ALBERT

Description: Background: Isocitrate dehydrogenase 2 (IDH2) mutations occur in 5-10% of patients (pts) with myelodysplastic syndrome (MDS) and are frequently associated with intermediate-risk cytogenetics, excess bone marrow blasts, neutropenia and sustained platelets. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). This study was designed to evaluate the efficacy and tolerability of ENA alone and in combination with azacitidine (AZA) in pts with high-risk IDH2-mutated MDS. Methods: This is a multicenter Phase II trial for pts with IDH2-mutated MDS, AML with 20-30% marrow blasts, or chronic myelomonocytic leukemia. The study includes two cohorts: HMA-naïve pts with high-risk MDS (IPSS int-2 or high-risk; IPSS-R high-risk or very high risk; or high-risk molecular features including TP53, ASXL1, EZH2 and/or RUNX1 mutations) (Arm A) receive AZA + ENA; pts relapsed/refractory with prior HMA therapy (Arm B) receive ENA alone. All pts receive ENA at a dose of 100 mg orally daily, on days 1-28 of each 28-day cycle. In Arm A, ENA is given in combination with AZA 75 mg/m2 IV or SC on days 1-7 of each cycle. The primary efficacy endpoint is overall response rate (ORR), including complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI) based on the Modified International Working group (IWG) Response Criteria for MDS. The primary safety endpoint is the incidence and severity of adverse events using the Common Toxicity Criteria for Adverse Events v4.0. Results: Using a pre-specified data cutoff of July 1st 2019, 25 pts have been enrolled with a median follow-up of 6.4 months (range, 2.4 - 17.1); 10 HMA-naïve pts (Arm A) and 15 HMA-failure pts (Arm B). The median age was 71 years (range, 46-83) (Table 1). Sixteen pts (64%) had neutropenia (absolute neutrophil count 〈 1.0 x 109/L) and 20 pts (80%) had anemia (hemoglobin 〈 11 g/dL), including 12 (48%) red blood cell (RBC) transfusion-dependent (TD) pts at baseline. Seventeen pts (68%) had high or very high risk IPSS-R. Nineteen pts (76%) had diploid or +8 cytogenetics, and 5 pts (20%) had -7 or complex karyotype. High-risk co-occurring mutations included ASXL1 (46%), RUNX1 (17%), EZH2 (8%) and TP53 (8%). Among 18 evaluable pts (7 too early for response assessment), the ORR was 67% (12/18) (Table 2). In HMA-naïve pts, 6/6 (100%) responded to therapy, including 2 CRs and 4 mCRs (1 with HI for neutrophils [HI-N]). In HMA-failure pts, 6/12 (50%) responded, including 2 CRs, 1 PR, 1 mCR (with HI-N) and 2 with stable disease with HI (1 with HI-N, 1 with HI erythroid). Interestingly, 3 pts who achieved CR also had clearance of the IDH2 mutation (1 in Arm A; 2 in Arm B). Two of 5 pts (40%) and 3/7 pts (43%) with neutropenia at baseline achieved HI-N in Arm A and B, respectively. Median time to first and best response were both 1.3 months (range, 0.9-2.1) in Arm A and 1.8 months (range, 0.9-3.7) and 2.7 months (0.9-4.6), respectively in Arm B. Among evaluable pts with RBC TD at baseline, 0/2 pt and 3/8 (38%) pts achieved transfusion independence, in Arm A and B, respectively. At last follow-up, 16 pts remain on treatment (7 with ongoing response) and 9 pts stopped treatment: 4 due to progression, 1 pt decision, 1 underwent allogeneic transplant and 3 responding pts with mCR died from pneumonia or other infectious complications while on study (Figure 1). Adverse events (AEs) of any grade were reported in 17/25 pts (68%) and grade 3-4 AEs were reported in 11/25 pts (44%). Most AEs were manageable without dose interruption. The most common non-hematological AEs were unconjugated hyperbilirubinemia (39%), nausea (33%), fatigue (33%), pneumonia (22%) and diarrhea (17%). Possible differentiation syndrome (DS) was reported in 3 pts on days 31, 38 and 42 of treatment; 2 pts received dexamethasone with resolution, and 1 pt required hydrea and was ultimately determined to have progression to AML. Four pts developed leukocytosis (white blood cell count of 15.3, 28.3, 35.7, 56.6 x 109/L), with 3 at the time of possible DS and 1 at day 119 considered unrelated to DS. Conclusion: Enasidenib is well tolerated and shows promising efficacy in IDH2-mutated high-risk MDS. The ORR was 67%, including 100% in newly diagnosed pts receiving the combination of azacitidine plus enasidenib and 50% ORR in HMA-failure pts receiving enasidenib alone. The study continues to accrue and updated results will be presented at ASH. Disclosures DeZern: Celgene: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy. Takahashi:Symbio Pharmaceuticals: Consultancy. Konopleva:Astra Zeneca: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Agios: Research Funding. Loghavi:MDACC: Employment; GLG Consultants: Consultancy; AlphaSights: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Ravandi:Selvita: Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Nazha:Abbvie: Consultancy; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Tolero, Karyopharma: Honoraria. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: 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; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: 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; Celltrion: 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; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Immunogen: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. DiNardo:medimmune: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria. OffLabel Disclosure: Enasidenib is not approved for the treatment of myelodysplastic syndrome

Description: Background: MYC mRNA overexpression has been described in acute myeloid leukemia (AML), but no studies have assessed MYC protein expression in AML where its clinical significance is unknown. In this study our aim is to assess MYC protein expression across all AML subtypes and explore its prognostic value in in a subset of patients (pts) with particularly poor prognosis, namely those with AML with myelodysplastic syndrome (MDS)-related changes (AML-MRC) and therapy-related AML (t-AML). Characterized by unfavorable cytogenetics, the prognosis of patients with AML-MRC and t-AML is often dismal, even in patients who undergo allogeneic stem cell transplant. There is a need for further molecular characterization of AML-MRC and t-AML to identify prognostic markers to optimally risk-stratify to better guide treatment decisions in these pts. Objectives: In the current study we sought to: (1) assess MYC protein expression by immunohistochemistry (IHC) performed on bone marrow (BM) specimens of pts with all types of AML, including acute promyelocytic leukemia (APL), and myelodysplastic syndromes (MDS), and (2) explore the prognostic significance of MYC protein expression in AML-MRC and t-AML (2008 WHO criteria). Methods: MYC protein expression was assessed by IHC on BM obtained from pts with AML, APL, and MDS, and from patients without hematologic neoplasms (normal controls). MYC expression was considered positive if 〉 5% blasts in BM showed nuclear reactivity. For cases classified as t-AML and AML-MRC by WHO 2008, MYC expression was correlated with molecular, cytogenetic, and clinical outcome data. X-tile software was used to identify the optimal cutoff point to dichotomize pts by MYC protein expression. Results: We evaluated BM MYC expression in 306 pts during 2006-2013 with newly diagnosed AML (n=246) or APL (n=11), previously treated AML (induction failure or relapse) (n=30), MDS (n=19), AML-MRC (n=68), t-AML (n=10), and normal BM (n=11). The median age was 61 yrs (13-88) with 54% men. Normal BM showed negligible MYC expression, ≤2% positive nuclei. The median MYC expression varied across diseases: newly diagnosed AML 25% (range 0-38%), APL 50% (range 19-75%), previously treated AML 20% (range 0-80), MDS 5% (range 0-30%) (differences between groups, p=0.0001). High MYC expression correlated with high LDH (rs = 0.285, p21% MYC-positive blasts have an inferior OS, DFS, and remission rate than pts with ≤ 21% MYC-positive blasts. Increased MYC protein expression is independent of rearrangement status by FISH. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Background Internal tandem duplication (ITD) mutation of the FMS-like tyrosine kinase-3 (FLT3) receptor gene occurs in about 25% patients with acute myeloid leukemia (AML) and confers a poor prognosis. Several studies have reported that a higher mutant allelic burden is associated with a worse prognosis. Methods Adult patients with FLT3-ITD mutated AML treated at our institution from January 2001 to January 2018, who had quantified FLT3-ITD allele burden, were identified. Patients with acute promyelocytic leukemia and core-binding factor AML were excluded.Patients were assigned into 2 groups; Group 1 included patients who received idarubicin and cytarabine (IA) containing induction and Group 2 included patients who received sorafenib in addition to IA containing regimens at induction. Mutant allelic burden was expressed as the ratio of area under the peak of mutant allele to total FLT3. Relapse free survival (RFS) for patients achieving complete response (CR)/CR with incomplete recovery (CRi) was defined as time from CR/CRi to relapse or death. Overall survival (OS) was defined as time from treatment to death. Patients were censored at last follow up. Time from therapy to allogeneic hematopoietic cell transplant (AlloHCT) was handled as a time-dependent variable. The optimal cutoff of mutant FLT3-ITD allelic burden was defined as the cutoff to divide the whole cohort with the highest statistical significance. Results A total of 183 patients withFLT3-ITD mutated AML were identified including 104 (57%) in Group 1 and 79 (43%) in Group 2. Baseline characteristics are summarized in Table 1. The median age was 52 years (range, 17-64). The median allelic burden of mutant was 33% (range, 0.3% to 88%). This was comparable between the two groups (p=0.6). The CR/CRi rates following induction for Group 1 vs Group 2 were 85% vs 99%, respectively (p=0.004). Overall, 111 (61%) patients received an AlloHCT, at any time during the follow up, more frequently in Group 2 than in Group 1 (67% vs 56%, respectively, p=0.1). The median RFS for Group 1 and 2 were 12 and 45 months, respectively (p=0.02); the median OS was 17 months in Group 1 and has not been reached in Group 2 (p=0.008) (Table 2). The optimal mutant allele burden cutoff for OS and RFS in the entire cohort was 1.55% (p=0.002) confirming the adverse effect of FLT3-ITD even at low level. The cutoff was 6.9% in Group 1, with no optimal cutoff value in Group 2 (Figure 1) confirming the value of sorafenib inFLT3-ITD mutated AML. When censored for AlloHCT; the FLT3-ITD cutoff for OS and RFS was 60% and 60% in the entire group. For Group 1 the cutoff values where 59% and 7.9% for OS and RFS, respectively. For Group 2 the cutoff values were 46% and 46%, respectively (Figure 2). On multivariate analysis, AlloHCT (HR 0.52; 95%CI 0.33-0.82; p=0.005), sorafenib (HR 0.6; 95%CI 0.38-0.93; p=0.02) and white blood cell count (HR 1.005; 95%CI 1.002-1.009) were independent predictors of OS with no impact by cytogenetics, concurrent NPM1, TP53, FLT3-D835 mutations or the FLT3-ITD allelic burden. Conclusion Although a higher FLT3-ITD allele burden is associated with a worse RFS and OS in patients with FLT3-ITD mutated AML treated with IA-based chemotherapy, it is no longer prognostic when sorafenib is added to the therapeutic regimen. Addition of sorafenib to intensive chemotherapy as well as AlloHSCT are associated with a significant improvement in OS on multivariate analysis. Disclosures Kadia: Novartis: Consultancy; BMS: Research Funding; Takeda: Consultancy; Celgene: Research Funding; Celgene: Research Funding; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; BMS: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy. Sasaki:Otsuka Pharmaceutical: Honoraria. Daver:BMS: Research Funding; ImmunoGen: Consultancy; Karyopharm: Consultancy; Sunesis: Research Funding; Novartis: Consultancy; Otsuka: Consultancy; Karyopharm: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Sunesis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Alexion: Consultancy; Kiromic: Research Funding. DiNardo:Medimmune: Honoraria; Bayer: Honoraria; Abbvie: Honoraria; Celgene: Honoraria; Agios: Consultancy; Karyopharm: Honoraria. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Short:Takeda Oncology: Consultancy. Bose:Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corporation: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria.

Description: Background: Single-arm studies have suggested that a 10-day schedule of decitabine (DAC) may result in better outcomes than the standard 5-day schedule in older patients (pts) with acute myeloid leukemia (AML), particularly in pts with TP53 mutations. We therefore designed a randomized phase II study to evaluate the relative safety and efficacy of these two different schedules of DAC in this older population. Methods: Adults ≥60 years of age with newly diagnosed AML were randomized using a Bayesian adaptive design to receive DAC at a dose of 20 mg/m2 IV daily for either 5 or 10 consecutive days as induction. Pts

Description: Introduction: The principle of precision cancer medicine is to customize therapy based on the genomic profiles of the cancer and the host constitution/response to the cancer. Since RNA expression is influence by many genetic mechanisms, RNA profiling may provide broader coverage of genomic changes and might be a better predictor of response to therapy. However, incorporating the many biological changes of the host and the cancer in the decision of selecting therapeutic approach is not practical without using computer-aided algorithms. This is particularly relevant when combination therapy is used. We explored the potential of developing algorithms for the prediction of complete response (CR) to novel combination therapy in patients with acute myeloid leukemia (AML) using targeted RNA expression profiling. Methods: RNA was extracted from the peripheral blood (PB) and bone marrow (BM) samples from patients with AML being treated on two different protocols: FLAG-IDA+venetoclax (F-I-V)( Abou Dalle I et al, ASH 2019; the NCT # is NCT03214562) and ivosidenib+venetoclax (I-V). In the initial study, 22 samples (9 PB and 13 BM) were used as training set. Subsequently 16 PB samples from the F-I-V arm and 4 from the I-V arm were collected and tested blindly as testing set after the development and locking of the algorithm. RNA was sequenced using NGS panel composed on compared of 1408 genes. The RNA sequencing is based on hybrid capture and the number of reads ranged from 5 to 10 million. RNA quantification was performed using Cufflinks. The RNA levels were normalized to ABL1 mRNA levels. Each gene is normalized by the mean and standard deviation of the gene. To develop a model for predicting CR, we used the training set in each arm and first evaluated the performance of each of the 1408 genes using receiver operating characteristic (ROC) curve. Then used the following mathematical methods for developing algorithms for predicting CR: Support Vector machine (SVM), Bayesian modeling with Gaussian Processes (GP), and Naïve Bayesian (NB). Results: In univariate analysis, multiple genes showed very high AUC. In the F-I-V arm, top genes in predicting CR were GLI3, SETBP1, SH3D19, ARHGAP20, ETS1, IKZF2, GNG4 and MAGEE1 with AUC ranged from 0.74 to 0.85. In the I-V arm, the top genes in predicting CR were STL, TNFRSF10D, PTGS2, RET, TFRC, NAV3, WSB1, and GAS1 with AUC varied from 0.91 to 0.96. Using the training samples we developed algorithms for predicting CR by SVM, NB and Bayesian GP. Upon testing these models using leave-one-out (LOO), the three algorithms performed similarly with AUC around 0.97 for the I-V arm and around 0.96 for the F-I-V arm. There was no difference between BM and PB in predicting CR. Therefore, we collected and sequenced only peripheral blood for blind testing. The three algorithms were tested using 16 PB samples from the F-I-V arm and 4 samples from the I-V arm. The SVM and NB algorithms predicted CR correctly in 15 of the 16 samples (94%) while Bayesian GP missed 4 of the 16 samples. As for the I-V arm, the NB predicted CR correctly in the 4 samples, while both SVM and Bayesian GP missed 3 of 4. Conclusions: While the data is limited and further validation is need, algorithms using RNA expression profiling of peripheral blood using targeted RNA NGS may provide an excellent tool for customizing therapeutic approach, especially in the age of combination therapy when number of cases for training can be limited. Furthermore, this study suggests that modeling using Nave Bayesian is reliable approach in developing prediction algorithms. Disclosures Albitar: Genomic Testing Ccoperative: Employment, Equity Ownership. Konopleva:Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Agios: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Astra Zeneca: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding. Loghavi:MDACC: Employment; AlphaSights: Consultancy; GLG Consultants: Consultancy. Takahashi:Symbio Pharmaceuticals: Consultancy. Kantarjian:Daiichi-Sankyo: Research Funding; Ariad: Research Funding; Cyclacel: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding. DiNardo:syros: Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees.

Description: Background: BPDCN is a clinically aggressive myeloid malignancy that has historically demonstrated poor outcomes. Recent patho-biological observations have led to new therapies and improved outcomes, including the first approved therapy in the field with CD123-directed therapy (Pemmaraju et al. NEJM April 2019). BPDCN is recognized for its overexpression of CD123+/IL3Rα in 100% of cases (Frankel Blood 2014); BPDCN is also characterized by its BCL-2 overexpression (Montero Cancer Discovery 2017) and splicing factor and other molecular abnormalities commonly seen in MDS, CMML, and AML (Alayed Am J Hematol 2013). It is well known that patients (pts) with BPDCN can subsequently transform to AML. However, little is known about pts with BPDCN with prior/or concomitant hematologic malignancies (PCHM) and we therefore sought to determine pt characteristics and outcomes for this important subset of pts with BPDCN. Patients: We analyzed all pts treated at our institution (1998-2019). 87 pts (83% male) were identified; n=57 untreated; n=27 prior therapy, with median number therapies = 1 [1-5]. Median age was 65 years [20-86 years]. Bone marrow (BM) was involved in 56 (64%), skin-only in 30 (34%), lymph node-only 1(1%). CD4+ and CD56+ were expressed in all pts tested; additionally, CD123+ and TCL-1+ was found in all pts tested. Cytogenetics were available in 74 pts: diploid (70%), complex (23%), deletion (12p13) (3%), miscellaneous (4%). Median BM blast count was 13% [0-95]. Frontline Therapies: a rapidly changing paradigm: Over time, a variety of treatments have been used in frontline setting: clinical trial/targeted therapy (including tagraxofusp) (n=29); HCVAD-based (including venetoclax) (n=27); other/miscellaneous regimens (n=13); CHOP (n=8); AML-based induction (n=5). hypomethylator-based (including venetoclax) (n=3); bortezomib-based (n=2). In the overall cohort (n=87), the median follow-up time was 15.5 months (mo) [4.3-65.4]. First complete remission (CR1) was achieved in 60%; median CR1 duration: 23.4 mo [1.5-155.6]. Median overall survival (OS) was 20.2 mo [1.0-158.0]. 67% of pts have died, with most common cause of death being sepsis/multi-organ failure. BPDCN with prior or concomitant hematologic malignancy (PCHM): Among the total BPDCN group (n=87), we found n=20 (23%) presented as BPDCN with PCHM. We compared these 20 pts with PCHM vs the remaining 67 pts without, and found no statistically significant differences between the two groups for baseline characteristics of age, sex, number of prior therapies or bone marrow blasts. Among BPDCN with PCHM cohort (n=20), breakdown of hematologic malignancy subtypes: MDS (n=9); CMML (n=5); myelofibrosis (n=3); lymphoid/myeloma (n=1 each: T-ALL, Hodgkin lymphoma, multiple myeloma). While there was no statistically significant difference found between the two groups for CR1 and OS, there was a trend towards significance for shorter CR1 in the BPDCN with PCHM group (p=0.06) (Figure). Molecular Analysis: Among the total cohort, n=50 (57%) pts have been captured for next-generation sequencing (NGS) (n=34 without PCHM; n=16 with PCHM): the most common abnormalities were: TET2 mutation/variant (76%); ASXL1 (20%); RAS (11%). There was no statistically significant difference in terms of mutation patterns between BPDCN with PCHM and those without PCHM. Conclusions: For the first time in our ongoing BPDCN clinic analysis, treatment with clinical trial has now become the most commonly employed therapeutic strategy for pts with BPDCN. In this new era of novel treatments, it is important to note that pts with BPDCN with PCHM are quite commonly encountered, most commonly with prior or concomitant MDS or CMML. Etiologies for this are multifactorial and will be an important area of research for the field, and will include further investigation of shared stem origin of these associated hematologic malignancies, older age of pts with BPDCN, and presence of CHIP, and/or myeloid mutation markers in many pts with BPDCN, including those with skin-only BPDCN. Because this entity of PCHM is so common in the BPDCN field, these pts should continue to be enrolled on all BPDCN clinical trials, and because this group may exhibit unique disease biology with trend towards shorter CR1, we propose the creation for a new category of BPDCN: BPDCN with PCHM. Figure: (a): CR1 of Dx2=0 (no PCHM) vs Dx2=1 (has PCHM); Figure: (b): OS of Dx2=0 (no PCHM) vs Dx2=1 (has PCHM) Figure Disclosures Pemmaraju: mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Jazz Pharma: Research Funding; Cyclacel: Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding; BMS: Research Funding; Astex: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; Pfizer: Honoraria, Research Funding. Khoury:Angle: Research Funding; Kiromic: Research Funding; Stemline Therapeutics: Research Funding. Loghavi:GLG Consultants: Consultancy; AlphaSights: Consultancy; MDACC: Employment. Cortes:Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Jabbour:BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Jain:BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Qazilbash:Autolus: Consultancy; Bioclinical: Consultancy; Genzyme: Other: Speaker; Amgen: Consultancy, Other: Advisory Board. OffLabel Disclosure: Venetoclax is not fda approved for BPDCN, but based on our pre-clinical and clinical work , we have found activity in BPDCN

Description: Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.