ALBERT

Description: The promising activity of BET protein inhibitors (BETi’s) is compromised by adaptive or innate resistance in acute myeloid leukemia (AML). Here, modeling of BETi-persister/resistance (BETi-P/R) in human postmyeloproliferative neoplasm (post-MPN) secondary AML (sAML) cells demonstrated accessible and active chromatin in specific superenhancers/enhancers, which was associated with increased levels of nuclear β-catenin, TCF7L2, JMJD6, and c-Myc in BETi-P/R sAML cells. Following BETi treatment, c-Myc levels were rapidly restored in BETi-P/R sAML cells. CRISPR/Cas9-mediated knockout of TCF7L2 or JMJD6 reversed BETi-P/R, whereas ectopic overexpression conferred BETi-P/R in sAML cells, confirming the mechanistic role of the β-catenin–TCF7L2–JMJD6–c-Myc axis in BETi resistance. Patient-derived, post-MPN, CD34+ sAML blasts exhibiting relative resistance to BETi, as compared with sensitive sAML blasts, displayed higher messenger RNA and protein expression of TCF7L2, JMJD6, and c-Myc and following BETi washout exhibited rapid restoration of c-Myc and JMJD6. CRISPR/Cas9 knockout of TCF7L2 and JMJD6 depleted their levels, inducing loss of viability of the sAML blasts. Disruption of colocalization of nuclear β-catenin with TBL1 and TCF7L2 by the small-molecule inhibitor BC2059 combined with depletion of BRD4 by BET proteolysis-targeting chimera reduced c-Myc levels and exerted synergistic lethality in BETi-P/R sAML cells. This combination also reduced leukemia burden and improved survival of mice engrafted with BETi-P/R sAML cells or patient-derived AML blasts innately resistant to BETi. Therefore, multitargeted disruption of the β-catenin–TCF7L2–JMJD6–c-Myc axis overcomes adaptive and innate BETi resistance, exhibiting preclinical efficacy against human post-MPN sAML cells.

Description: Background Recent advances have led to higher response rates and improved survival in patients with newly diagnosed AML. However, early death, lack of response, and long term leukemia-free survival remain important challenges. Early mortality in AML has been reported to be as high as 20-30%. Similar to relapse risk, disease related factors (along with patient and treatment factors) may also contribute significantly to early mortality. Here we investigated predictors of early (4- and 8-week) mortality, response, relapse-free survival, and overall survival in a contemporary cohort from a single large academic medical center. Methods We analyzed all newly diagnosed patients with AML presenting to and treated at our institution from January 2012 to January 2020. For 4- and 8-week mortality and overall response rate (CR/CRi), logistic regression models were generated to identify factors associated with these outcomes. Kaplan-Meier methods were used to determine the median of the time to event outcomes. Cox proportional hazards modelswere used to identify any association with each of the variables and survival outcomes. Multivariate models were performed for all the outcomes, the models included variables with p

Description: Background Anemia is common in patients (pts) with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF). Furthermore, anemia is an on-target effect of therapeutic Janus kinase 2 (JAK2) inhibition, and may be the most frequent cause of ruxolitinib (rux) discontinuation (d/c) in clinical practice (Kuykendall, Ann Hematol 2018). Current therapies for anemia of MF (erythropoietin and analogs, danazol, IMiDs®) are unsatisfactory. Sotatercept (ACE-011) is a first-in-class, activin receptor type IIA ligand trap that may improve anemia by sequestering stromal transforming growth factor beta superfamily ligands that suppress terminal erythropoiesis (Iancu-Rubin, Exp Hematol 2013). Methods This is a phase 2, investigator-initiated, open-label, single institution study of sotatercept, administered subcutaneously every 3 weeks, in 2 cohorts of anemic pts (Hgb

Description: Background: The combination of INO with hyper-mini-CVD with or without blinatumomab offers a safe and effective treatment modality for pts with R-R ALL. However, the outcomes of some pts remain poor and the predictors of survival are not well understood. CA are frequently used as predictors of outcomes in leukemia. We present an exploratory analysis evaluating the relationship between baseline CA and outcome in pts with R-R ALL treated at our institution in a phase 2 study of INO in combination with mini-hyper-CVD with or without blinatumomab. Methods: Ninety-six pts with R-R ALL received low-intensity chemotherapy referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). INO was given on Day 3 of each of the first 4 courses at 1.8-1.3 mg/m2 for course 1 followed by 1.3-1.0 mg/m2 for subsequent courses. From pt #68 onwards, INO was reduced and fractionated into biweekly doses (0.6 mg/m2 and 0.3 mg/m2 during course 1 and 0.3 mg/m2 and 0.3 mg/m2 during subsequent courses), and blinatumomab for up to 4 courses after INO therapy was added. By performing univariate and multivariate analyses of factors associated with survival, we identified 11q23 rearrangements and low hypodiploidy / near triploidy (Ho-Tr) as high-risk CA. Pts were categorized based on their CA as low-risk if they carry diploid, complex or other cytogenetics. Pts with 11q23 rearrangements and those with Ho-Tr were classified as having high-risk CA. Response rates and overall survival (OS) outcomes are compared between the two cytogenetic risk categories. Results: Pts characteristics are summarized in Table 1. Karyotype was diploid in 23 (24%) pts, complex in 12 (13%) pts, and other in 21 (22%) pts. Ten (10%) pts had Ho-Tr, 10 (10%) pts had KMT2A rearrangements, 3 (3%) pts had high hypertriploidy (HeH), 2 (2%) pts had near triploidy (Tt) and 15 (16%) pts had insufficient metaphases/ not determined karyotype. TP53 mutation was detected in a significantly higher proportion of pts with Ho-Tr (6 out of 7 tested pts or 86%) compared to pts with other cytogenetic abnormalities (10 out of 40 tested pts or 25%) (p=0.002). We performed univariate and multivariate analyses for the association of different cytogenetics with survival. By multivariate analysis, baseline cytogenetics independently associated with worse survival included Ho-Tr [HR= 18.262 (95% CI= 5.935-56.196); p

Description: INTRODUCTION: Atypical chronic myeloid leukemia (aCML) is a rare subtype of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) associated with shorter survival and higher risk of transformation to acute myeloid leukemia (AML) than other MDS/MPNs. However, the clonal mechanisms underlying transformation to leukemia remain unclear. There is a need to develop predictive models and identify the optimal therapeutic management of these pts. METHODS: We evaluated all consecutive pts with aCML treated at the University of Texas MD Anderson Cancer Center from 2005 to 2020. Whole bone marrow (BM) DNA was subject to 28 or 81 gene targeted next-generation sequencing (NGS) analysis in a subset of pts. Variant allele frequency (VAF) estimates were used to evaluate clonal relationships within each sample using Pearson goodness-of-fit tests and VAF differences. Response to therapy was assessed following MDS/MPN IWG response criteria. Cox proportional hazards regression was used to study association of variables with survival. RESULTS: A total of 65 pts were identified. Median age was 67 years (range 46-89). Median WBC, Hgb and platelets were 44.5x109/L (5.9-474.9x109/L) 10.0g/dL (5.7-14.7g/dL) 93x109/L (12-560x109/L), respectively. Median neutrophil, promyelocyte, myelocyte and metamyelocyte percentages were 64%, 0%, 0% and 16%. Forty-one (63%) pts had normal karyotype, 5 (8%) trisomy 8, 2 (3%) i(17q) and 2 (3%) del(20q). Splenomegaly was observed in 26 (40%) pts and 7 (11%) had extramedullary disease. NGS data was available in 35 (54%) pts. The most frequently mutated genes included ASXL1 in 83%, SRSF2 in 68% and SETBP1 in 58%. Frequency and VAF of identified mutations is shown in Figure 1A. Mutations in SETBP1, SRSF2, TET2 and GATA2 tended to appear within dominant clones while other RAS pathway mutations were more likely to appear as minor clones. SRSF2 and SETBP1 tended to be co-dominant while ASXL1 appeared within minor clones in up to 50% of pts (Figure 1B). Therapy consisted of single agent hypomethylating agent (HMA) in 19 (29%), hydroxyurea in 8 (12%), HMA in combination with ruxolitinib in 7 (11%), other HMA combinations in 5 (8%), ruxolitinib single agent in 5 (8), induction chemotherapy in 3 (5%) and other investigational agents in 1 (2%) pts. Response outcomes by therapy are detailed in Figure 1C. With a median follow up of 35.6 months (95% CI 28.2-43.1) 18 (28%) of pts experienced transformation to AML within a median of 18 months (1-123 months). Median survival after transformation of 8.3 months (95% CI 5.5-11.0 months). NGS at the time of transformation was available in 12 (67%) pts with matched NGS at diagnosis of aCML and AML in 8 (44%) pts. Acquisition of new previously undetectable mutations was observed in 5 pts the most common involving signaling pathway mutations (Figure 1D). Acquisition of new cytogenetic abnormalities was observed in 9/14 pts (Figure 1D) the most frequent involving i(17q). The median OS was 25 months (95% CI 20.0-30.0) with pts who received intensive chemotherapy having significantly worse OS than those receiving HMA-based therapy or other agents such as ruxolitinib or hydroxyurea (p=0.012, Figure 1E). By multivariate analysis for survival, age, platelet count, BM blast percentage and serum LDH levels influenced prognosis. Based on these factors we developed a multivariable Cox model to generate a nomogram which assigned a score to each of the prognostic variables and allowed to predict 1-year and 3-year OS based on the total score among all prognostic variables (Figure 1F). CONCLUSIONS: aCML is characterized by high frequency of co-dominant SRSF2 and SETBP1 mutations. HMA therapy is associated with the best response outcomes. Clinicopathological features can help predict outcomes of these pts. Figure 1 Disclosures Sasaki: Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Pfizer Japan: Consultancy; Otsuka: Honoraria. Jabbour:Genentech: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding. DiNardo:Agios: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; Novartis: Consultancy; MedImmune: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Konopleva:F. Hoffmann La-Roche: Consultancy, Research Funding; Ablynx: Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; AbbVie: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Calithera: 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; Ascentage: Research Funding; Amgen: Consultancy; AstraZeneca: Research Funding; Cellectis: Research Funding. Pemmaraju:MustangBio: Honoraria; Incyte Corporation: Honoraria; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Daiichi Sankyo: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Novartis: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Cellectis: Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Kadia:Celgene: Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Incyte: Research Funding; Cellenkos: Research Funding; BMS: Honoraria, Research Funding; Ascentage: Research Funding; Astra Zeneca: Research Funding; Cyclacel: Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; JAZZ: Honoraria, Research Funding. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Daver: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; 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; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Borthakur:AstraZeneca: Research Funding; PTC Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Jannsen: Research Funding; Curio Science LLC: Consultancy; Novartis: Research Funding; Argenx: Consultancy; BioTherix: Consultancy; Polaris: Research Funding; BioLine Rx: Consultancy; Incyte: Research Funding; PTC Therapeutics: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Consultancy; Abbvie: Research Funding; GSK: Research Funding. Verstovsek:Gilead: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding; Roche: Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding. Kantarjian:Adaptive biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; BioAscend: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Delta Fly: Honoraria; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Aptitute Health: Honoraria; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Oxford Biomedical: Honoraria. Bose:Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; Promedior, Inc.: Research Funding. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Amphivena Therapeutics: Research Funding.

Description: Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm. Ruxolitinib, a Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor and fedratinib, a JAK2/FLT3 inhibitor, are the only approved treatment options for MF. Despite the benefits reported with ruxolitinib in the front-line setting, a high proportion of patients discontinue treatment, the 1-, 2-, and 3-year discontinuation rates are 49%, 71%, and 86%, respectively (Abdelrahman et al, 2015). For patients who discontinue treatment with ruxolitinib, the median overall survival (OS) is dismal and ranges from 13 to 16 months (Kuykendall et al, 2018; Newberry et al, 2017; Schain et al, 2019; Palandri et al, 2019; Mcnamara et al, 2019). There remains a great unmet need for patients who are non-responsive to and have discontinued treatment with a JAK inhibitor. Imetelstat, a first-in-class telomerase inhibitor, has shown meaningful clinical improvement in symptom response and improved OS in IMbark, a Phase 2 study in patients with intermediate-2 or high-risk MF who have relapsed after or are refractory to JAK inhibitors (Mascarenhas et al, ASH 2018 #685; Mascarenhas et al, EHA 2020 #EP1107). Nineteen (32.2%) patients in the 9.4 mg/kg arm and 3 (6.3%) patients in the 4.7 mg/kg arm achieved symptom response (total symptom score [TSS] reduction ≥50%) at Week 24. As of clinical cutoff (7 February 2020), with an overall study follow up of 42 months, median OS was 28.1 months for the 9.4 mg/kg arm (95% confidence interval [CI]: 22.8, 31.6) and 19.9 months for the 4.7 mg/kg arm (95% CI: 17.1, 33.9). The improvement in OS for patients treated with 9.4mg/kg imetelstat was further supported by analyses of IMbark patients with closely matched real world controls (Kuykendall et al, EHA 2019 #PS1456). Taken together, these findings support continued study of imetelstat 9.4 mg/kg dose in a well-designed Phase 3 randomized controlled study in patients with refractory MF. Methods: Study MYF3001 is an open label, randomized (2:1), multicenter, Phase 3 study of imetelstat compared with best available therapy (BAT) in approximately 320 patients with intermediate-2 or high-risk MF (primary MF, post-essential thrombocythemia-MF, or post-polycythemia vera-MF) who are refractory to JAK inhibitor treatment. Approximately 214 patients will be randomized to Arm A to receive imetelstat, and approximately 106 patients will be randomized to Arm B to receive BAT. Eligible patients will be stratified based on: a) intermediate-2 or high-risk per Dynamic International Prognostic Scoring System (DIPSS); and b) platelet count at study entry (platelets ≥75 x 109/L and

Description: Background: Detection of measurable residual disease (MRD) has been shown to provide important prognostic information in patients (pt) with acute myeloid leukemia (AML) receiving standard cytotoxic chemotherapy. The predictive value of MRD detection after low intensity regimens is less well established. Methods: We conducted a post-hoc analysis of a phase 2 trial to determine the prognostic value of MRD after frontline therapy with venetoclax (VEN) plus decitabine (DEC; DiNardo CD, et al, Lancet Haematology, 2020). MRD was assessed on bone marrow (BM) specimens using 8-color multiparametric flow cytometry (FCM) that was validated to a sensitivity level of 0.01-0.1%. Negative results were considered valid only if there had been acquisition of at least 200,000 events or a minimum of 200 CD34+ myeloid precursors. Pts were treated with DEC 20 mg/m2 for 10 days for induction followed by DEC for 5 days after CR/CRi with cycles repeated every 4-6 wks. Response and relapse were defined using the ELN 2017 criteria. Overall survival (OS) was determined from start of treatment until death or censored at last follow-up (LFU). Relapse-free survival (RFS) was determined from date of CR/CRi till morphologic relapse, death, or censored at LFU. Results: Between January 2018 and April 2020 we enrolled 121 pts in the frontline cohort including de novo AML (n=74), untreated secondary AML (sAML, n=16) and sAML with prior therapy for antecedent hematological disorder (n=31). No pts had received prior therapy for AML. The median age was 72 yrs (interquartile range [IQR] 68-77) and 34 pts (28%) had ECOG PS ≥2 (Table 1). The overall response rate was 81% with CR/CRi rate of 71%. Over half (53%) of responding pts achieved MRD negative status at any time point. (Table 2). The median time to response was 1.4 mo (IQR 1.1-2.6) and median time to MRD negativity was 2.0 mo (IQR 0.9-3.1). 16 pts (13%) underwent allogeneic hematopoietic stem cell transplant after achievement of response. The median OS was 11.7 mo (95% CI 9.1, 14.8) and the median RFS was 9.0 mo (95% CI 6.7, 15.0). After a median FU of 20.2 mo (95% CI 15.7, 23.0) 51 pts are alive. Pts achieving negative MRD at the time of morphologic response (CR/CRi/MLFS) had significantly longer OS compared to pts who were MRD positive, median OS 25.1 vs 11.6 mo, respectively, hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.24, 0.85, p=.02. Pts achieving CR MRD- per ELN guidelines at any time point had longer OS compared to those with an inferior response i.e. CR MRD+ or CRi/MLFS MRD± (median OS 25.1 mo vs 10.9 mo, HR 0.31, 95% CI 0.18, 0.55, p