<i>Trans</i>-vaccenic acid reprograms CD8⁺ T cells and anti-tumour immunity

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP–PKA–CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours

Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies

Abstract 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

Preliminary Results of Fixed-Dose Oral Clofarabine (CLO) In Patients Who Have Failed Hypomethylating Agents for the Treatment of Myelodysplastic Syndromes (MDS)

Abstract Abstract 1869 Background: Three disease-modifying drugs have been approved by the US Food and Drug Administration for first-line therapy of myelodysplastic syndromes (MDS). There is no accepted standard of care for patients (pts) who fail currently approved therapies, particularly the hypomethylating agents. This is the first study designed to determine the appropriate dose, and to assess the efficacy and safety of oral clofarabine (CLO) specifically in higher-risk MDS or secondary acute myeloid leukemia (sAML) pts who failed treatment with a hypomethylating agent. Methods: This phase IIa, open-label, multi-center study of fixed-dose oral CLO (daily × 5 days of a 4-week cycle) enrolled adult pts with pathologically confirmed MDS or sAML (following a history of MDS) who failed up to 2 prior treatment regimens (including ≥ 1 hypomethylating agent) with failure defined as no evidence of response or being progressive under therapy (pts must have received 4 cycles of hypomethylating agents). The primary endpoints were unacceptable drug-related toxicities and overall response rate (ORR) defined as complete remission (CR) + marrow CR + partial remission (PR) + hematological improvement (HI) for MDS pts and CR + CR with incomplete peripheral blood count recovery (CRi) + PR for AML pts. Initially, pts were randomized to receive 55mg or 35mg of oral CLO daily × 5 days. Based on emerging safety data, primarily renal and infectious complications, the protocol was amended and randomization into the 55mg cohort was closed. After review of the initial data for 35mg cohort (n=8), the dose of CLO was reduced to 25mg, with the intent of improving the adverse event profile observed in these pts. Patients could receive a maximum of 8 cycles and response was assessed after cycles 2, 4, 6, and 8. Results: Of the 27 pts enrolled in the study from Sep 2007 - Jan 2010 (55mg [n=4], 35mg [n=8] and 25mg [n=15]) demographic and safety data are available for 22 pts (55mg [n=4], 35mg [n=8] and 25mg [n=10]). Median age was 70 years (range 41–82) with 55% male. IPSS scores at study entry were (median=2.0): 1.5–2.0 (n=16), ≥2.5 (n=6); 8 pts (36%) had intermediate, 6 pts (27%) had poor risk and 8 pts (36%) had favorable cytogenetics; and 11 pts (50%) were transfusion dependent at baseline. Previous treatment with hypomethylating agents included: decitabine (n=10 [45%], azacitidine (n=11 [50%]), or both agents (n=1 [5%]). At study entry 8 pts (36%) had relapsed disease while 13 pts (64%) were refractory and 1 pt (5%) had prior inadequate treatment. Grade 3 or higher hematologic adverse events (regardless of relationship) reported in ≥10% of pts included anemia (54%), thrombocytopenia (41%), neutropenia (36%), febrile neutropenia (32%), leukopenia (32%). Grade 3 or higher non-hematologic toxicities (regardless of relationship) included pneumonia (36%), hypokalemia (27%), hypertension (23%), renal failure (18%), asthenia (14%), fatigue (14%), respiratory distress and/or failure (14%). Serious adverse events (SAE, regardless of relationship) were reported in 77% of pts. The most frequently reported SAE was febrile neutropenia (32%). The 30-day mortality was 50% in the 55 mg cohort (n=2), 13% in the 35 mg cohort (n=1) and 0% in the 25 for an overall 30-day mortality rate of 14%. Pts came off study for the following reasons: adverse event (n=8), progressive disease (n=7), other (n=5). Preliminary efficacy data are available for 16 pts, 35mg (n=6) and 25mg (n=10). Efficacy data are not available for pts enrolled in the 55mg cohort, because no pts completed the required two cycles for efficacy assessment, before the protocol was amended to allow for bone marrow evaluation at the end of cycle 1. The ORR is 31% (5/16 pts). Complete remission was achieved in 1 pt (35mg cohort) and marrow CR in 4 pts (25mg cohort). Among pts with marrow CR, 1 achieved HI-Erythroid and became transfusion independent and 1 pt had unconfirmed HI-Neutrophil. The median number of treatment cycles for the 16 patients with response assessment was 2 with a majority of responses occurring after the first cycle. Conclusions: These preliminary data suggest that fixed-dose oral CLO administered at 25mg daily × 5 days in pts previously treated for MDS with hypomethylating agents has an acceptable response rate and safety profile and warrants continued investigation. Disclosures: Sekeres: Genzyme: Research Funding. Off Label Use: Clofarabine injection (Clolar) is approved by the US FDA for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This trial examines the use of oral clofarabine in patients with MDS. Roboz:Genzyme Corporation: Research Funding. Odenike:Genzyme Corporation: Research Funding. Agura:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Powell:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ewesuedo:Genzyme Corporation: Employment, Equity Ownership. Vasconcelles:Genzyme Corporation: Employment, Equity Ownership. Faderl:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding

Additional file 1: Table S1. of Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies

Dose adjustment and toxicity management guidelines—non-hematologic toxicities. Table S2 Serious adverse events and deathsa occurring in phase 1 component of the study (n = 43). Table S3 Day 1 pharmacokinetics of pacritinib in the phase 1 part of the study (n = 43). Table S4 Day 15 pharmacokinetics of pacritinib in the phase 1 part of the study (n = 43). Table S5 Percent change from baseline at week 24 for individual and total symptom scores from the Myelofibrosis Quality of Life and Symptom Assessment Tool—phase 2 (efficacy evaluable population). Table S6 Median percent change from baseline in hematologic parameters over time in the phase 2 component of the study (n = 31). Table S7 Serious adverse events and deathsa occurring in the phase 2 component of the study (n = 31). Figure S1 Mean concentration-time profiles of pacritinib when dosed as hydrochloride and citrate salts at a dose of 200 mg. (DOC 296 kb

Cellular Composition and 5hmC Signature Predict the Treatment Response of AML Patients to Azacitidine Combined with Chemotherapy

Abstract Azacitidine (AZA) is a DNA methyltransferase inhibitor and epigenetic modulator that can be an effective agent in combination with chemotherapy for patients with high‐risk acute myeloid leukemia (AML). However, biological factors driving the therapeutic response of such hypomethylating agent (HMA)‐based therapies remain unknown. Herein, the transcriptome and/or genome‐wide 5‐hydroxymethylcytosine (5hmC) is characterized for 41 patients with high‐risk AML from a phase 1 clinical trial treated with AZA epigenetic priming followed by high‐dose cytarabine and mitoxantrone (AZA‐HiDAC‐Mito). Digital cytometry reveals that responders have elevated Granulocyte‐macrophage‐progenitor‐like (GMP‐like) malignant cells displaying an active cell cycle program. Moreover, the enrichment of natural killer (NK) cells predicts a favorable outcome in patients receiving AZA‐HiDAC‐Mito therapy or other AZA‐based therapies. Comparing 5hmC profiles before and after five‐day treatment of AZA shows that AZA exposure induces dose‐dependent 5hmC changes, in which the magnitude correlates with overall survival (p = 0.015). An extreme gradient boosting (XGBoost) machine learning model is developed to predict the treatment response based on 5hmC levels of 11 genes, achieving an area under the curve (AUC) of 0.860. These results suggest that cellular composition markedly impacts the treatment response, and showcase the prospect of 5hmC signatures in predicting the outcomes of HMA‐based therapies in AML