ALBERT

Description: The mechanisms that regulate the selective infiltration of eosinophils in certain allergic diseases are still poorly understood. The CC chemokine eotaxin is a potent chemoattractant, highly specific for eosinophils. Recent studies have implicated that eotaxin plays an important role in the recruitment of eosinophils in different inflammation processes. A number of other chemokines, cytokines, and chemoattractants also have chemotactic activities for eosinophils and some of them present high selectivity for eosinophils. To further study the role of eotaxin in inflammation, we generated mutant mice with the eotaxin gene disrupted and replaced by the Escherichia coliβ-galactosidase gene. These mice developed normally and had no histologic or hematopoietic abnormalities. Furthermore, our studies showed that the lack of eotaxin did not affect the recruitment of eosinophils in the inflammation models induced by Sephadex beads and thioglycollate, as well as in an experimental lung eosinophilia model induced by ovalbumin aerosol challenge, even at the onset of the inflammatory response. The replacement of the eotaxin gene by the β-galactosidase gene provided a useful marker to monitor the activity of the eotaxin promoter under normal conditions and after antigen challenges. Immunohistochemical staining suggested that endothelial cells were the major sources of eotaxin expression.

Description: The mechanisms that regulate the selective infiltration of eosinophils in certain allergic diseases are still poorly understood. The CC chemokine eotaxin is a potent chemoattractant, highly specific for eosinophils. Recent studies have implicated that eotaxin plays an important role in the recruitment of eosinophils in different inflammation processes. A number of other chemokines, cytokines, and chemoattractants also have chemotactic activities for eosinophils and some of them present high selectivity for eosinophils. To further study the role of eotaxin in inflammation, we generated mutant mice with the eotaxin gene disrupted and replaced by the Escherichia coliβ-galactosidase gene. These mice developed normally and had no histologic or hematopoietic abnormalities. Furthermore, our studies showed that the lack of eotaxin did not affect the recruitment of eosinophils in the inflammation models induced by Sephadex beads and thioglycollate, as well as in an experimental lung eosinophilia model induced by ovalbumin aerosol challenge, even at the onset of the inflammatory response. The replacement of the eotaxin gene by the β-galactosidase gene provided a useful marker to monitor the activity of the eotaxin promoter under normal conditions and after antigen challenges. Immunohistochemical staining suggested that endothelial cells were the major sources of eotaxin expression.

Description: Introduction: Venetoclax (VEN) is an oral BCL2 inhibitor, that has been shown to overcome apoptotic stress in cells from patients (pts) with high-risk myelodysplastic syndrome (MDS). Pre-clinical evidence indicates that VEN plus azacytidine (Aza) combination results in synergistic effects in myeloid malignancies. The objective of this trial is to evaluate the safety, tolerability, and overall response rate (ORR) of VEN in combination with Aza in pts with treatment-naive high-risk MDS or chronic myelomonocytic leukemia (CMML) and pts that were relapsed/refractory (R/R) to prior hypomethylating agent (HMA) therapy. Methods: This is a single-arm phase I/II clinical trial for pts with treatment-naive high-risk MDS or CMML, or pts with R/R MDS or CMML post-HMA failure (NCT04160052). Pts with prior BCL2 inhibitor therapy or low-risk disease (IPSS low or Int-1) are excluded. Aza is administered at 75mg/m2 IV or SC for 5 days on days 1-5 of each treatment cycle. VEN is studied at 100 mg, 200 mg, or 400 mg daily, on days 1-7 or 1-14 of each cycle. The primary endpoint is to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of VEN in combination with Aza, as well as to evaluate ORR, defined as achieving complete remission (CR), marrow complete remission (mCR), partial response (PR), or hematologic improvement (HI) lasting ≥4 weeks. Response is assessed based on the modified International Working Group 2006 criteria (Cheson et al Blood 2006). Overall survival (OS) is calculated from the start date of treatment to the date of death, or last follow-up. Progression-free survival (PFS) is calculated from the start date of treatment to the date of disease progression, or last follow-up. Duration of response is calculated from the date of response to the date of disease progression, or last follow-up. Safety profile events were recorded according to the CTCAE v5.0. Results: To date 9 pts were enrolled. Four pts received VEN at 100mg dose, 3 pts at 200mg dose, and 2 pts at 400mg dose on days 1-7. There has been no protocol defined DLTs. The median age was 66 years (range, 59-83), 89% were male, 67% with MDS, 67% with normal karyotype. Five pts (56%) were treatment-naive, and 4 (44%) with R/R disease. Of the treatment-naive cohort (N=5), 4/5 (80%) pts had normal karyotype and none had TP53 mutations. ORR rate in this treatment-naive cohort was 100%, all pts achieving mCR, of which 1 (20%) had neutrophil response. Of the R/R cohort (N=4), cytogenetics were normal in 2/4 (50%) and complex in 2/4 (50%), and 2/4 (50%) had TP53 mutations. ORR in this R/R cohort was 3/4 (75%), all achieving mCR. One pt (25%) had stable disease (Table 1 and Figure 1). With a median follow-up duration of 3.6 months (95% CI: 1.4-8.4), 3 (33%) had disease progression and 1 (11%) died. Pts received median 2 courses of therapy (range, 1-4). One pt went to transplant. Median progression-free survival (PFS) for the entire cohort was 4.6 months (95% CI: 3.4-NA) and median OS has not been reached (Figure 2). Median duration of response is 4.1 months (95% CI: 2.4-NA). Possibly/probably related grade 3/4 adverse events included neutropenia in 4/9 (44%), thrombocytopenia in 3/9 (33%), and anemia in 1/9 (11%) pts. There were no grade 5 events (Table 2). Conclusions: The administration of VEN with Aza appears safe and well tolerated in treatment-naive and R/R pts with high-risk MDS and CMML. The study continues to accrue. Disclosures Thompson: Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria. Alvarado:BerGenBio ASA: Research Funding; FibroGen: Research Funding; Sun Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Kantarjian:BioAscend: Honoraria; Delta Fly: Honoraria; Abbvie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Ascentage: Research Funding. Garcia-Manero:Amphivena Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding.

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: 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

Description: Background: The combination of low intensity therapy with InO improved outcome compared to intensive chemotherapy and to single agent InO in Salvage 1. The sequential addition of blina may allow the administration of weekly lower dose of InO and distancing allogeneic stem cell transplant (ASCT) from the last dose of InO, while deepening the minimal residual disease response. This will lead to less veno-occlusive disease (VOD) and better long-term efficacy. The aim of this study is to evaluate the outcome of pts in first relapse treated with this combination. Methods: The mini-hyper-CVD (cycles 1, 3, 5, 7) comprised cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracycline. Even cycles (cycles 2, 4, 6, 8) comprised methotrexate (250 mg/m2 on day 1) and cytarabine (0.5 g/m2 given every 12 h on days 2 and 3). Rituximab and intrathecal chemotherapy were given for first 4 courses. InO was originally given on day 3 of the first four cycles at the dose of 1.3-1.8 mg/m2 at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. After 38 pts were treated, an amendment was made to incorporate 4 cycles of blina after 4 cycles of mini-hyper-CVD + InO. InO was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 at cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 at subsequent cycles; blina was continuously infused over 28 days every 42-day cycle for 4 cycles. The decision to proceed with ASCT was based on the discretion of the treating physician after discussion with the pt. Results: From 2/2013 to 9/2019, 65 pts were enrolled and received first salvage therapy including 27 pts with mini-hyper-CVD + InO + blina. Patient characteristics and outcome are summarized in Table 1. The median age at diagnosis was 39 years (range, 18-87). Among 65 pts, 8 (12%) pts had primary refractory disease; 25 (38%), CR1 duration less than 12 months. 7 (11%) pts had prior history of ASCT. The overall response rate was 91% (CR, 66%, CRp/CRi, 25%). These rates were 100% in pts with primary refractory disease (CR 100%); 84 % in pts with CR1 duration 12 months (CR 63%, CRi/CRp 31%) (Table 2). Among 56 evaluable pts for minimal residual disease (MRD) assessment at morphologic response and 57 overall, 57% of pts achieved negative MRD by multicolor flow cytometry at response and 88% overall. Among 59 who achieved remission, 26 (44%) relapsed, 35 (59%) underwent allogeneic SCT in CR2, and 6 (9%) died in CR/CRp. Overall, 6 pts (9%) developed VOD; 4 after subsequent ASCT. The rate of VOD was 5/38 (13%) in pts who did not receive blina. In contrast, only 1 case of VOD was observed among the 27 pts (4%) who received the weekly lower dose of InO and sequential addition of blina; this pt had VOD post ASCT in CR2. With a median follow-up of 36 months (range, 1-87 months), 27 pts (42%) were alive, 21 of whom (32%) were in CR and MRD negative status. The median CR duration (CRD) and overall survival (OS) were 13 and 16.5 months, respectively. The estimated 3-year CRD and OS rates were 25% and 42%, respectively. Using the IPTW analysis, compared to a similar historical cohort of pts treated with standard salvage chemotherapy (n=77), the mini-hyper-CVD + InO with or without blina (n=58) resulted in significantly improved survival (P

Description: Background: Low-dose hypomethylating agents (HMAs) (azacitadine or decitabine) are safe and effective in patients with myelodysplastic syndromes (MDS). The aims of this study are to report the long-term follow-up of the phase 2 study of azacitidine or decitabine in lower-risk MDS and to identify specific populations of patients with lower-risk MDS who may benefit from early intervention with HMA therapy. Methods: Patients with previously untreated MDS or chronic myelomonocytic leukemia with low or intermediate-1 risk by the international prognostic scoring system (IPSS) were randomized with a Bayesian response-adaptive design, and received either decitabine 20 mg/m2 daily or azacitidine 75 mg/m2 daily on days 1-3 every 28-day cycle. The primary efficacy end point is overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points are HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Overall survival (OS) was defined as the time duration from the start of therapy to the date of death from any cause or the date of last follow-up, whichever came first. A linear mixed effect model with fixed and random effect was assessed for the longitudinal repeated measurements of the percentage of blasts in bone marrow during the study treatment. Multivariate Cox regression analysis was performed to identify prognostic factors for survival after variable selection with a P-value cutoff of 0.250 by univariate analysis. Historical comparison was performed to identify subgroups of patients who had benefit from HMA therapy. Results: Between November 12, 2012 and February 15, 2016, 113 patients were enrolled and treated with a median follow-up of 59 months: 73 (65%) patients were treated with decitabine and 40 (35%) were treated with azacitadine (Table 1; Figure 1). The median time from MDS diagnosis to the first date of therapy was 1.4 months (range, 0.2-49.8) and 0.9 months (range, 0.3-62.5) in the decitabine and azacitidine groups, respectively (P=0.052). The overall response rate was 67% and 48% in the decitabine and azacitidine groups, respectively (P=0.042); among 59 patients with baseline transfusion dependency, 19 (32%) achieved transfusion independence [decitabine, 16/39 (41%); azacitidine, 3/20 (15%); P=0.039]. The linear mixed effect model showed the equivalent longitudinal estimation of the percentage of blasts during the study (azacitadine vs. decitabine: P=0.989; estimate, -0.015; 95% CI, -2.325 - 2.295) (Figure 2). The median OS were 30 months and 37 months in the azacitadine and decitabine, respectively (P=0.625); the 5-year OS rates were 32% and 33%, respectively. By MD Anderson low-risk prognostic scoring system (MDA-LR-PSS), the median OS were not reached, 34 months, and 28 months in the low-, intermediate-, and high-risk groups, respectively (P

Description: Introduction Activating mutations in RAS have been reported in about 10-15% of patients with AML. Previous studies have not identified a prognostic significance for RAS mutations in AML treated with conventional chemotherapy. However, RAS mutations have emerged as a potential mechanism of resistance to treatment with small molecule inhibitors of FLT3, IDH, and BCL2. With broader availability of next generation sequencing, and the identification of wider heterogeneity in AML, we aimed to better characterize the genomic landscape of RAS mutated AML and outcomes within various subsets. Methods We conducted a retrospective analysis in 1410 consecutive patients with newly diagnosed (ND) AML) treated at out institution from 12/2011 to 01/2020, who had a baseline genomic testing available. Patients were treated with a variety of therapies, classified as: HMA-alone, HMA+Venetoclax (Ven), Intensive chemotherapy (HiDAC based), Intensive+Ven, low intensity double nucleoside analogue (cladribine+LDAC; Clad/LDAC), and Clad/LDAC + Ven. Response rates and outcomes were analyzed by age, cytogenetic prognostic subgroup (favorable [FAV], diploid [DIP], other intermediate [INT], adverse [ADV]), and type of therapy in the context of mutated (RAS-mut) or wild type RAS (RAS-WT). We sought to characterize the impact of RAS mutations on AML outcomes in the era of targeted therapy. Results Baseline patient and disease characteristics are detailed in table 1. Among 1410 patients with ND AML, 273 (20%) were RAS-mut; of these, 196 (72%) had NRAS-mut, 47(17%) had KRAS-mut, and 29(11%) had both. Patients with RAS-mut were younger(median age 62 vs. 66 years; P=0.001) and had higher a median WBC (P=0.02) and platelet count (P=0.01) at diagnosis compared to those with RAS-WT. Among the cytogenetic groups: FAV, INT, DIPLOID, ADV, RAS-mut were present in 39%, 20%, 16%, and 6%, respectively. Patients with RAS-mut were more likely to have concomitant mutations in ASXL1 (13%; P=0.03), , RUNX1 (10%; P=0.03), and less likely to have concomitant mutations in JAK2 (1%; P=0.03) and TP53 (8%; P

Description: Background: Single-agent gilteritinib and quizartinib (quiz) met their primary endpoints of improved overall survival (OS) in relapsed/refractory (R/R) FLT3-mut AML in phase III studies, but CRc durations were short (4-11 months). Quiz demonstrated potent synergy with venetoclax (VEN) (a BCL-2 inhibitor) in AML cell lines and PDX models (Mali et al. Haematologica 2020). Methods: Newly diagnosed or R/R AML with ECOG ≤2, and adequate organ function were eligible. The protocol initially evaluated safety of the doublet of decitabine (DAC) plus quiz regardless of FLT3 status [Fig 1A]. After the first 10 pts were treated on the doublet, the protocol was amended to add VEN (triplet) in a safety dose escalation lead in [Fig 1B]. CRc criteria were as published in the phase III ADMIRAL and QUANTUM-R studies. Results: 21 pts including DAC10 + quiz (phase 1: N=10) and DAC10 + VEN + quiz (phase IB/II: n=11) were evaluable at the time of this report (Table 1). DAC10 + Quiz Of 10 pts treated with DAC10 + quiz (Table 1), CRc rate was 40% (1 CRp and 3 CRi). No FLT3 R/R WT (n=3) pts responded. Four of 7 FLT3-ITD mut pts (1 frontline and 5/6 R/R, who had all received ≥1 FLT3 TKI) achieved CRc (57%), with 3/6 FLT3-PCR negative at response. 1 pt experienced QTcF prolongation 〉 500 msec on quiz 40mg/day (resolved after holding quiz with no clinical cardiac events). Grade 3/4 toxicities in 〉/= 2 pts, irrespective of attribution, included infection (12), neutropenic fever (3), mucositis (3), diarrhea (2), and prolonged QTcF 〉450 (2). With a median (med) follow-up (f/u) of 12 months (mos), the med OS was 5.7 months in the 6 R/R FLT3-mut pts (Fig 2A). Three of 4 CRc pts proceeded to allogeneic stem cell transplantation (ASCT) and 2 were alive in remission at last f/u. DAC10 + VEN + Quiz Of 11 enrolled pts (Table 2), 10 treated prior to July 1 2020 were evaluable. CRc achieved in 9/10 (90%) (1 CR, 3 CRp, 5 CRi) with 5/9 responders FLT3-PCR negative. Excluding the 1 frontline evaluable pt, 8 of 9 R/R FLT3-ITD (88% with ≥1 prior FLT3 TKIs) pts achieved CRc. No pts developed a DLT with 30 mg/day quiz, however with the 40mg/day quiz 2 pts developed hematologic DLT (grade ≥3 neutropenia with a /=2 pts, irrespective of attribution, included infection (7) and neutropenic fever (4). No QTcF prolongations 〉500msec noted. 60-day mortality was 0. With a med f/u of 6 mos, med OS was not reached and 6-month OS was 86% (one death) (Fig 2B). Of 9 CRc pts, 5 remain on protocol in CRc, 2 underwent ASCT and are alive post-ASCT, and 2 have relapsed. CyTOF (single-cell mass cytometry) analysis was performed in longitudinal samples collected on the triplet therapy. In a pt (baseline FLT3-ITD, NRAS, IDH1/2, SRSF2, DNMT3A, RUNX1, CSF3R) with a 3 week CRc duration, we identified two distinct blast populations at C1D1; monocytic (CD33+/CD34-/CD68+) and myeloid (CD33+/CD34+) (Fig 3A). The monocytic blasts had low BCL-2 and high MCL-1 at baseline, with modest reduction at EOC1 (from 25.8% to 10.8%) (Fig 3B-C). However, the myeloid blasts with high BCL-2 and lower MCL-1 showed significant reduction at EOC1 (from 52% to 5.5%) (Fig 3B-C). Heat-map demonstrated major downregulation in signaling pathways (MCL-1, STAT, BCL-XL, and MAPK) in the myeloid blasts at EOC1 of triplet therapy (Fig 3D). However, these signaling pathways remained active in the monocytic blasts at EOC 1 (Fig 3D). Pt relapsed prior to starting C2, driven by monocytic blasts (Fig 3C).On the other hand, in a pt (baseline FLT3-ITD only) who remains in CR (DOR 11 mos), both myeloid and monocytic populations had high BCL-2 at baseline (Fig 4A-B). Despite almost complete elimination of myeloid blasts (Fig 4C), monocytic blasts were detectable at a low level at C1D28 (Fig 4C). Importantly, converse to the prior pt, the active signaling pathways at diagnosis (MCL-1, STAT, MAPK, c-MYC) were significantly downregulated in both populations at EOC1 (Fig 4D). This patient underwent ASCT on D35 of therapy, and remains in CR. Conclusion: DAC10 + venetoclax + quiz is highly active in R/R FLT3-ITD mut AML pts, with CRc rates of 90% and projected 6-month OS of 86%. CYTOF profiling may predict for response based on pre- and on-therapy apoptotic and signaling pathway profiles enabling potential optimal selection of future combinatorial or sequential approaches. Accrual to the triplet continues and updated clinical and correlative data will be presented. Disclosures Yilmaz: Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Kantarjian:Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; BMS: Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Astex: Research Funding; Immunogen: Research Funding; Ariad: Research Funding. Kadia:Cellenkos: Research Funding; Cyclacel: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Pulmotec: Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Incyte: Research Funding; Astellas: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding. Konopleva:Eli Lilly: Research Funding; Amgen: Consultancy; Cellectis: Research Funding; Agios: Research Funding; AbbVie: 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; Forty-Seven: Consultancy, Research Funding; Sanofi: Research Funding; Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Kisoji: Consultancy. Borthakur:PTC Therapeutics: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy. DiNardo:Takeda: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Calithera: Research Funding; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria. Pemmaraju:Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; SagerStrong Foundation: Other: Grant Support; MustangBio: Honoraria; Celgene: Honoraria; Pacylex Pharmaceuticals: Consultancy; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Blueprint Medicines: Honoraria; DAVA Oncology: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Cellectis: Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding. Short:Amgen: Honoraria; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy. Alvarado:Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; Astex Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Garcia-Manero:Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Onconova: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding. Ravandi:AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Andreeff: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; Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding. Daver:Daiichi Sankyo: 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; 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.