Citations

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).

AbstractDisease OverviewChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (~15% over 3–5 years).DiagnosisDiagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109/L; monocytes ≥10%), usually with accompanying bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~30% of patients, while >90% have somatic gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and the oncogenic RAS pathway (~30%) are frequent, while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact overall survival.Risk‐StratificationMolecularly integrated prognostic models include the Groupe Français des Myélodysplasies, Mayo Molecular Model (MMM), and the CMML specific prognostic model. Risk factors incorporated into the MMM include presence of truncating ASXL1 mutations, absolute monocyte count >10 × 109/L, hemoglobin <10 g/dL, platelet count <100 × 109/L, and the presence of circulating immature myeloid cells. The MMM stratifies CMML patients into four groups: high (≥3 risk factors), intermediate‐2 (2 risk factors), intermediate‐1 (1 risk factor), and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively.Risk‐adapted therapyHypomethylating agents such as 5‐azacitidine and decitabine are commonly used, with overall response rates of ~40%–50% and complete remission rates of ~7%–17%; with no impact on mutational allele burdens. Allogeneic stem cell transplant is the only potentially curative option but is associated with significant morbidity and mortality.

AbstractErdheim–Chester disease (ECD) is a histiocytic neoplasm that predominantly harbors mitogen‐activated protein kinase (MAPK) pathway variants. MAPK inhibitors typically are effective treatments, but mutations outside the MAPK pathway, such as CSF1R variants, may cause refractory ECD. We describe a patient with a novel somatic mutation in CSF1R (CSF1RR549_E554delinsQ) that resulted in refractory ECD affecting the central nervous system. Cell model studies, RNA sequencing analysis, and in silico protein modeling suggested that she had a gain‐of‐function mutation occurring in a region critical for autoinhibition. The patient was treated with pexidartinib, a CSF1R inhibitor, and has had a complete clinical and metabolic response lasting more than 1.5 years to date. To our knowledge, this is the first report to describe successful treatment of a patient with ECD by using an agent that specifically targets CSF1R. This case also highlights the critical role of individualized molecular profiling to identify novel therapeutic targets in ECD.

Abstract Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity toward transformation to acute myeloid leukemia. Type I JAK inhibitors (JAKi) are the only approved therapy and can provide symptom control and reduction of splenomegaly in eligible patients. However, JAKi do not significantly impact disease progression, and many patients are not eligible due to coexisting cytopenias. Patients with MF who have relapsed and/or are refractory (R/R) to JAKi have poor survival. Therefore, novel agents, moving beyond JAKi-based treatments, are urgently needed. CD123, also known as the interleukin-3 receptor alpha chain, is expressed on maturing myeloid cells and progenitors in MF, making it an attractive therapeutic target. Tagraxofusp (TAG, SL-401) is a CD123-targeted therapy which is FDA and EMA approved for the treatment of blastic plasmacytoid dendritic cell neoplasm. A phase 1/2 study of TAG monotherapy in patients with MF who were R/R to approved JAKi (NCT02268253) was initiated. Herein, we present updated safety and efficacy data. Methods: A 2-stage multicenter, phase 1/2 study enrolled patients with R/R MF. Patients in Stage 1 (dose escalation) received 7, 9, or 12 mcg/kg/day TAG intravenously on days 1-3, every 21 days (cycles 1-4), every 28 days (cycles 5-7), and every 42 days (for cycles 8 and beyond); 12 mcg/kg/day was given every 21 days (cycles 1-4), and every 28 days (cycles 5+) in Stage 2. Enrollment in Stage 2 (expansion) was restricted to patients who met the DIPSS-plus intermediate-2 or high-risk disease criteria, those who were R/R or intolerant to JAKi therapy, and those who were not eligible for immediate stem cell transplantation. Responses were assessed on the basis of the International Working Group MPN Research and Treatment/European LeukemiaNet (IWG-MRT/ELN) criteria (Tefferi et al. Blood 2013;122:1395-1398). Results: As of July 1, 2021, 39 patients with MF were treated. Median age was 70 years (range 54-87) and 46% were female. The baseline characteristics comprised thrombocytopenia (&lt;100 × 10 9/L; 64%), including 36% with platelets &lt;50 × 10 9/L; monocytosis (≥1.0 × 10 9/L; 21%), and splenomegaly (74%). Genomic assessments at study entry demonstrated molecular mutations in JAK2, CALR, MPL, and ASXL1 in 62%, 8%, 5%, and 23%, respectively; cytogenetic abnormalities were observed in 10 patients (4 patients: 20q-, 3 patients: 7/7q-, 2 patients: -5/5q-, 2 patients: 12p-, and 1 patient: 17q). Treatment-related adverse events are depicted in Table 1. The most common treatment-related adverse events (incidence ≥10%) included hypoalbuminemia (21%), headache, pyrexia, thrombocytopenia, and elevated alanine aminotransferase (15% each). Capillary leak syndrome (CLS) was reported in 3 patients, including 1 patient with grade 4; there was no grade 5 CLS. Stable disease was achieved in 21 patients (60%). In total, 12/24 patients (50%) with baseline splenomegaly achieved a spleen response (Table 2), 3/4 (75%) with concomitant monocytosis, and 13/24 (54%) with concomitant thrombocytopenia. Spleen responses were confirmed objectively by imaging, with the spleen volume reduction (SVR) thresholds for response set at 35%. Updated information on SVR will be reported at the time of presentation. Total Symptom Score (TSS) was reduced in 20/39 patients (51%), and 10/39 (26%) had reductions from baseline in both TSS and spleen size. Median overall survival was 29.2 months (95% CI 12.0-49.5; range 1-51 months). Conclusions: TAG monotherapy demonstrated clinical efficacy and a predictable and manageable safety profile in patients with MF characterized as high-risk, including those who are refractory to JAKi and those with associated monocytosis, thrombocytopenia, advanced disease, and high-risk genetic features. This phase 1/2 study confirms the safety and clinical efficacy of TAG administered as a monotherapy in a cohort of poor-prognosis patients with MF. Given the genomic and epigenomic complexity of MF, with the clonal heterogeneity and additional subclones, TAG is planned to be tested as part of a combination strategy in high-risk patients with MF who are either R/R, intolerant to, or who have had a prior suboptimal response to JAKi. Figure 1 Figure 1. Disclosures Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Wang: Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Gupta: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Lee: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schiller: FujiFilm: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Actinium Pharmaceuticals, Inc: Research Funding; Samus: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Geron: Research Funding; Bluebird Bio: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Onconova: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Regimmune: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; Forma: Research Funding; Delta-Fly: Research Funding; Sangamo: Research Funding; Elevate: Research Funding; Biomed Valley Discoveries: Research Funding; Bio: Research Funding; Actuate: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Leukemia & Lymphoma Society: Research Funding; Ono-UK: Consultancy, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Arog: Research Funding; Trovagene: Research Funding; Tolero: Research Funding; Takeda: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Pharma: Consultancy; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Taparia: Novartis: Consultancy. Verstovsek: Protagonist Therapeutics: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; CTI BioPharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Ital Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Khoury: Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Brooks: Stemline Therapeutics: Current Employment. Mughal: Stemline: Current Employment, Current holder of stock options in a privately-held company; Oxford University Press, Informa: Other: financial benefit and/or patents . Pemmaraju: LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; DAVA Oncology: Consultancy; Aptitude Health: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; CareDx, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Sager Strong Foundation: Other; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy.

Abstract Background: Venetoclax, a small-molecule inhibitor of B cell leukemia/lymphoma-2, in combination with hypomethylating agents (HMA) has shown improved efficacy and survival benefit compared to HMA alone (DiNardo et al, 2020) in elderly/unfit patients with acute myeloid leukemia (AML). Since FDA-approval of this regimen for elderly/unfit AML patients, it is frequently utilized both in the upfront and relapsed/refractory setting. Cardiac events with venetoclax are not well described. In the VIALE-E trial, which included patients ineligible for standard induction chemotherapy due to congestive heart failure or stable angina, 15% of patients receiving azacitidine plus venetoclax experienced atrial fibrillation as a serious adverse event, vs. 1% in the azacitidine plus placebo group (DiNardo et al, 2020). Our objective was to provide an estimate of the prevalence of and a description of all cardiac events that occurred in AML patients undergoing treatment with venetoclax + HMA. Methods: 170 consecutive patients with AML who received venetoclax +HMA (azacitidine or decitabine) outside the context of a clinical trial between 1/2017-11/2020 at the Mayo Clinic were included. Patients received venetoclax + HMA either as upfront treatment or for relapsed/refractory disease. Patients with relapse following allogeneic stem cell transplant were excluded. We evaluated all cardiac events that occurred while treatment with venetoclax + HMA was ongoing. Baseline patient and treatment characteristics were compared using the Mann-Whitney U-test and the Fisher's exact test. All statistics were computed using EZR (Version 1.53). Results: 1. Patient characteristics A total of 170 patients who received venetoclax + HMA (median age 69 years [range 17-91], 63% males) were included. ELN risk category was either adverse risk (48%, 82/170) or intermediate risk (48%, 82/170) in the majority of patients. 64% (109/170) of patients received venetoclax + HMA as upfront treatment. Characteristics including age, ELN cytogenetic risk, cardiovascular risk factors, and upfront vs relapsed therapy were similar among patients with or without cardiac events. The only exception was a higher incidence of CEBPA mutation amongst those with cardiac events (12% vs 2%, p=0.03). The majority (83%, 141/170) of patients underwent an echocardiogram prior to initiation of therapy. 2. Cardiac events Of 170 patients treated with venetoclax + HMA during the study period, 34 (20%) patients experienced a total of 48 cardiac events. Of patients experiencing cardiac events, 32% (11/34) had no pre-existing cardiac disease and 12% (4/34) had no cardiovascular risk factors (Table 1). The majority of events occurred early in treatment course: 41% during cycle 1, 26% during cycle 2 and 15% during cycle 3 (Table 1). The most frequently occurring cardiac event (21%, 10/48 events) was a decrease in left ventricular ejection fraction on echocardiography, which was associated with symptoms in all ten patients. Second most frequent was atrial fibrillation with rapid ventricular response at 17% (8/48 events), followed by troponin elevation without electrocardiogram changes at 15% (7/46 events). Of patients with troponin elevation, 57% (4/7 events) occurred in the setting of another inciting factor such as severe anemia, while 43% represented a troponin elevation without explanation (Table 1). Other cardiac events included heart failure with preserved ejection fraction (n=4), other symptomatic arrhythmia (n=4), and symptomatic pericardial effusion or pericarditis (n=3). In addition, 2 of 34 (6%) patients experienced fatal cardiopulmonary arrest. The majority (88%) of cardiac events required either inpatient admission (62%, 21/34 patients) or intensive care unit (ICU) care (26%, 9/34 patients). 77% of patients required new cardiac medications or procedural intervention (n=4). In 27% of cases (9/34 patients), the cardiac event directly contributed to death (Table 1). Conclusions: Cardiac complications were observed in one-fifth (20%) of AML patients treated with venetoclax + HMA, despite the absence of preexisting cardiac disease in a third of cases; moreover 27% of events were fatal. Further comparative studies are required to identify salient clinical features predictive of cardiac complications in these patients. Figure 1 Figure 1. Disclosures Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Litzow: Astellas: Research Funding; Amgen: Research Funding; Omeros: Other: Advisory Board; AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee. Patnaik: Kura Oncology: Research Funding; StemLine: Research Funding.

Abstract Background: SARS-Cov-2 infections are associated with increased mortality and morbidity, largely due to inflammatory cascades and cytokine release syndrome (CRS). Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence and subsequent expansion of somatic, leukemia-associated driver mutations in apparently healthy individuals with normal blood counts. CHIP has been associated with increased inflammation, with cytokines such as IL1-b, IL6 and TNF-a being elevated at baseline in affected individuals. We hypothesized that the presence of CHIP in patients with COVID-19 would result in excessive inflammation-related mortality and morbidity. Methods: We used the Mayo Clinic COVID-19 database to identify patients with COVID-19 on whom peripheral blood mononuclear cells (PBMC) were available for research use (IRB approved). We carried out target-capture next generation sequencing for 220 CH related genes, by previously described methods (1000 x coverage, variant allele fraction/VAF detection limit &gt;0.5%; Kusne Y et al AJH 2021). CHIP was defined by the presence of a CH mutation with a VAF&gt;1% in an individual with normal baseline blood counts. Demographics, blood counts, and inflammatory markers (CRP and cytokine levels- ELISA assay) at COVID-19 diagnosis and during follow-up (as clinically indicated) were collected. COVID-19 disease severity was classified based on the presence and severity of CRS, graded using the Penn Grading Scale (Porter et. al., 2018), and the WHO ordinal scale (WHO Blueprint, 2020). We used Fisher's exact test and the Wilcoxon rank sum test to compare categorical and continuous variables. Survival analysis was performed using the Kaplan-Meier method. We accounted for differences in age and sex using multivariable-adjusted proportional hazards regression models. Results: Seventy-two CHIP mutations were detected in 56 (25%) of the 227 patients with COVID-19 that had PBMC available; median age 69 years (range; 42-99 years), 61% male. Fifteen (26%) patients had 2 CHIP mutations, while 1 patient had 3 CHIP mutations. Common mutations encountered included DNMT3A (32%) , TET2 (19%) , SF3B1 (8%) , ASXL1 (6%) , MPL (5%) , and TP53 (5%; Figure 1A). COVID-19 patients with CHIP were older in age (median 69 vs 57 years; p&lt;0.0001) and had higher baseline MCP-1 (p=0.04) levels. However, there were no differences in sex, comorbidities, blood counts, IL1-b, IL6 and TNF-a levels between the two groups. The median follow-up for the entire cohort was 9 months. The relative change from baseline in blood counts and inflammatory markers (CRP and cytokines) during follow-up was similar in CHIP and non-CHIP patients, with the exception that COVID-19-onset neutropenia was more common in CHIP patients (8% vs 1%; p=0.017) compared to those without CHIP. At last follow up neutropenia had resolved in all patients. Both groups had comparable number of patients with CRS (61% CHIP vs 53% non-CHIP patients, p=0.354, Figure 1B), however, CHIP patients had more severe CRS (median Penn Grade 3 versus 2 in non-CHIP, p=0.018, Figure 1C). Based on the WHO ordinal scale, CHIP patients were more likely to experience hospitalization with severe disease and death (61% versus 45% in non-CHIP, p = 0.049). Moreover, COVID-19 CHIP patients experienced worse overall survival in comparison to patients without CHIP (median 13.1 months vs not reached, p&lt;0.001, Figure 1D). This association remained consistent after adjusting for age and sex at the time of COVID-19 diagnosis (HR 3.15, 95% 1.32 - 7.55, p = 0.010). At last follow-up, 22 deaths were documented: 13 (23%) in patients with CHIP and 9 (5%) in the non-CHIP group (p=0.02), with the primary cause for mortality being hypoxic respiratory failure (62% in CHIP vs 44% non-CHIP, p=0.04). Conclusions: In this study, we observe an age-independent impact of CHIP on COVID-19 associated inflammatory morbidity (CRS) and mortality (hypoxemic respiratory failure). We are currently carrying out detailed single cell (ssDNA, RNA and ATAC-seq) and proteomic studies (O-link PEA assays) to better elucidate this pathophysiology. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; StemLine: Research Funding.

Abstract Background: Clonal cytopenia of undetermined significance (CCUS) is defined as persistent unexplained cytopenia with evidence of clonality [myeloid-associated somatic mutations (MTs) or cytogenetic [CG] abnormalities] but without definitive evidence of myeloid neoplasms (MN). The outcomes in CCUS patients (pts) are not well understood. Methods: The CCUS International Study database includes pts from 17 institutions who meet the criteria of CCUS and do not have other causes of cytopenia. Pts with MDS defining CG abnormalities were excluded. We collected baseline clinical data, laboratory parameters, CGs, molecular genetics, treatment, and disease course. Diverse gene panels from different institutions were collated to include a total of 70 myeloid-related somatic genes (30 genes in common). 2018 IWG MDS response criteria were used to determine response rate (RR). Disease progression (DP) is defined by progression to MN. The relationship between independent variables and DP and death was assessed using Cox proportional hazards models. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. All statistical analysis was performed using SAS. Results: A total of 258 pts were captured by July 2021. The median age was 71 (IQR 63-77) years, and 66% were male. Among 73 (28%) pts with known malignancy history, 27 (37%) pts received previous chemo- or radiation therapy. 27 (10%) pts had non-malignant hematology comorbidities. 91 (35%) had cardiovascular disease, and 33 (13%) had inflammatory disease. (Table 1) The red blood cell and platelet transfusion-dependent rates were 7.3% and 2.3%, respectively. The median number of MTs was 2 (IQR 1-3), with 221 (86%) pts had ≥1 MT, of which 116 (53%) had ≥ 2 MTs. The most common 5 MTs were TET2 (n=78, 30%), SRSF2 (n=50, 19%), DNMT3A (n=47, 18%), ASXL1 (n=40, 16%), and U2AF1 (n=22, 9%) (Figure 1). The median VAF (mVAF) was 28% (IQR: 9.2%, 43%) with VAF &lt; 10% in 47 (18%) and VAF ≥40% in 78 (30.2%) of the MTs. mVAF of the all genes are shown in Figure 2. Among pts with CG abnormalities (n=62, 24%), trisomy 8 and -Y are the most common karyotypes (n=15 for each, 24%) (Table 2). Eighty one (31%) patients received various treatments for CCUS with modest RR, including growth factors (n=47, 18.2%, RR: 25.5%), supportive care (n=23, 9%, RR: 26%), immunoglobulin/immunosuppressive therapy (n=15, 6%, RR: 40%), and DNMTi (n=8, 3%, RR=13%). The median length of follow-up was 15.6 (IQR 6.9-30.6) months. 24 pts progressed to MN, 14 (58.3%) of which were MDS, 8 (33.3%) CMML, and 2 (8.3%) AML. The 2-year PFS was 86.1% (95% CI: 80-93%) with a median PFS of 16.3 (IQR: 3.7, 21) months. In the multivariable model, positive MT of KRAS (HR: 8.4, 95% CI: 1.9-36.9, p=0.005) and CBL (HR: 16.5, 95% CI: 3.7-73.8, p=0.003) were significantly associated with DP. In the functional pathway analysis, having at least 1 splicing factor MT was significantly associated with DP (HR: 2.6, 95% CI:1.2-5.9, p=0.02). TP53 was not significantly associated with DP (HR: 1.2, 95% CI: 0.2-8.7, p=0.88). Having &gt;1 MT (HR: 3.57, 95% CI: 1.19-10.7, p=0.02) compared to a single MT was significantly associated with DP (Figure 3). Over the follow-up period, 35 pts died. The 2-year OS was 81% (95% CI: 74.9-87.9%). In the multivariable model, MT of KRAS (HR: 6.1, 95% CI: 1.8-20, p=0.003), CBL (HR: 7.3, 95% CI: 1.7-31, p=0.007), and FLT3 (HR: 19.9, 95% CI: 2.5-155, p=0.004) were significantly associated with inferior survival. In the functional pathway analysis, MTs in activated signaling pathway were significantly associated with death (HR: 4.1, 95% CI: 1.8-9, p&lt;0.001). None of the pts with TP53 MT died. Having &gt;1 MT was not statistically significantly associated with higher risk of death (HR: 1.5, 95% CI: 0.7-3.0, p=0.28) (Figure 4). After adjustment for co-MT status and comorbidities, baseline Hb&lt;10 g/dL (HR: 3.7, 95% CI: 1.8-7.9, p&lt;0.001) was significantly associated with greater mortality. Conclusion: This large retrospective study summarizes the CCUS pts' characteristics, with different MT patterns and VAF. We confirmed the impact of having &gt;1 MT on DP, but not OS. Genes involved in activated signaling had a significant impact on both DP and OS. TP53 MT was not associated with worse outcome. Findings may be due to limited cases in the particular genes and different gene panels from multiple institutions. A longer follow-up is planned to further describe the predictors for outcome in this ongoing study. Figure 1 Figure 1. Disclosures Komrokji: Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy. Zeidan: BioCryst: Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Geron: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Janssen: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; AstraZeneca: Consultancy; Agios: Consultancy; BeyondSpring: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Astex: Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; Pfizer: Other: Travel support, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; Jasper: Consultancy; Astellas: Consultancy; ADC Therapeutics: Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Madanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda Oncology: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Novartis: Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Consultancy, Honoraria. Lai: Astellas: Speakers Bureau; Jazz Pharma: 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; Genentech: 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; Jazz Pharma: Speakers Bureau; Macrogenics: 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. Foran: trillium: Research Funding; actinium: Research Funding; kura: Research Funding; boehringer ingelheim: Research Funding; takeda: Research Funding; abbvie: Research Funding; aptose: Research Funding; pfizer: Honoraria; novartis: Honoraria; servier: Honoraria; bms: Honoraria; revolution medicine: Honoraria; OncLive: Honoraria; gamida: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; taiho: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Desai: Astex: Research Funding; Janssen R&D: Research Funding; Kura Oncology: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy. Ades: ABBVIE: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; TAKEDA: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Brunner: Novartis, Celgene, Takeda, AstraZeneca: Research Funding; Celgene, Forty Seven Inc, Jazz: Other: Advisory Board. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Prebet: BMS: Research Funding; BMS, Curios, Daichi: Consultancy. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Savona: Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: 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; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.

Abstract Introduction: The interleukin-3 receptor alpha chain (CD123) is a cell-surface target aberrantly expressed on various myeloid neoplasms including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelofibrosis (MF). Tagraxofusp (TAG, SL-401), a first-in-class CD123-targeted therapy, is the only treatment approved by the FDA and EMA for patients (pts) with BPDCN. It has also been investigated in phase 1/2 clinical trials for AML (including pts with minimal residual disease [MRD]), CMML, and MF. We report the aggregated safety data of TAG monotherapy from trials in BPDCN, AML, CMML, and MF. Methods: An integrated safety analysis was performed for pts who received TAG monotherapy in three phase 1/2, multicenter clinical studies: Study 0114 (NCT02113982; BPDCN/AML), Study 0214 (NCT02270463; AML with/without MRD), and Study 0314 (NCT02268253; CMML/MF; Table 1). Pts received the recommended phase 2 dose of 12 mcg/kg/day (d) IV on d1-3 (MF and CMML) or d1-5 (BPDCN and AML) and were analyzed for incidence and timing of treatment-related adverse events (TRAEs), AEs of interest, and discontinuations. Safety data for TAG monotherapy, reported as individual case study reports (ICSRs) postapproval (US) and from an early access program (EAP; EU) are also presented. Results: In total, 201 pts receiving TAG (12 mcg/kg/d) in a clinical trial setting were included: BPDCN, n=86; AML, n=36; AML with/without MRD, n=10; CMML, n=33; MF, n=36. As of Jul 2021, 11 (6%) pts discontinued TAG due to any-grade (Gr) TRAE. Most common TRAEs (any-Gr) are shown in Table 2 and included hypoalbuminemia (41%), increased alanine aminotransferase (ALT; 40%), increased aspartate aminotransferase (AST; 39%), and thrombocytopenia (26%). The most common Gr ≥3 TRAEs were thrombocytopenia (n=41; 20%), increased AST (n=40; 20%), and increased ALT (n=35; 17%). Tumor lysis syndrome occurred in 5% of pts and 1.5% had infusion-related reactions. Any-Gr and Gr ≥3 hematologic TRAEs are presented in Table 3. Most common was thrombocytopenia. All TRAEs were transient in nature; prolonged bone marrow suppression was not observed. Overall, 23% (47/201) of pts experienced ≥1 treatment-related serious AE. Onset of most TRAEs, irrespective of Gr, commonly occurred in cycle 1 and resolved by cycle 2. Although the number of pts in cycles ≥2 was lower than in cycle 1, the incidence rates of common TRAEs also substantially decreased in subsequent cycles. Capillary leak syndrome (CLS) occurred in 17% of the overall 201 pts. The majority of all CLS events were nonsevere, Gr ≤2 (n=22; 63%); also reported were Gr 3, n=10 (29%); Gr 4, n=3 (9%), and 2 pts experienced a Gr 5 event. Onset of CLS was usually within the first week of cycle 1 (median time to onset [range], d: 5.5 [1-51]) and resolved quickly (median time to resolution [range], d: 5.0 [2-69]); no pts experienced the first onset after cycle 2. Of the 15 pts who resumed treatment after an initial CLS event, only 1 pt experienced a recurrence. The most common AEs reported as ICSRs postapproval and from an EAP (December 2018 to June 2021) were CLS, blood albumin decreased, thrombocytopenia, pyrexia, and hepatic enzyme increased. No new safety signals that would alter the safety profile were observed. Conclusions: This integrated analysis represents the largest collection of safety data (N=201) following treatment with TAG monotherapy. TAG has an established and manageable safety profile, with the vast majority of AEs reported as transient and decreasing in frequency/severity with increasing cycles. CLS was reported in 17% of pts; onset was usually within cycle 1, resolved quickly (median time to resolution: 5.0 d) by early intervention measures including holding treatment, and no pts experienced first onset after cycle 2. Risk-minimization guidelines for CLS were developed and implemented during clinical trials and incorporated into prescribing information. No myelosuppression or cumulative toxicity was observed over multiple treatment cycles. The safety profile observed postapproval and in the EAP was consistent with the clinical trial data reported, reflecting successful adoption of risk-management strategies in real-world practice. These data confirm the favorable benefit-risk profile of TAG monotherapy has been maintained in the 3 years following US approval. Figure 1 Figure 1. Disclosures Pemmaraju: ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Blueprint Medicines: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Pacylex Pharmaceuticals: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Aptitude Health: Consultancy; Celgene Corporation: Consultancy; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Samus: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; DAVA Oncology: Consultancy; Plexxicon: Other, Research Funding; Roche Diagnostics: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ImmunoGen, Inc: Consultancy. Kantarjian: NOVA Research: Honoraria; Aptitude Health: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Jazz: Research Funding; Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang: Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Takeda: Consultancy, Honoraria, Other: Advisory board; Astellas: 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; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Lane: N-of-One: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; AbbVie: Research Funding. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Rizzieri: Celltron/Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: presentation to FDA for biosimilar review ; AROG: Other; Amgen: Other: personal fee; Bayer: Consultancy, Honoraria; Kite: Other: personal fee; Mustang: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Other: personal fee; Gilead: Other: personal fee; Jazz: Other: personal fee; Pharmacyclics: Other. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Gupta: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Lee: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schiller: Sangamo: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; FujiFilm: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Celator: Research Funding; Actuate: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Trovagene: Research Funding; Deciphera: Research Funding; Gamida Cell Ltd.: Research Funding; Forma: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding; Takeda: Research Funding; Geron: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Constellation Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Tolero: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Samus: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Elevate: Research Funding; Delta-Fly: Research Funding; Genentech-Roche: Research Funding; Ariad: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Foran: trillium: Research Funding; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; OncLive: Honoraria; servier: Honoraria; gamida: Honoraria; takeda: Research Funding; boehringer ingelheim: Research Funding; abbvie: Research Funding; certara: Honoraria; bms: Honoraria; pfizer: Honoraria; sanofi aventis: Honoraria; revolution medicine: Honoraria; taiho: Honoraria; syros: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Walter: Macrogenics: Consultancy, Research Funding; Jazz: Research Funding; Pfizer: Consultancy, Research Funding; Selvita: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Sieminski: Stemline Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Konopleva: Calithera: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; KisoJi: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Cellectis: Other: grant support; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding.