Ye Yuan

Treatment with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL1 is currently the standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP). In this study, we present results of the ENESTchina (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-China) that was conducted to investigate nilotinib 300 mg twice daily vs imatinib 400 mg once daily in a Chinese population. ENESTchina met its primary end point with a statistically significant higher rate of major molecular response (MMR; BCR-ABL1 ≤0.1% on the International Scale) at 12 months in the nilotinib arm vs the imatinib arm (52.2% vs 27.8%; P < .0001), and MMR rates remained higher with nilotinib vs imatinib throughout the follow-up period. Rates of complete cytogenetic response (0% Philadelphia chromosome-positive [Ph+] metaphases by standard cytogenetics) were comparable and ≥80% by 24 months in both arms. The estimated rate of freedom from progression to accelerated phase/blast crisis at 24 months was 95.4% in each arm. The safety profiles of both drugs were similar to those from previous studies. In conclusion, rates of MMR at 12 months were superior with nilotinib vs imatinib in Chinese patients with newly diagnosed Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01275196.

Lung cancer stands as the leading cause of mortality among all types of tumors, with over 40% of cases being lung adenocarcinoma (LUAD). Family with sequence similarity 83 member A (FAM83A) emerges as a notable focus due to its frequent overexpression in LUAD. Despite this, the precise role of FAM83A remains elusive. This study addresses this gap by unveiling the crucial involvement of FAM83A in maintaining the cancer stem cell-like (CSC-like) phenotype of LUAD. Through a global proteomics analysis, the study identifies human epidermal growth factor receptor 2 (HER2 or ErbB2) as a crucial target of FAM83A. Mechanistically, FAM83A facilitated ErbB2 expression at the posttranslational modification level via the E3 ubiquitin ligase STUB1 (STIP1-homologous U-Box containing protein 1). More importantly, the interaction between FAM83A and ErbB2 at Arg241 promotes calcineurin (CALN)-mediated dephosphorylation of ErbB2, followed by inhibition of STUB1-mediated ubiquitin-proteasomal ErbB2 degradation. The maintenance of the CSC-like phenotype by FAM83A, achieved through the posttranslational regulation of ErbB2, offers valuable insights for identifying potential therapeutic targets for LUAD.

OBJECTIVE: To assess complete remission (CR), the overall survival (OS), event-free survival (EFS) and adverse events of newly diagnosed acute promyelocytic leukemia (APL) with homoharringtonine (HHT) plus ATRA, to evaluate the therapeutic effect by comparing HHT plus ATRA with daunorubicin plus ATRA as induction regimen (HA with DA as post-remission regimen). METHODS: 115 APL patients (54 in HHT group, 61 in DNR group) after long-term follow-up were enrolled in the analyses of clinical feature, chromosome karyotype, molecular biology, OS and EFS. RESULTS: The overall CR of 115 patients was 100%, the median interval to achieve hematological CR was 32 (22 - 43) days, the overall median OS was within 0.23 - 77.34 months, median EFS was within 0.23 - 77.34 months. 3-year OS rate was 93%, 5-year OS rate 93%, 3-year EFS rate 85% and 5-year RFS rate 75% respectively. Converting to PML-RARα PCR-negative after the induction therapy in the HHT and DNR group was 31.3% and 15.5% respectively, at the end of 1 consolidation course was 68.6% and 77.6% respectively, while the remaining 4 patients tested PML-RARα PCR-negative at the end of 2 consolidation courses in the DNR group. While both groups obtained the identical molecular biology relapse rate (9.8% and 8.6%, respectively). Survival analysis indicated that no significant difference was found on OS and EFS between the HHT group and the DNR group (P = 0.206 and 0.506). 5-year OS rate was 87% for the HHT group while 98% for the DNR group, 5-years EFS rate was 80% for the HHT group while 71% for the DNR group. And the risk group was not the factor affecting OS and EFS (P = 0.615 and 0.416). Grade 2 fever in the HHT group was less than in the DNR group during induction therapy. And no difference was found in terms of liver dysfunction, renal dysfunction, cardiac dysfunction, and hematologic toxicity between two groups. CONCLUSION: Our study demonstrated comparable therapeutic effect of HHT or DNR on APL. HHT was also well tolerated and didn't cause serious adverse events.

Abstract Background In global clinical trials, nilotinib has shown superior efficacy vs imatinib for treating patients (pts) with CML-CP. The Evaluating Nilotinib Efficacy and Safety in Clinical Trials–China (ENESTchina) study is assessing the efficacy and safety of frontline nilotinib vs imatinib in Chinese pts with CML-CP. Methods ENESTchina (NCT01275196) is a multicenter, open-label, phase 3 study of Chinese adults with newly diagnosed (≤ 6 mo) CML-CP. Pts were randomized to nilotinib 300 mg BID (n = 134) or imatinib 400 mg QD (n = 133). The primary endpoint was the rate of major molecular response (MMR; ≤ 0.1% BCR-ABL on the international scale) at 12 mo. Molecular assessments were performed at a central laboratory. This analysis was conducted when all randomized pts had ≥ 12 mo of follow-up or discontinued early. Results Baseline characteristics were similar between the arms (Table). Most pts (nilotinib, 93%; imatinib, 95%) remained on treatment at the data cutoff. Median actual dose intensities were nilotinib 565 mg/day (range, 167-600 mg/day) and imatinib 393 mg/day (range, 204-550 mg/day). Sixteen pts (nilotinib, n = 9; imatinib, n = 7) discontinued, mainly due to adverse events (AEs; nilotinib, n = 3; imatinib, n = 1), withdrawal of consent (nilotinib, n = 3; imatinib, n = 1), or disease progression (nilotinib, n = 2; imatinib, n = 2). The primary endpoint was met, with a significantly higher rate of MMR at 12 mo in the nilotinib arm vs the imatinib arm (52% vs 28%, respectively; P &lt; .0001). The MMR rate at 12 mo was higher in the nilotinib arm vs the imatinib arm across all Sokal risk groups (Table). The rate of complete cytogenetic response (CCyR) by 6 mo was higher in the nilotinib arm vs the imatinib arm, but by 12 mo CCyR rates were similar in both arms. By the cutoff date, 2 pts (1.5%) in each arm had progressed to accelerated phase/blast crisis (AP/BC) on treatment. Three deaths were reported (all ≥ 28 days after discontinuing treatment), 2 in the nilotinib arm (due to cerebral hemorrhage [n = 1] and study indication [n = 1]) and 1 in the imatinib arm (due to recurrent non-Hodgkin lymphoma).There was no difference between the arms in time to progression to AP/BC on treatment or overall survival. Both drugs were well tolerated, with safety profiles similar to those reported in prior studies. The most common AEs on nilotinib were rash and myalgia; on imatinib, fluid retention and nasopharyngitis were most common (Table). One pt in the imatinib arm had a grade 1 increase in creatine phosphokinase-MB with no clinical signs indicative of ischemic heart disease. No cases of peripheral arterial occlusive disease, ischemic cerebrovascular events, or QTcF &gt; 480 ms were observed in either arm. Newly occurring/worsening grade 3/4 thrombocytopenia and neutropenia occurred at similar rates in both arms, while leukopenia, lymphopenia, and anemia were more frequent in the imatinib arm. The most common newly occurring/worsening grade 3/4 biochemical abnormality in both arms was elevated lipase. Conclusions In Chinese pts with newly diagnosed CML-CP, nilotinib was well tolerated and demonstrated superior efficacy over imatinib, as shown by higher rates of MMR in all Sokal risk groups, despite similarly high rates of CCyR after 1 y with both drugs. These results highlight the utility of MMR as a more sensitive efficacy endpoint for differentiating tyrosine kinase inhibitors in pts with CML-CP and provide the first evidence-based, prospective confirmation of the superiority of nilotinib over imatinib observed in the ENESTnd trial. Disclosures: Wang: Novartis: Employment; Bristol Myers Squibb: Consultancy. Baccarani:Ariad: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Jevtic:Novartis: Employment, Equity Ownership. Ortmann:Novartis: Employment. Yuan:Novartis: Employment. Menssen:Novartis: Employment. Saglio:ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

<b>Introduction:</b> CRTH2 antagonists are a promising therapy for T2-high disorders, particularly uncontrolled eosinophilic asthma. Biomarkers to identify patients likely to respond to treatment would be a useful advance. We set out to investigate the relationship between the effect of 12 weeks’ treatment with the CRTH2 antagonist timapiprant on the induced sputum eosinophil count and a range of blood and sputum biomarkers. <b>Methods and Materials:</b> Peripheral blood and induced sputum samples were collected from 20 patients with severe eosinophilic asthma at baseline and 12 weeks after oral treatment with 50 mg timapiprant daily. Immune cell counts in blood were determined with flow cytometry. Cell numbers in sputum were determined by slide counting. Correlations were assessed non-parametrically using Prism 7. <b>Results:</b> Timapiprant treatment reduced the geometric mean sputum eosinophils from 11% to 2.5% (Fold reduction 4.5; 95% CI 1.9 to 9.7; p=0.001). Baseline blood total CRTH2+ cells (r=0.75; p&lt;0.001), eosinophils (r=0.76; p&lt;0.001), basophils (r=0.53; p=&lt;0.05), Type-2 cytotoxic T (Tc2) cells (r=0.52; p=&lt;0.05), and sputum eosinophils (r=0.82; p&lt;0.0001) were correlated significantly with the reduction in the sputum eosinophil count with timapiprant treatment. <b>Conclusion:</b> High levels of blood total CRTH2+ cells, eosinophils, basophils, Tc2 cells, and sputum eosinophils are associated with the anti-inflammatory effect of timapiprant treatment and could be potential predictive biomarkers of response.