A series of 31 chalcone- and flavonoid-based derivatives were synthesized in good overall yields and screened for their inverse agonist activity on the US28 receptor of human cytomegalovirus (HCMV). With one exception (e.g., 2-(5-bromo-2-methoxyphenyl)-3-hydroxy-4H-chromen-4-one), halogen-substituted flavonoids were typically more potent inverse agonists than their related hydro derivatives. While toxicity could be used to partially explain the inverse agonist activity of some members of the series, 5-(benzyloxy)-2-(5-bromo-2-methoxyphenyl)-4H-chromen-4-one (11b) acted on the US28 receptor as a nontoxic, inverse agonist. The full inverse agonism (efficacy, -89%) and potency (EC50 = 3.5 μM) observed with flavonoid 11b is especially important as it provides both a new tool to study US28 signaling and a potential platform for the future development of HCMV-targeting drugs.
Introduction: Treatment-free remission (TFR) is an emerging treatment goal in chronic phase chronic myeloid leukemia (CP-CML). The NCCN guidelines suggest patients must meet the following criteria in order to be eligible for an attempt at TKI discontinuation: use of a TKI for at least 3 years with no history of TKI resistance who have maintained a deep molecular response (MR4 - BCR-ABL IS ≤0.01%) for at least 2 years. The aim of this study was to identify predictors of long-term TFR in CP-CML patients who discontinue TKI therapy at our institution. Methods: We retrospectively identified all CP-CML patients who had discontinued TKIs after meeting TKI discontinuation criteria at Moffitt Cancer Center. Patient charts were reviewed to collect data on demographics, disease characteristics, and outcomes. TFR was calculated from date of TKI discontinuation to date of molecular recurrence (defined as loss of MMR (BCR-ABL IS ≥0.1%) or date of last follow up). Statistical analysis was performed utilizing Kaplan-Meier curves and log rank (Mantel-Cox) test. Results: A total of 102 patients met TKI discontinuation criteria and stopped treatment to attempt TFR. The median age at diagnosis was 53.5 years (19-83 years). The median age at TKI discontinuation was 61 years (28-92 years). Fifty (49.5%) patients were male. Four patients (3.9%) had previously received interferon α. At a median follow up of 29 months, the TFR rate was 56.8%, with molecular recurrence occurring in 44 patients. 93 patients had a follow up of at least 6 months. Of the 44 patients with molecular recurrence, 37 (84%) recurred within 6 months and 41 (93%) within 12 months of TKI cessation. The rate of TFR at 12 months and 24 months was 58% (95% CI: 48-68%) and 53% (95% CI: 43-64%), respectively [Figure 1]. Baseline characteristics along with univariate analysis of the 102 patients included in the study are shown in Table 1. Age, BMI at discontinuation, gender, Sokol risk index, last TKI prior to discontinuation, lines of therapy, or duration on TKI prior to discontinuation did not significantly affect rates of TFR. Patients with sustained MR4.5 (BCR-ABL IS <0.0032%) for 2 years prior to discontinuation showed a trend toward higher probability of TFR at 12 months compared to those in MR4 (62% vs 49%; p=0.055). Median time to regain MMR after restarting treatment in patients with molecular recurrence was 90 days (range 28-443 days). 32 patients (31%) developed TKI withdrawal syndrome with symptoms including headache, arthralgia, myalgia and fatigue. Conclusions: At our center, 102 CP-CML patients qualified for TKI cessation. The rate of TFR at 12 months was 58% which is consistent with published data from numerous TKI discontinuation clinical trials. We were unable to identify any factors that were predictive of successful TFR, however those patients with a deeper molecular response (MR 4.5) at the time of TKI cessation trended towards higher rates of TFR at 12 months, suggesting that the depth of response is important for achieving prolonged TFR. Identifying methods to further deepen molecular response in CP-CML patients may ultimately lead to higher rates of TFR in the future. Figure 1 Figure 1. Disclosures Nodzon: Takeda: Consultancy. Komrokji: Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy. Sallman: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Incyte: Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Padron: Blueprint: Honoraria; Incyte: Research Funding; Stemline: Honoraria; Taiho: Honoraria; Kura: Research Funding; BMS: Research Funding. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; PharmaEssentia: Honoraria. Lancet: Jazz: Consultancy; Astellas: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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