapy in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin lymphoma, is efficacious and tolerable. It could be a treatment option for patients whose aggressive non-Hodgkin lymphoma has failed to respond to at least two previous chemotherapy regimens. FUNDING: Cell Therapeutics, Inc. [ABSTRACT FROM AUTHOR]

PIX306 was a phase 3, randomised, single-blind, multicentre trial conducted in adult patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade 3 who relapsed after ≥1 rituximab-containing regimen and were not eligible for a stem cell transplant. Patients were randomised 1:1 to pixantrone 50 mg/m 2 or gemcitabine 1000 mg/m 2 on days 1, 8 and 15 of a 28-day cycle, combined with rituximab 375 mg/m 2 on day 1, for up to six cycles. Patients were followed for up to 96 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), complete response (CR) rate, overall response rate (ORR) and safety. Overall, 312 patients were randomised (median age 73·0 years). The study did not meet its primary endpoint. Median PFS [95% confidence interval (CI)] was 7·3 months (5·2-8·4) with pixantrone + rituximab (PIX + R) and 6·3 months (4·4-8·1) with gemcitabine + rituximab [GEM + R; hazard ratio (HR): 0·85; 95% CI 0·64-1·14; P = 0·28]. Median OS was 13·3 (10·1-19·8) months with PIX + R and 19·6 (12·4-31·9) months with GEM + R (HR: 1·13; 95% CI 0·83-1·53). ORR was 61·9% and 43·9% respectively and CR rate 35·5% and 21·7%. The incidence of adverse events, including cardiac events, was not statistically significant different between PIX + R and GEM + R., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling is critical to multiple cellular processes, including survival, differentiation, and proliferation. JAK-STAT signaling dysregulation has been noted in inflammatory disorders, and aberrant JAK2 pathway activation has been implicated in myelofibrosis and polycythemia vera. Moreover, 4 therapeutic JAK2 inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) have either been approved or are in advanced clinical development for myelofibrosis. Although all inhibit JAK2, reports indicate that they also inhibit other kinases. Profiling based solely on in vitro potencies is insufficient to predict the observed clinical effects. To provide further translational insights into clinical outcomes, we compared phenotypic biomarker profiles of ruxolitinib, fedratinib, momelotinib, and pacritinib in the BioMAP® Diversity PLUS panel of 12 human primary cell systems designed to recapitulate key aspects of tissue and disease states. Biomarker activity profiles that represent mechanistic signatures for each agent were compared with each other and a database of reference benchmark profiles. At clinically relevant concentrations, these agents had distinct biomarker impacts indicating diverse mechanistic signatures, suggesting divergent clinical effects for each agent. They disparately modulated inflammatory cytokine production and immune function. At clinically relevant concentrations, ruxolitinib had the broadest scope of activities across all 12 cellular systems, whereas pacritinib was more specific for the BT system (modelling T cell-dependent B cell activation) and exhibited the strongest inhibition of sIL-17A, sIL-2, and sIL-6. All 4 agents were antiproliferative to B cells, but ruxolitinib and momelotinib were also antiproliferative to T cells. These differential activities likely reflect distinct secondary pharmacology for these agents known primarily as JAK2 inhibitors. The phenotypic analysis reported herein represents key data on distinct modes-of-action that may provide insights on clinical outcomes reported for these agents. Such translational findings may also inform the development of next-generation molecules with improved efficacy and safety., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JWS is a paid employee of, has a leadership role with, has stock in, has received travel funding from, and has had a consulting/advisory role for CTI BioPharma Corp. SAF is a paid employee of, has stock in, has received travel funding from, and has had a consulting/advisory role for CTI BioPharma Corp.; he is also a paid employee of of Zafgen and Noxopharm. JT is a paid employee of CTI BioPharma Corp.; he has received honoraria, travel expenses, and research funding from CSL Behring, and has also received research funding from Shire. SV and AOM are paid employees of, and have stock in, Eurofins Discovery. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

JAK inhibitors for myelofibrosis (MF) reduce spleen size, control constitutional symptoms, and may improve survival. We studied the clinical characteristics of 548 MF patients treated with JAK inhibitors from 2008 to 2016 to better understand predictors of splenic response. Response was defined as a 50% decrease in spleen size at early (3-4 months on therapy) and late (5-12 months) timepoints after therapy initiation. Early response positively correlated with higher doses of JAK inhibitor, baseline spleen size 5-10 cm, and hemoglobin. Early response negatively correlated with baseline spleen size >20 cm and high WBC. The strongest predictor of late response was whether a patient had a response at the earlier timepoint (OR 8.88). Our response models suggest that clinical factors can be used to predict which patients are more likely to respond to JAK inhibitors, and those who do not achieve an early response, i.e. within 3-4 months, should consider alternative treatments.

Interleukin-1 receptor-associated kinase 1 (IRAK1), an essential mediator of innate immunity and inflammatory responses, is constitutively active in multiple cancers. We evaluated the role of IRAK1 in acute myeloid leukemia (AML) and assessed the inhibitory activity of multikinase inhibitor pacritinib on IRAK1 in AML. We demonstrated that IRAK1 is overexpressed in AML and provides a survival signal to AML cells. Genetic knockdown of IRAK1 in primary AML samples and xenograft model showed a significant reduction in leukemia burden. Kinase profiling indicated pacritinib has potent inhibitory activity against IRAK1. Computational modeling combined with site-directed mutagenesis demonstrated high-affinity binding of pacritinib to the IRAK1 kinase domain. Pacritinib exposure reduced IRAK1 phosphorylation in AML cells. A higher percentage of primary AML samples showed robust sensitivity to pacritinib, which inhibits FLT3, JAK2, and IRAK1, relative to FLT3 inhibitor quizartinib or JAK1/2 inhibitor ruxolitinib, demonstrating the importance of IRAK1 inhibition. Pacritinib inhibited the growth of AML cells harboring a variety of genetic abnormalities not limited to FLT3 and JAK2. Pacritinib treatment reduced AML progenitors in vitro and the leukemia burden in AML xenograft model. Overall, IRAK1 contributes to the survival of leukemic cells, and the suppression of IRAK1 may be beneficial among heterogeneous AML subtypes.

Interleukin-1 receptor-associated kinases (IRAK1, IRAK2, IRAK3 [IRAK-M], and IRAK4) are serine-threonine kinases involved in toll-like receptor and interleukin-1 signaling pathways, through which they regulate innate immunity and inflammation. Evidence exists that IRAKs play key roles in the pathophysiologies of cancers, and metabolic and inflammatory diseases, and that IRAK inhibition has potential therapeutic benefits. Molecules capable of selectively interfering with IRAK function and expression have been reported, paving the way for the clinical evaluation of IRAK inhibition. Herein, we focus on IRAK1, review its structure and physiological roles, and summarize emerging data for IRAK1 inhibitors in preclinical and clinical studies., Competing Interests: CONFLICTS OF INTEREST AF – Speakers bureau (Incyte), travel/accomodations (Incyte, Gilead) AA – Research funding (CTI) SAF – Employment, equity ownership, travel/accomodations (CTI) JM – Consulting/advisory role (CTI), research funding (CTI, Incyte, Janssen, Novartis, Merck, Promedior) QY – Nothing to disclose JS – Employment, leadership role, equity ownership (CTI).

Importance: Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib., Objective: To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia., Design, Setting, and Participants: For this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly., Interventions: Patients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT., Main Outcomes and Measures: Coprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data., Results: Overall, 311 patients (mean [SD] age, 63.70 [9.08] years; 171 men [55%] and 140 women [45%]) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients [18%] vs 2 patients [3%]; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients [25%] vs 10 patients [14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; ≥50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients [31%], 34 patients [32%], 18 patients [18%]), and anemia (28 patients [27%], 23 patients [22%], 14 patients [14%]). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%)., Conclusions and Relevance: In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms., Trial Registration: clinicaltrials.gov Identifier: NCT02055781.

Background: Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias., Methods: This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187., Findings: Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8-28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8-6·7). The most common grade 3-4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study., Interpretation: Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited., Funding: CTI BioPharma Corp., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Monocytes and their progeny are abundant constituents of the tumor microenvironment in lymphoproliferative disorders, including chronic lymphocytic leukemia (CLL). Monocyte-derived cells, including nurse-like cells (NLC) in CLL, promote lymphocyte proliferation and survival, confer resistance to chemotherapy, and are associated with more rapid disease progression. Colony-stimulating factor-1 receptor (CSF-1R) regulates the homeostatic survival of tissue-resident macrophages. Therefore, we sought to determine whether CSF-1R is similarly required for NLC survival., Experimental Design: CSF-1R expression by NLC was examined by flow cytometry and IHC. CSF-1R blocking studies were performed using an antagonistic mAb to examine its role in NLC generation and in CLL survival. A rational search strategy was performed to identify a novel tyrosine kinase inhibitor (TKI) targeting CSF-1R. The influence of TKI-mediated CSF-1R inhibition on NLC and CLL viability was examined., Results: We demonstrated that the generation and survival of NLC in CLL is dependent upon CSF-1R signaling. CSF-1R blockade is associated with significant depletion of NLC and consequently inhibits CLL B-cell survival. We found that the JAK2/FLT3 inhibitor pacritinib suppresses CSF-1R signaling, thereby preventing the generation and survival of NLC and impairs CLL B-cell viability., Conclusions: CSF-1R is a novel therapeutic target that may be exploited in lymphoproliferative disorders, like CLL, that are dependent upon lymphoma-associated macrophages. Clin Cancer Res; 22(24); 6118-28. ©2016 AACR., Competing Interests: Conflict-of-interest disclosure: Jack W. Singer is employed by CTI Biopharma. The remaining authors declare no competing financial interests., (©2016 American Association for Cancer Research.)

Background: Pacritinib (SB1518) is a highly selective kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. This multicenter phase 1/2 study evaluated the maximum tolerated dose (MTD), safety, and clinical activity of pacritinib in patients with myelofibrosis (MF) and other advanced myeloid malignancies., Methods: In the phase 1 dose-escalation part of the study, 43 adults with advanced myeloid malignancies received pacritinib 100 to 600 mg once daily (QD). In the phase 2 part of the study, 31 adults with refractory or intermediate- or high-risk newly diagnosed MF and any degree of cytopenia received pacritinib 400 mg QD. The primary endpoint is a ≥35% reduction in spleen volume at week 24 as determined by magnetic resonance imaging., Results: Five patients (11.6%) experienced a dose-limiting toxicity during cycle 1 of phase 1. The clinical benefit rate was 86.0% (13 patients achieving clinical improvement and 24 patients having stable disease). The MTD was established at 500 mg QD, and the recommended phase 2 dose was 400 mg QD. In phase 2, the primary endpoint was achieved by 23.5% of evaluable patients (4/17), with 47.4% (9/19) achieving a ≥50% spleen length reduction at week 24 as measured by physical examination. At week 24, 38.9% of evaluable patients (7/18) achieved a ≥50% decrease in MF Quality of Life and Symptom Assessment total score. Gastrointestinal toxicities were the most common adverse events and were predominantly grade 1/2 in severity. Grade 3/4 anemia was reported in 5/31 patients and grade 3/4 thrombocytopenia was reported in 3/31 patients. The most frequent AEs considered to be treatment related were diarrhea (28/31), nausea (15/31), vomiting (9/31), and fatigue (4/31). Grade 3 treatment-related AEs were reported in seven patients (22.6%), four of whom had diarrhea. No grade 4/5 treatment-related AEs were reported. No leukopenia, neutropenia, or lymphopenia were reported., Conclusions: Pacritinib was well tolerated and demonstrated clinical activity in MF. The study suggests that pacritinib has unique characteristics, namely a lack of substantial myelosuppression and manageable side effects, making it an attractive target for further evaluation in MF., Trial Registration: Retrospectively registered at www.clinicaltrials.gov (# NCT00719836 ) on July 20, 2008.

This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28-d cycles of 85 mg/m(2) pixantrone dimaleate (equivalent to 50 mg/m(2) in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2-6) with pixantrone and 3 (2-6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression-free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26-1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B-cell NHL in the 3rd or 4th line setting, independently of previous rituximab., (© 2016 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

Pacritinib, potent inhibitor of Janus kinase 2 (JAK2), JAK2V617F, and fms-like receptor tyrosine kinase 3, is in Phase III development in myelofibrosis. Among type 1 inhibitors, pacritinib shows a lack of myelosuppression at doses that both inhibit JAK2/signal transducer and activator of transcription 3 pathway and demonstrate clinical efficacy. To elucidate these mechanisms and identify other disease targets, a kinome analysis screened 439 recombinant kinases at 100 nM pacritinib concentration. For kinases with >50% inhibition, pacritinib was titrated from 1 to 100 nM. JAK2, JAK2V617F, FLT3, colony-stimulating factor 1 receptor, and interleukin-1 receptor-associated kinase 1 achieved half-maximal inhibitory concentrations <50 nM. Pacritinib did not inhibit JAK1 (82% control at 100 nM). Lack of myelosuppression may stem from inhibiting JAK2 without affecting JAK1 and reducing hematopoietic inhibitory cytokines by suppressing interleukin-1 receptor-associated kinase 1 or colony-stimulating factor 1 receptor. The pacritinib kinome suggests therapeutic utility in acute myeloid leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, solid tumors, and inflammatory conditions.

The combination effect of pacritinib, a novel JAK2/FLT3 inhibitor, with erlotinib, the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), on non-small cell lung cancer cells with EGFR activating mutations was investigated. The combination showed synergistic effects on JAK2-mediated EGFR TKI-resistant PC-9/ER3 cells in some cases. The combination markedly suppressed pAKT and pERK although pSTAT3 expression was similar regardless of treatment with the pacritinib, pacritinib + erlotinib, or control in PC-9/ER3 cells. Receptor tyrosine kinase array profiling demonstrated that pacritinib suppressed MET in the PC-9/ER3 cells. The combined treatment of pacritinib and erlotinib in PC-9/ER3 xenografts showed more tumor shrinkage compared with each drug as monotherapy. Western blotting revealed that pMET in tumor samples was inhibited. These results suggest MET suppression by pacritinib may play a role in overcoming the EGFR-TKI resistance mediated by JAK2 in the PC-9/ER3 cells. In conclusion, pacritinib combined with EGFR-TKI might be a potent strategy against JAK2-mediated EGFR-TKI resistance., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Aggressive non-Hodgkin's lymphoma (aNHL) is associated with poor long-term survival after relapse, and treatment is limited by a lack of consensus regarding standard of care. Pixantrone was studied in a randomized trial in patients with relapsed or refractory aNHL who had failed ≥ 2 lines of therapy, demonstrating a significant improvement in complete or unconfirmed complete response and progression-free survival (PFS) compared with investigators' choice of single-agent therapy. The objective of this study was to assess the health economic implications of pixantrone versus current clinical practice (CCP) in the United Kingdom for patients with multiply relapsed or refractory aNHL receiving their third or fourth line of treatment., Methods: A semi-Markov partition model based on overall survival and PFS was developed to evaluate the lifetime clinical and economic impact of treatment of multiply relapsed or refractory aNHL with pixantrone versus CCP. The empirical overall survival and PFS data from the PIX301 trial were extrapolated to a lifetime horizon. Resource use was elicited from clinical experts, and unit costs and utilities were obtained from published sources. The analysis was conducted from the perspective of the United Kingdom's National Health Service and personal social services. Outcomes evaluated were total costs, life-years, quality-adjusted life-years (QALYs), and cost per QALY gained. Deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty around the results., Findings: Pixantrone was estimated to increase life expectancy by a mean of 10.8 months per patient compared with CCP and a mean gain of 0.56 discounted QALYs. The increased health gains were associated with an increase in discounted costs of approximately £18,494 per patient. The incremental cost-effectiveness ratio of pixantrone versus CCP was £33,272 per QALY gained. Sensitivity and scenario analyses suggest that the incremental cost-effectiveness ratio was sensitive to uncertainty in the PFS and overall survival estimates and the utility values associated with each health state., Implications: Pixantrone may be considered both clinically effective and cost-effective for patients with multiply relapsed or refractory aNHL who currently have a high level of unmet need., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)