Patnaik, Mrinal M.

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 >0.5%; Kusne Y et al AJH 2021). CHIP was defined by the presence of a CH mutation with a VAF>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<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<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 < 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 >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<0.001). None of the pts with TP53 MT died. Having >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<10 g/dL (HR: 3.7, 95% CI: 1.8-7.9, p<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 >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.

Abstract Introduction: Imetelstat is a first-in-class telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase (hTERT) expression, characteristics observed in MDS patients (pts) across all disease stages. IMerge (MDS3001, NCT02598661) is a Phase 2/3 global study of imetelstat for red blood cell (RBC) transfusion dependent (TD) pts with non-del 5q LR-MDS ESA-R/R, who have limited treatment options. The results from the Phase 2 part indicated that imetelstat achieved durable transfusion independence (TI) with a manageable safety profile. Among 38 pts with median follow-up of 24 months, ≥8-week (w), ≥24-w, ≥1-year (y) TI rates were 42%, 32% and 29%, respectively (Steensma JCO 2020, Platzbecker ASH 2020). Aims: To assess the correlation between imetelstat's on-target activity with clinical benefits and safety data as of 10-May 2021 in the Phase 2 part of IMerge. Methods: Peripheral blood samples pre and after 1 and 2 cycles of imetelstat administration were collected to analyze hTERT level by Taqman RT-PCR assay. ≥50% hTERT reduction by imetelstat was considered optimal pharmacodynamic (PD) effect. Correlation analyses between the optimal PD and efficacy, including TI rates ≥8-w, ≥24-w, and ≥1-y, duration of the longest TI, and OS, as well as hematological and liver function lab parameters were performed. Results: hTERT analyses on 35/38 pts with matched pre- and post-1 to 2 cycles of treatment samples available demonstrated on-target activity/optimal PD effect of imetelstat in 54.3% (19/35) of pts. Pts who achieved optimal PD had significantly higher rates of TI compared to pts who did not achieve optimal PD: 63.2% (12/19) vs 25% (4/16) had ≥8-w TI (p=0.0411); 57.9% (11/19) vs 12.5% (2/16) had ≥24-w TI (p=0.0125); and 52.6% (10/19) vs 6.3% (1/16) had ≥1-y TI (p=0.0125) (Fig A). Pts who achieved optimal PD effect had a greater reduction in transfusions (both absolute change in transfusion units and % of change in transfusion burden) in the best 8-week interval compared to pts who did not. In addition, pts who achieved optimal PD had a significantly longer median TI duration (68.4 w, 95% CI 4.9, 92.4) compared to those who did not (5.5 w, 95% CI 2.3, 6.6) with a hazard ratio of 0.364 (95% CI 0.167, 0.794, log-rank p value=0.0087, Fig B). Furthermore, median OS was 57.0 months (95% CI 34.6, -) in pts who achieved optimal PD vs 40.7 months (95% CI 26.9, -) in pts who did not, and the 4-year OS rate was 58.4% vs 31.0%, respectively, although not statistically significant. Pts who achieved optimal PD also had lower rates of Grade 3+neutropenia (52.6%), thrombocytopenia (57.9%), or liver function elevations (5.3%) compared to pts who did not achieve optimal PD (68.8%, 68.8% and 18.8%, respectively), although the differences were not statistically significant. Conclusion: Optimal PD effect of imetelstat treatment was demonstrated by ≥50% hTERT reduction. A significant correlation was observed between optimal PD effect of imetelstat and durable TI and improved 4-year OS rate, effectively linking imetelstat activity to clinical efficacy. Additionally, pts who achieved an optimal PD effect by imetelstat treatment did not have higher rates of cytopenias or liver enzyme elevations compared to pts without optimal PD effect. Enrollment is ongoing for the Phase 3 part of IMerge, a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo. Figure 1 Figure 1. Disclosures Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux: JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Raza: Celgene Inc: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Kura Oncology: Research Funding; Janssen R&D: Research Funding; Syros Pharmaceuticals: Research Funding; Onconova Therapeutics: Research Funding, Speakers Bureau. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria. Font: CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses; GILEAD: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Abbvie: Other: Travel, accomodations, expenses. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, 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. Sherman: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Platzbecker: Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Celgene/BMS: Honoraria. OffLabel Disclosure: Imetelstat, a first-in-class telomerase inhibitor, is under clinical development but not approved for treatment of MDS

Abstract Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence and subsequent expansion of leukemia-associated driver mutations (MT). These MT predominantly involve epigenetic regulators such as DNMT3A, ASXL1, and TET2 (DAT, 75%). CHIP is a disease of aging and is associated with increased all-cause mortality. Clonal Hematopoiesis (CH), when present in the context of unexplained cytopenias and MT variant allele fractions (VAF) >20%, is termed as clonal cytopenias of undetermined significance (CCUS). Chronic myelomonocytic leukemia (CMML) is a hematological malignancy characterized by TET2, ASXL1, and SRSF2MT as well as sustained monocytosis. It usually arises in the setting of existing CH and clonal monocytosis. Here, we assessed the clonal compositions involving DAT genes in patients (pts) with CHIP, CCUS, and CMML. Methods: We included 1008 pts: 54 (5%) with CHIP, 334 (33%) with CCUS, and 620 (62%) with CMML. Demographics, laboratory parameters, and mutational spectrum at diagnosis were collected. We characterized and compared DAT MT in all three cohorts and assessed correlations with clinical parameters. MT locus and type along with protein sequences were analyzed using ProteinPaint. All statistical analyses were performed using R. Results: Of the 1008 pts, 427 (42%) had DAT MT; 36 had CHIP (67%); 96 had CCUS (29%), and 296 had CMML (48%). The median age was 71 years (IQR 65-76), and 68% were male. CMML pts had higher white blood cell counts, absolute neutrophil counts, absolute monocyte counts, and lower hemoglobin and platelet counts in comparison to CCUS and CHIP pts. The distribution of age and sex were similar among the three groups. After a median follow-up of 11 months (IQR 9.5-12.8), there were no myeloid progressions in the CHIP group and 17 (18%) in the CCUS group (8 of which developed CMML, Table 1). There were 738 protein-altering or splice-site DATMT in 495 unique MT hotspots. Pts with TET2MT were older (71 years, compared to DNMT3AMT: 69 years and ASXL1MT: 69 years , p<0.022). ASXL1MT were more common in males (75%, compared to DNMT3AMT: 52% and TET2MT: 66%, p=0.005). The mean VAF (mVAF) were 15.5% for DNMT3AMT, 35% for ASXL1MT and 39.2% TET2MT, respectively (p<0.001). We then compared DATMT characteristics in CHIP, CCUS, and CMML groups: DNMT3AMT were most common in CHIP, followed by CCUS, and were very rare in CMML (35% vs. 15% vs. 3%, p<0.001), with mVAF of DNMT3AMT increasing across this spectrum (CHIP: 6.5% vs. CCUS: 17.1% vs. CMML: 43.4%, p<0.0001). While DNMT3A missense MTs were most common (n=62, 67.4%), the AML-associated R882 hotspot MT was seen in 26 (28%) pts (CHIP: n=3, 5%, CCUS: n=10, 16%, and CMML n=13, 21%, Figure 1a). None of the DNMT3AMT CHIP and CCUS pts progressed to CMML.ASXL1MT were most frequently seen in CMML (n=178, 28.6%), followed by CHIP (n=4, 7.4%), and CCUS (n=17, 5%, p<0.001). The mVAF of ASXL1MT was significantly lower in CHIP, followed by CCUS, and CMML (11% vs. 34% vs. 36%, p<0.0001). Truncating ASXL1 MTs were most common (n=205, 53%). Mutational hotspots included G646W (n=81, CCUS: n=6, 3%, CMML: n=75, 37%) and E635 (n=27, CHIP: n=1, 0.5%, CCUS: n=1, 0.5%, CMML: n=27, 13%, Figure 1b). Four ASXL1MT CCUS pts transformed to CMML (R965, E635, G646W, Q910*, and Q925*); of which 2 co-mutated with TET2MT, one with SRSF2MT, and one with an additional ASXL1MT.TET2MT were frequently encountered in CMML, followed by CCUS and CHIP pts (CMML: n=205, 33% vs. CCUS: n=88, 26.3% vs. CHIP: n=15, 27.8%, p=0.02). The mVAF of TET2MT progressively increased across the 3 groups (CHIP: 14.1%, CCUS: 31.9%, CMML: 45.5%, p<0.001). TET2MT occurred across the span of the gene, with no clear hotspots identified, with nonsense MT being most frequent (n=150, 37.3%, Figure 1c). Among the nonsense and frameshift TET2MT (n=209), 131 (63%) involved the N terminal region, and 78 (37%) involved the catalytic domain. Among 8 CCUS pts that transformed to CMML, 6 had TET2MT, including 4 with spliceosome co-MT. Conclusion: While CMML, a disease of aging, arises in the background of CH, the most common CH MT, DNMT3AMT, plays a minor role in this process, and in fact, DNMT3AMT tend to occur at younger ages. While DNMT3A MT and ASXL1MT are preferentially observed in hotspots, TET2MT span the entire gene. Clonal compositions largely involving truncating TET2MT and frameshift ASXL1MT, in conjunction with splicing MT, shape the CMML genotype. Figure 1 Figure 1. Disclosures Komrokji: Geron: Honoraria; Novartis: Honoraria; Agios: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria. Zeidan: Genentech: Consultancy; BeyondSpring: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Amgen: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Astex: Research Funding; Epizyme: Consultancy; Geron: Other: Clinical Trial Committees; Boehringer Ingelheim: Consultancy, Research Funding; AstraZeneca: Consultancy; Acceleron: Consultancy, Research Funding; Astellas: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Agios: Consultancy; Aprea: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; ADC Therapeutics: Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Ionis: Consultancy; Jasper: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; BioCryst: Other: Clinical Trial Committees. 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. Madanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Griffiths: Takeda Oncology: Consultancy, Honoraria; Novartis: Honoraria; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Consultancy, Honoraria. Lai: Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Jazz Pharma: Speakers Bureau; Macrogenics: 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; 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; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Savona: CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, 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. Litzow: AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Amgen: Research Funding; Astellas: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding.

Abstract Background: Therapy-related acute myeloid leukemia (AML) is a well-described entity and known to carry a worse prognosis, compared to de novo AML. In the current study, we sought to describe the presenting features and outcome of patients with AML, in the setting of previous history of cancer with or without exposure to chemotherapy or radiotherapy. Methods: A Mayo Clinic database of patients with AML was queried to identify patients with a previous history of cancer, both hematologic and solid tumors. A comparative analysis of presenting features, treatment details and survival were performed between patients with therapy-related AML (Group A) and those with AML and a history of cancer that had been managed with surgery alone (Group B). Results: A total of 250 patients (median age 68 years, range 19-90; 60% males) with AML and a previous history of cancer (both hematologic and solid) were identified; 182 (73%) cases were determined to be therapy-related AML (Group A) while the remaining 68 (27%) did not receive chemotherapy or radiotherapy for their antecedent cancer (Group B) (Table). Among group A patients 106 (58%) were exposed to chemotherapy, 37 (20%) to radiotherapy and 39 (22%) to combination chemotherapy and radiotherapy for their cancer. At the time of AML diagnosis, adverse karyotype was noted in 91 (51%) group A and 12 (19%) group B patients (p<0.0001); the incidence of adverse karyotype in patients exposed to chemotherapy vs radiotherapy alone vs combined chemoradiotherapy was 54% (57/106), 30% (11/37), and 59% (23/39) respectively (p=0.04). Group A patients, compared to those in group B, included more females (46% vs 24%; p=0.001), and more preceding hematologic malignancies (p=<0.0001). Next generation sequencing was performed in 74 patients and the results showed no significant difference between groups A and B (Table). Treatment and outcome in Groups A and B: Intensive and less intensive AML-directed chemotherapy were given to 100 (55%) and 44 (24%) patients in group A and 38 (56%) and 14 (21%) patients in group B (P=0.8). 79 (65%) remissions (complete remission (CR) 42 (29%) and CR with incomplete count recovery (CRi) 37 (26%) were documented in Group A and 37 (71%) remissions (CR: 21 (40%) and CRi=16 (31%) in Group B (P=0.2). After a median follow-up of 8.4 months (range: 0.9-217), 184 deaths were documented: 132 (72.5%) in Group A and 52 (76.5%) in Group B (P=0.5). 52 (36%) patients from Group A and 25 (48%) from Group B relapsed (P=0.1). The median (range) overall survival (OS) rates of patients from Group A was 13 (9-17) months and that of Group B was 14 (10-35) months (P=0.6). The 1-, 3- and 5-year OS rates were 52%, 28%, and 24% in Group A; and 62%, 33%, and 24% in Group B patients (Fig 1). Multivariable analysis identified relapse (HR 2.8, 95% CI 1.7-4.7) and failure to achieve CR/CRi (HR 2.8 95% CI 1.9-4.7) as risk factors for inferior survival (Fig 2a and 2b). The median (range) relapse free survival of patients in Group A was 28 (17 -81) and that of Group B was 27 (14 - 76) months (P=0.9) (Fig 2c). 28 patients underwent allogenic stem-cell transplant (25 in CR1 and 3 in CR2), 23 in Group A and 5 in Group B; the 1-, 3-, and 5-year OS of patients who underwent allogenic stem cell transplant were 88%, 72%, and 72% regardless of the group (Fig 2d). Conclusion: The current study did not find significant differences between AML patients with previous history of cancer with or without exposure to chemo/radiotherapy, in terms of either response to AML-directed therapy or overall or relapse-free survival, despite a higher prevalence of adverse karyotype in therapy-related AML. Figure 1 Figure 1. Disclosures 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. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee.

Abstract Introduction CMML is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Current therapeutic options for patients (pts) with CMML are limited, leaving a significant unmet medical need. Pts classified to have the MPN subtype, compared with the MDS subtype, and those with high-risk genetic features tend to have a higher rate of transformation to acute myeloid leukemia (AML) and median survival of 2-3 years. The seminal observation of increased expression of CD123 (interleukin-3Rα) on leukemia stem cells and clonal plasmacytoid dendritic cells led to the clinical investigation of a novel CD123-targeted agent, tagraxofusp (TAG, SL-401), in CD123-positive hematologic malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), CMML, AML, and myelofibrosis. TAG demonstrated robust clinical activity in pts with BPDCN and is now approved in the US and EU for this indication. Data from an ongoing phase 1/2 study of TAG monotherapy for pts with relapsed/refractory (R/R) CMML (NCT02268253) also demonstrated clinical activity (Patnaik et al. J Clin Oncol 2019;37: abstr 7059). Herein, we present updated safety and efficacy results of this study in first-line (1L) high-risk and R/R pts. Methods A multicenter, multistage, phase 1/2 trial was designed initially to assess the safety and efficacy of TAG monotherapy in adult pts with R/R CMML (Stages 1 and 2), and subsequently expanded to include 1L high-risk and R/R pts (Stage 3A). Clinical responses were initially assessed by the International Working Group/MDS 2006 criteria, and subsequently amended to the MDS/MPN 2015 criteria. Splenomegaly was assessed by palpation in Stages 1 and 2, and by palpation and imaging in Stage 3A. TAG was administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days (d)1-3 every 21 d (cycles [C]1-4), 28 d (C5-7), and 42 d (C8 and beyond) in Stage 1, and at 12 mcg/kg (recommended phase 2 dose defined in Stage 1) every 21 d (C1-4) and 28 d (C5 and beyond) in Stages 2-3A. Results As of July 2021, 36 pts have been enrolled, comprising 20 pts with CMML-1 and 16 with CMML-2; median age is 69 years (range 42-81); 75% are male. Twenty-three (64%) pts had either high- or intermediate-risk genetics based on CPSS, GFM, MMM, or ELN risk-stratification systems. Prior therapies included HMA in 16 (43%) pts, allogeneic stem cell transplantation (allo-SCT) in 3 (8%), and other in 12 (32%); 7 (19%) pts were high-risk and treatment naive. Overall, 16 (44%) pts had baseline palpable splenomegaly, of whom 12 pts' spleen size was ≥5 cm below left costal margin. The most common (in ≥20% of pts, n=34) treatment-related adverse events (TRAEs) were hypoalbuminemia (26%), thrombocytopenia (24%), nausea (24%), and capillary leak syndrome (CLS, 21%; grade 2, n=4; grade 3, n=3). Grade ≥3 TRAEs were thrombocytopenia (21%), CLS (9%), anemia (9%), and nausea (3%). Discontinuation rate due to TRAEs was low (n=1). Overall, 4 of 36 (11%) pts achieved bone marrow morphologic complete responses (BMCRs), of whom 1 pt was bridged to allo-SCT; all 4 pts had splenomegaly at baseline. Noteworthy, 2 of the 4 BMCRs were observed in pts with high-risk genetic features. Fifteen (42%) pts with baseline splenomegaly had spleen responses; 9 (60%) pts had a ≥50% reduction in spleen size, including 5 (42%) with splenomegaly ≥5 cm at baseline. Median follow-up was 11 weeks (range 1-163 weeks). In the Stage 3A cohort, 2 high-risk 1L pts had BM partial remissions, with 1 also having clinical benefit. Three pts had a spleen volume reduction by MRI scans following C1 (range 7%-36%) and 1 pt had a reduction of 57% after C4. While on study, none of the 7 pts (2 transfusion dependent at baseline) have required blood or platelet transfusions. Updated results on Stage 3A, including total symptom scores, will be presented. Conclusions Ongoing results in pts with CMML demonstrate TAG monotherapy has significant clinical activity in 1L pts with high-risk disease as well as those with R/R disease. The responses were particularly notable in those with baseline splenomegaly. As Stage 3A of the trial continues, mutational correlates and BM PDCs are being assessed. TAG treatment is well-tolerated, with a manageable and predictable safety profile. Overall, the data suggest that TAG may offer a novel targeted approach for pts with CMML. Stage 3A of the trial continues. Disclosures 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: BMS: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Wang: Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Advisory Board; 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; DAVA Oncology: Consultancy, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; GlaxoSmithKline: 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; 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. Yacoub: Incyte: Consultancy, Honoraria, Speakers Bureau; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Gupta: Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Constellation Pharma: Consultancy, Honoraria; Roche: Consultancy. Lee: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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. Schiller: Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; FujiFilm: Research Funding; PrECOG: Research Funding; Karyopharm: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Geron: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Constellation Pharmaceuticals: Research Funding; Trovagene: Research Funding; Actuate: 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; Regimmune: Research Funding; Delta-Fly: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Celator: Research Funding; Daiichi-Sankyo: Research Funding; Arog: Research Funding; Forma: Research Funding; Samus: Research Funding; Deciphera: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Abbvie: Research Funding; Mateon: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Onconova: Research Funding; Novartis: Consultancy, 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; Ariad: Research Funding; 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: takeda: Research Funding; taiho: Honoraria; syros: Honoraria; boehringer ingelheim: Research Funding; trillium: Research Funding; abbvie: Research Funding; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; sanofi aventis: Honoraria; gamida: Honoraria; certara: Honoraria; servier: Honoraria; revolution medicine: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; OncLive: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Brooks: Stemline Therapeutics: Current Employment. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Pemmaraju: Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Springer Science + Business Media: Other; Bristol-Myers Squibb Co.: Consultancy; Sager Strong Foundation: Other; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ImmunoGen, Inc: Consultancy; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Pacylex Pharmaceuticals: Consultancy.

Abstract Background Systemic mastocytosis (SM) is formally classified as advanced, smoldering (SSM), or indolent (ISM). Advanced SM indicates the presence of an associated non-mast cell lineage hematologic neoplasm (SM-AHN) or at least one "C finding" (i.e. features of organopathy from mast cell infiltration); the latter defines aggressive SM (ASM). Both advanced SM and ISM might be associated with MC mediator symptoms (MC-MSs) or urticaria pigmentosa (UP). Current drug therapy for SM is primarily directed at reversing C findings or alleviating symptoms/UP, and includes cladribine, midostaurin, and avapritinib. The former has a long track-record of safety while the latter two are recent additions that target the associated KIT mutation, but with concerning gastrointestinal and neurological side effects. We retrospectively reviewed our experience with cladribine therapy in SM, in order to maintain a proper perspective in making treatment choices. Methods The current study includes 42 patients with SM (22 advanced and 20 indolent/smoldering), recruited from the Mayo Clinic SM database, based on documentation of treatment with cladribine. Conventional criteria were used for diagnosis and classification (Blood 2016;127:2391) and definitions of response (Eur J Clin Invest. 2007 Jun;37(6):435); in the latter regard, we utilized modified Valent criteria that incorporated a minimum of one-month duration to qualify as response. Results Advanced SM: 22 patients (median age 65 years, range 48-80; males 68%) had advanced SM, including 13 SM-AHN, 8 ASM, and 1 mast cell leukemia. Median (range) BM MC burden was 30% (10%-90%), serum tryptase 193 ng/ml (21-1370), hemoglobin 10.6 g/dL (7-15), leukocytes 6 x 10(9)/L (0.5-63), and platelets 115 x 10(9)/L (8-320). KITD816V was detected in 86% of 19 evaluated and abnormal karyotype in 14% of 21 evaluated. 50% of patients had palpable hepatomegaly, 59% palpable splenomegaly, 100% MC-MSs, and 14% UP; 87% displayed at least one C finding. Median time from BM biopsy confirmed diagnosis to initiation of cladribine therapy was 1.5 months (range 0.1-17). 55% of patients received at least 3 cycles of treatment. Overall response (OR) was documented in 17 (77%) patients with similar OR rates in ASM (88%) vs SM-AHN (69%; p=0.32), with median time to response of 3.7 months (range 0.4-9). OR included 45% major response (MR) and 32% partial response (PR). 17 patients were evaluated for BM MC response with 44% showing >50% reduction, in MCs, including 19% with complete resolution. Organomegaly response was complete in 36% and partial in 27%. Tryptase response of >50% was documented in 32%. Cladribine side effects were limited to cytopenias with 36% showing grade 3 or 4 myeloid cytopenia. Median duration of response was 6 months (range 1-67). Six patients, including 5 with SM-AHN, progressed to either AML or MCL. Among the 5 patients who did not respond to cladribine, one with ASM was successfully treated with midostaurin. Indolent or smoldering SM: 20 patients (median age 56 years, range 36-73; males 45%) had ISM (n=17) or SSM (n=3). Median (range) BM MC burden was 13% (5%-60%) and serum tryptase level 49 ng/ml (14-1630). KITD816V was detected in 95% of 19 evaluated patients and abnormal karyotype in 12% of 17 evaluated. All patients displayed MC-MSs and 46% UP. Median time from BM biopsy confirmed diagnosis to initiation of cladribine therapy was 4 months (range 0-92). 85% of patients received at least 3 cycles of cladribine therapy. OR was documented in 14 (70%) patients, including 60% complete or major regression of symptoms or UP, with median time to maximal response of 8.5 months (range 1-98); response rates in patients with UP were similar with 57% complete or major regression; 10 patients were evaluable for BM MC response with 50% showing >50% reduction in MC burden. Serum tryptase response was evaluated in 13 patients with 46% showing >50% reduction in levels. Treatment-emergent cladribine side effects were limited to cytopenias with only 3 (15%) patients experiencing grade 3 or 4 myeloid cytopenia and (n=3; 15%) and 6 (30%) experiencing grade 3 or 4 lymphopenia. Conclusions: The current study confirms the favorable side effect profile and long-term safety of cladribine as a first-line drug of choice for both indolent and advanced SM. Response to cladribine therapy was evident in all aspects of the disease, including MC-associated organopathy, UP, MC-MSs, serum tryptase level and bone marrow MC burden. Disclosures Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.

Abstract Background: DDX41 gene is located on chromosome 5q35 and is believed to be a tumor suppressor gene involved in splicing of mRNA. Mutated DDX41 have been identified as germline mutation (m) in families with cases of myeloid neoplasm and have shown to cause acquisition of other somatic mutations resulting in MDS/AML. At the same time, somatic pathogenic DDX41 mutations are known to occur. Variant of unknown significance (VUS) is an intermediate tier between benign and pathogenic (path) mutations (hence uncertain) and can be re-classified based on their clinical impact. In this report we analyzed the clinical impact and relevance of DDX41VUS in patients (pts) being evaluated for myeloid disorders. Methods: We reviewed 4,524 consecutive pts who underwent NGS (MC OncoHeme 42 genes panel) testing between 2018 and 2021 performed on cases of suspected or known myeloid disorders. We identified 58 (1%) consecutive pts with DDX41VUS, among them one pt had proven concurrent DDX41 germline VUS and 7 pts with DDX41VUS had concurrent DDX41path mutation. We analyze clinical characteristics of pts with DDX41VUS and compared it with cohort of 32 DDX41path mutated pts. Results: Baseline characteristics are summarized in Table 1, and Figure 1 illustrates DDX41VUS per case with variant allele frequency (VAF) and observed concurrent mutations. The median VAF for DDX41 VUS was 48 % (range, 14-91%). Co-mutations were found in 14 (28%) pts with VUS, and the reminder (n=44, 72 %) had isolated DDX41VUS. Among them AML (16 [32%]), MDS (14 [28%]), cytopenia (14 [28%]) MPN (3 [6%]), CNL (1 [2%]) and aplastic anemia (1 [2%]) were the commonly occurring myeloid disorder (Table 1, Figure 1). Eleven of 14 pts with isolated cytopenia had isolated DDX41VUS. Conversely, among 15 evaluable pts with isolated DDX41VUS, 13 (87%) pts had normal cytogenetics and 40% of pts had family history of solid or hematological malignancies. We observed a significant difference in hematologic diagnoses: DDX41VUS patients were significantly less often diagnosed with MDS or CCUS, and more often associated with cytopenias NOS. Recurrent, non-random DDX41VUS sequences were observed; most frequent occurring amino acid change among the 58 pts were Gly173Arg (n=6), Met155lle (n=5), Pro258Leu (n=3) Arg479Gln (n=3), Val303Met (n=2), Lys331del (n=2), Arg479His (n=2) and Tyr33His (n=2) (Figure 1). 5 of 6 pts with Gly173Arg had isolated DDX41VUS, and among them 4 were diagnosed with MDS suggesting this could be a clonal event, and possible driver mutation, notable in Figure 1. The median overall survival (OS) of pts with high risk MDS/AML harboring DDX41VUS was not reached (60% alive at 2 years). Between pts with DDX41path and DDX41VUS, proportion of pts with co-mutations (p >0.99), cytogenetic abnormalities (p >0.99), family history of malignancies (p 0.52), time to treatment (p >0.99), MDS progression to AML (p 0.36) and OS (among high risk MDS/AML pts) (p 0.55) was not significantly different, suggesting that phenotypic features of DDX41VUS are similar to DDX41path , and that both carry a similar, more indolent prognosis (Table 1). Conclusion: Our reports demonstrated that DDX41VUS occurs in 1% of patients with myeloid disorders and shares distinct diagnostic features but comparable prognostic features vs. DDX41path, including family history of hematological malignancies. It is possible that many of the cases with 'cytopenias' and DDX41VUS would meet criteria for CCUS if the variant was isolated classified as pathogenic, confirming the importance of extending our understanding of DDX41 variants. Further analysis to characterize the biological impact of DDX41VUS is underway. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. 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. Litzow: Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Pluristem: Research Funding; Amgen: Research Funding; Biosight: Other: Data monitoring committee; Actinium: Research Funding; AbbVie: Research Funding. Foran: boehringer ingelheim: Research Funding; abbvie: Research Funding; takeda: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; bms: Honoraria; servier: Honoraria; novartis: Honoraria; pfizer: Honoraria; aptose: Research Funding; taiho: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; actinium: Research Funding; gamida: Honoraria; OncLive: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.