ALBERT

Description: Background Treatment of older patients with newly diagnosed AML has been limited by modest response rates with low-intensity therapy and higher levels of toxicity with intensive therapy. We previously reported on a low-intensity backbone of cladribine + LDAC (CLAD/LDAC) alternating with hypomethylating agent (HMA) for older patients with AML, yielding higher rates of CR and improved outcomes compared to HMAs alone. Recently, addition of the BCL-2 inhibitor venetoclax to HMAs was shown, in a randomized study, to improve survival over HMAs alone. We hypothesized that the addition of venetoclax to the low intensity CLAD/LDAC backbone may further improve response rates and outcomes for this group of patients. Methods This is a phase II clinical trial studying the combination of venetoclax with CLAD/LDAC alternating with 5-azacytidine (AZA) in older (age ≥ 60y) or unfit patients with newly diagnosed AML (excluding APL, CBF). Induction was cladribine 5 mg/m2 IV over 30 minutes on D1-5 followed by araC 20mg SQ BID on D1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV on D1-3 + araC 20 mg SQ BID on D1-10 alternating with 2 cycles of AZA 75 mg/m2 on D1-7, for up to 18 cycles. Venetoclax 400 mg was added on days 1-21 of each cycle with dose adjustments for concomitant CYP3A inhibitors. One cycle was 4 weeks and up to 2 cycles of induction were allowed. Results A total of 48 patients were treated on study, with a median age of 68 yrs (57-84); 18 (38%) pts were ≥ 70 yrs and 1 pt 〈 60 yrs who was unfit for intensive chemotherapy was enrolled. 12 (25%) patients had secondary AML (sAML) and 12 (25%) had adverse karyotype. The baseline patient characteristics are summarized in Table 1. Among 48 evaluable pts, 37 (77%) achieved a complete remission (CR), 8 (17%) had a CR with incomplete count recovery (CRi) for a CR/CRi rate of 94%. The median number of cycles to response was 1 (1-3) and 36 (80%) pts were negative for MRD by multi-parameter flow cytometry at the time of CR/CRi. Among the subset of patients who had CR with complete count recovery, the MRD negative rate was 92% (34/37). Among pts with sAML or with adverse karyotype, the CR/CRi rate was 83% (58%/25%) and 83% (50%/33%), respectively. The regimen was well tolerated, with 4- and 8-week mortality rates of 0% and 6%, respectively. The most frequent grade 3/4 non-heme adverse events were neutropenic fever (n=20), lung infection (9), decreased urine output (2), nausea (1), acute kidney injury (1), dizziness (1), and mucositis (1). Eleven (24%) of the 45 responding pts proceeded with allogeneic stem cell transplant (SCT). With a median follow-up of 11+ months, the median overall survival (OS) has not been reached (NR), with 6- and 12-month OS rates of 86% and 70%, respectively (Figure 1). The median OS of pts with or without MRD at CR were 10.7m and NR, respectively (P=0.056). For pts with sAML vs. de novo AML, the median OS was 10.6m vs. NR, respectively (P=0.09). OS by cytogenetic risk is shown in Figures 2. OS among different subgroups are summarized in Table. The median RFS was not reached, with 6- and 12-month RFS rates of 79% and 64%, respectively. Conclusion CLAD/LDAC plus venetoclax alternating with AZA plus venetoclax is an effective, lower-intensity regimen that is well tolerated among older patients with newly diagnosed AML, producing high rates of durable MRD negative remission and meaningful blood count recovery. With approximately 1-year follow-up, the rates of overall and relapse-free survival are encouraging in this cohort of older AML patients. Further study of this backbone in combination approaches is warranted. Disclosures Kadia: Incyte: Research Funding; Novartis: Honoraria; Cellenkos: Research Funding; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; Celgene: Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Borthakur:Treadwell Therapeutics: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; BioTherix: Consultancy; Incyte: Research Funding; PTC Therapeutics: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; GSK: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; Nkarta Therapeutics: Consultancy. Pemmaraju:Samus Therapeutics: Research Funding; Cellectis: Research Funding; Roche Diagnostics: Honoraria; Celgene: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; DAVA Oncology: Honoraria; SagerStrong Foundation: Other: Grant Support; AbbVie: Honoraria, Research Funding; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria; Incyte Corporation: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; Affymetrix: Other: Grant Support, Research Funding; Daiichi Sankyo: Research Funding; MustangBio: Honoraria. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees. DiNardo:Novartis: Consultancy; ImmuneOnc: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Calithera: Research Funding; MedImmune: Honoraria. Sasaki:Otsuka: Honoraria; Daiichi Sankyo: Consultancy; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy. Jain:AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding. Jabbour:BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Popat:Bayer: Research Funding; Novartis: Research Funding. Andreeff:Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding. Cortes:Telios: Research Funding; Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Merus: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Immunogen: Research Funding. Garcia-Manero:AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding. Konopleva:Rafael Pharmaceutical: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Amgen: Consultancy; Kisoji: Consultancy; Ablynx: Research Funding; Genentech: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Cellectis: Research Funding; Forty-Seven: Consultancy, Research Funding; Ascentage: Research Funding; Sanofi: Research Funding; AbbVie: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Eli Lilly: Research Funding; Agios: Research Funding. Ravandi:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kantarjian:Astex: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria. OffLabel Disclosure: This combination is investigational.

Description: Several new heterocyclic systems based on a hydroxybenzofuro[2,3-b]pyridine building block were prepared. This benzofuropyridine is easily available from the Meerwein reaction of benzoquinone and a heterocyclic diazonium salt, followed by reduction and cyclization. Electrophilic substitution and further condensations give polycyclic systems, including oxazolo- and chromeno-fused analogues.