Nanaa, Ahmad

Abstract Objectives Patients with clonal cytopenia of undetermined significance (CCUS) are at increased risk of developing myeloid neoplasia (MN). We evaluated whether a simple flow cytometry immunophenotyping (FCIP) assay could differentiate the risk of development of MN in patients with CCUS. Methods Bone marrow aspirates were assessed by FCIP panel in a cohort of 80 patients identified as having CCUS based on next-generation sequencing or cytogenetics from March 2015 to May 2020, with available samples. Flow cytometric assay included CD13/HLA-DR expression pattern on CD34-positive myeloblasts; CD13/CD16 pattern on maturing granulocytic precursors; and aberrant expression of CD2, CD7, or CD56 on CD34-positive myeloblasts. Relevant demographic, comorbidity, and clinical and laboratory data, including the type and extent of genetic abnormalities, were extracted from the electronic health record. Results In total, 17 (21%) patients with CCUS developed MN over the follow-up period (median survival follow-up, 28 months [95% confidence interval, 19-31]). Flow cytometry immunophenotyping abnormalities, including the aberrant pattern of CD13/HLA-DR expression, as detected at the time of the diagnosis of CCUS, were significantly associated with risk of developing MN (hazard ratio, 2.97; P = .006). Additional FCIP parameters associated with the development of MN included abnormal expression of CD7 on myeloblasts and the presence vs absence of any FCIP abnormality. Conclusions A simple FCIP approach that includes assessment of CD13/HLA-DR pattern on CD34-positive myeloblasts can be useful in identifying patients with CCUS at higher risk of developing MN.

e19014 Background: Stromal Antigen 2 ( STAG2), located on Xq25, is the most mutated (m) cohesin-complex gene in myeloid neoplasm (MN) patients (pts). mSTAG2 is present in around 5% of MN and has been linked to secondary AML and potential poor impact on outcome. Methods: We retrospectively screened MN pts who had next-generation sequencing (NGS) (OncoHeme) performed at Mayo Clinic between 2018-2021. m STAG2 pts were included at the date of NGS. Charts were reviewed for clinical information after obtaining IRB approval. BlueSky Software V7.40 was used for statistical analysis. Results: Characteristics: 70 pts with mSTAG2 MN were identified, their median age was 72 years (range 25-91); with 55 pts (79%) being males. Complete blood counts showed median white blood cell count of 2.8 x109/L, hemoglobin of 8.9 gm/dL and platelets of 89 x109/L. The diagnosis was MDS in 38 pts (54%), AML in 20 (29%), MDS/MPN in 9 (13%), MPN in 2 (3%), and CCUS in 1 (1%). 11 cases (16%) were defined as therapy-related MN (tMN). Cytogenetics were normal in 45 pts (64%) and abnormal in 22 (31%). 10/50 non-AML pts progressed to AML (after median time of 9.8 months). Hematopoietic cell transplantation (HCT) was done in 20 pts (29%). mSTAG2: median VAF (mVAF) was 50% (range, 5%-100%). Males had higher mVAF compared to females (64% vs. 27%, p= .001), and tMN pts had higher mVAF compared to de novo (dn) MN pts (66% vs. 43%, p= .03). mVAF had no correlation with disease classification (50% in AML, 52% in MDS, 41% in MDS/MPN, 36% in MPN and 5% in CCUS, p= .5). STAG2 mutations were nonsense, frameshift, and splice site in 50%, 37%, and 13%, respectively. Co-mutations : median number of co-mutations was 3 (range, 0-6). Most common co-mutations were ASXL1 (66%), SRSF2 (37%), TET2 (36%), RUNX1 (29%), IDH2 (21%), BCOR (20%) and U2AF1 (16%) while least common were TP53, SETBP and ZRSR2 (1% each). Neither number (p= .08) nor type of co-mutation correlated with MN classification. There was no difference in the co-mutational pattern between tMN and dnMN pts. Survival : median overall survival (mOS) was 16.3 months with a median follow up time of 24.5 months. Pts who received HCT had better OS compared to non-HCT pts (mOS not reached vs. 14.9 months, p= .003). Pts with an isolated m STAG2 had better OS than co-mutated pts (p= .04), while the type of STAG2 mutation did not affect OS (p= .3). Pts with tMN had worse OS than dnMN pts (9.9 vs. 20.4 months, p= .02). VAF ≥75% had a negative impact on OS (20.5 vs 8.1 months, p= .008). mOS did not differ based on MN diagnosis. On multivariate analysis, only HCT (HR 0.3, p= .01) and VAF ≥75% (HR 2.3, p= .02) had impact on OS. Conclusions: mSTAG2 was more common in elderly males and MDS diagnosis. mSTAG2 was uncommon as an isolated mutation, indicating a possible role in disease progression with preferred certain co-mutations ( ASXL1/SRSF2/RUNX1/IDH2). mOS was poor regardless of MN diagnosis indicating a molecularly driven significance of an aggressive disease. The study needs to be validated by larger studies.

e19010 Background: Mutated DEAD-box helicase 41 (m DDX41), and mutated GATA2 are germline mutations associated with familial predisposition syndromes. In this study, we compare the clinical characteristics and survival outcomes (OS) of m DDX41 and m GATA2 MN patients (pts). Methods: We retrospectively screened pts who had next-generation sequencing (NGS) (OncoHeme panel) performed at Mayo Clinic. 4,524 consecutive pts (2018-2021) were screened for DDX41 mutations and 3,872 for GATA2 mutations (2015-2020) and included 36 MN pts with m DDX41 genetic alterations, and 55 m GATA2 MN pts. m GATA2 cases were included at NGS date while m DDX41 were included at diagnosis date. Germline workup was not done in all cases. JMP 16.2.0 Software was used for statistical analysis. Results: Patient characteristics: The most common diagnosis was MDS (N = 22, 61% in m DDX41 N = 17, 31% in m GATA2 group; p = .0044). MDS/MPN overlap was seen in m GATA2 group only; (29% vs. 0%; p = .0004). Majority of pts were males with median age of 68 and 67 years for m DDX41 and m GATA2 pts; respectively (p = .7). m DDX41 pts had higher hemoglobin, platelets, and MCV (< .0001, 0.005, < .0001; respectively) and significantly lower white blood cells (WBC) count compared to m GATA2 pts (< .0001). All m DDX41-AML pts were (ELN) intermediate-risk, and 64% of m DDX41 MDS were intermediate risk (IPSS-R). In contrast, of m GATA2 pts 62% of AML were adverse risk and 44% of MDS very high risk. Majority of m DDX41 pts had normal karyotype (N = 32; 91% vs. N = 19, 37%; p < .0001), had isolated mutations (N = 23; 64%) and the most common co-mutations were DNMT3A (38%), ASXL1 (30%), JAK2 (23%). The majority of m GATA2 pts were co-mutated (96%) with a different co-mutation pattern ASXL1 (60%), SRSF2 (34%), RUNX1 (19%). Germline data: One m GATA2 pts had proven germline mutation, and 10/11 (91%) m DDX41 pts were confirmed Survival and progression in MDS/AML: After median follow-up of 30 months in MDS/AML, 7 (21%) m DDX41 and 23 (77%) m GATA2 pts died with superior OS in m DDX41 compared to m GATA2 pts with median OS of (136.7 vs. 6.8 months, p < .0001). Seven (31%) of 22 m DDX41 and 6 (35%) m GATA2 MDS pts progressed into AML with a median time to progression of (11.2 vs. 5.2 months, p = .045). The leukemia free survival (LFS) for m DDX41 MDS pts was significantly longer than LFS of m GATA2 MDS pts (24.4 vs. 6 months, p < .0001). Conclusions: We compare the outcomes of two unique mutations associated with germline predisposition. We found m DDX41 pts had fewer cytogenetic aberrations, no MDS/MPN overlap, and lower WBC count. Majority of m DDX41 MDS/AML pts were intermediate risk category, compared to predominance of adverse risk disease in m GATA2 pts, translating into better OS and LFS. This study is limited by the small size, lack of germline workup in all cases, and retrospective nature. However, it supports the favorable prognosis and indolent course of m DDX41 pts recently described.

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 &gt;0.99), cytogenetic abnormalities (p &gt;0.99), family history of malignancies (p 0.52), time to treatment (p &gt;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.

Abstract Background: The DEAD-box helicase 41 (DDX41), an RNA helicase, have been described as a component of the RNA spliceosome (Cheah et al. International Journal of Hematology 2017). Although DDX41 mutations predispose to late-onset higher grade myeloid neoplasms (MN), these patients may have a trend toward favorable prognosis and outcomes. In this work, we describe the clinical characteristics and survival outcomes of isolated and co-mutated DDX41 patients (pts). Methods: We retrospectively analyzed 4,524 consecutive pts who underwent next-generation sequencing (NGS) (OncoHeme 42 genes panel, Mayo Clinic) testing and included 32 pts harboring pathogenic DDX41 mutation and one pt with proven DDX41 germline variant of unknown significance (VUS). Chart review of DDX41-mutated (m) cases between 2009 and 2021 was conducted after IRB approval. We compared overall survival (OS) of unmatched 27 t(8;21)AML and 40 inv(16) AML pts with 10 m DDX41-AML pts. JMP® Pro 14.1.0 Software was used for statistical analysis. Results: DDX41 mutations characteristics: Our cohort included 19 (58%) myelodysplastic syndromes (MDS), 10 (30%) acute myelogenous leukemia (AML), 2 (6%) myeloproliferative neoplasms (MPN), one clonal cytopenia of undetermined significance (CCUS) (3%) and one (3%) germline carrier. Germline testing was carried out in 10 pts, 9 of whom (90%) were confirmed to be germline). The start-loss variant (p.M1I) was the most common mutation type (N=10, 31%). Other types were frameshift (N=9, 28%), missense mutation (N=8, 25%), nonsense (N=3, 9%), and splice site mutation (N=2, 2%). Twenty-one (65.6%) DDX41 mutations clustered in the N-terminus (NT), 7 (22%) in the helicase-C domain (HCD), and 4 (12.5%) in the DEAD-box domain. Compared to NT mutations, patients with HCD mutation had no family history of solid tumors and were more likely to have an accompanying additional DDX41-VUS (0% vs 70%; p=.001) and (N=6, 86% vs. N=2,10%; p=.0001); respectively. I solated vs. co-mutated DDX41: Twenty (60%) pts were isolated-DDX41 and 13 (40%) were co-mutated. The median DDX41-VAF was 48% vs. 45% (p= .2) in the isolated compared to the co-mutated cases, respectively. The median number of co-mutations in the 13 co-mutated cases was 1 (range,1-3) with DNMT3A (38%), ASXL1 (30%), JAK2 (N=3, 23%), and EZH2 (N=2, 15%) were the most common co-mutations detected. Isolated DDX41 had more males (85% vs. 54%, p=.05), the p.M1I variant (47% vs. 8%, p=.02), normal cytogenetics (100% vs. 91%, p= .02), and less family history of solid tumors (77% vs. 33%, p= .02) compared to their co-mutated counterparts. However, there was no difference in OS (p=.99). Comparison of clinical characteristics and hematological features of isolated and co-mutated DDX41 pts are reported in (Table 1). Treatment and survival outcomes in DDX41-MDS/AML : Twenty-three (80%) patients were treated, MDS pts received hypomethylating agents (HMA) (N=10, 71%), HMA plus Venetoclax (HMA+VEN) (N=1, 7%), erythropoiesis-stimulating agents (N=2, 14%) and lenalidomide (N=1 ,7%). AML pts were treated with induction chemotherapy (N=6, 67%) and HMA+VEN (N=3, 33%). Overall response rate of MDS/AML patients was 77% and 100% of AML pts achieved complete remission (CR) when treated with induction chemotherapy or HMA+VEN regimen. There was no significant difference in OS between responders vs. non-responders 2-yr-OS (90% vs. 50%; p=.38) and treated vs. untreated 2-yr-OS (83% vs. 100%; p=.52). Comparing m DDX41-AML vs. core binding factor-AML: After a median follow-up of 33.3 months, all m DDX41-AML patients were alive. There was a significantly better OS in mDDX41-AML patients compared to pts with t(8;21) AML with 2-yr-OS (100% vs. 51%; p=.024) and a trend of better survival when compared to inv(16) AML 2-yr-OS (100% vs. 84%; p=.2). Conclusion We describe the characteristics and outcomes of m DDX41 patients. We demonstrated that isolated and co-mutated m DDX41 patients have different features. Isolated DDX41 patients had male predominance, more p.M1I variant, normal cytogenetics and less family history of solid tumors. In this study we found that m DDX41 AML has high response to treatment and has comparable (if not possibly better) OS compared to other "favorable risk" AML. This study, although limited by the small number of patients, supports the universal testing for DDX41 mutation in adults with MN diagnosis. Figure 1 Figure 1. Disclosures Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Foran: abbvie: Research Funding; OncLive: Honoraria; boehringer ingelheim: Research Funding; trillium: Research Funding; pfizer: Honoraria; takeda: Research Funding; revolution medicine: Honoraria; bms: Honoraria; gamida: Honoraria; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; servier: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; certara: Honoraria; kura: Research Funding; 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. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Litzow: Astellas: Research Funding; Biosight: Other: Data monitoring committee; Amgen: Research Funding; AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board. Patnaik: Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Abstract DDX41 mutations (germline and somatic) are associated with late onset myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Myeloid neoplasms (MN) with germline predisposition was identified as a distinct category in the 2016 WHO classification revision, including MN with germline DDX41 mutation. We retrospectively analyzed the molecular findings and clinical characteristics of thirty-three DDX41-mutated (mDDX41) patients at our institution. We identified 14 distinct pathogenic DDX41 variants in 32 patients and 8 DDX41 variants of unknown significance (VUS) in 9 patients. Five (16%) patients had a second DDX41 somatic mutation p.R525H and 13 (40%) had at least one additional oncogenic co-mutation in other genes. The median age at the time of diagnosis was 66 years, with male predominance (72%) and the majority of patients had normal cytogenetics (91%). Two-year overall survival (OS) was 86% and 6 (21%) MDS/AML patients with relatively preserved hematopoietic function were observed without further intervention. In comparison to AML patients with prognostically more favorable subtypes [t(8;21), n=27 and inv(16), n=40], mDDX41 patients in our cohort showed similarly favorable OS. Our study highlights that mDDX41-MN patients often have an indolent course and mDDX41-AML has comparable OS to favorable-risk AML.

The accurate diagnosis of chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) subtypes with monocytic differentiation relies on the proper identification and quantitation of blast cells and blast-equivalent cells, including promonocytes. This distinction can be quite challenging given the cytomorphologic and immunophenotypic similarities among the monocytic cell precursors. The aim of this study was to assess the performance of convolutional neural networks (CNN) in separating monocytes from their precursors (i.e., promonocytes and monoblasts). We collected digital images of 935 monocytic cells that were blindly reviewed by five experienced morphologists and assigned into three subtypes: monocyte, promonocyte, and blast. The consensus between reviewers was considered as a ground truth reference label for each cell. In order to assess the performance of CNN models, we divided our data into training (70%), validation (10%), and test (20%) datasets, as well as applied fivefold cross validation. The CNN models did not perform well for predicting three monocytic subtypes, but their performance was significantly improved for two subtypes (monocyte vs. promonocytes + blasts). Our findings (1) support the concept that morphologic distinction between monocytic cells of various differentiation level is difficult; (2) suggest that combining blasts and promonocytes into a single category is desirable for improved accuracy; and (3) show that CNN models can reach accuracy comparable to human reviewers (0.78 ± 0.10 vs. 0.86 ± 0.05). As far as we know, this is the first study to separate monocytes from their precursors using CNN.

Background: Clonal cytopenias of Undetermined Significance (CCUS) have a higher risk of progression to myeloid neoplasm (MN) compared to idiopathic cytopenias of undetermined significance (ICUS) (Malcovati et al., Blood, 2017). The implementation of flow cytometric (FC) immune-phenotyping and next generation sequencing (NGS) in clinical practice has improved the diagnosis of these entities but the clinical significance and interaction of these abnormal results are still unknown. In this study we investigated predictive factors that play role in survival and progression to MN in patients with ICUS/CCUS. Methods: Patients (Pts) who had undergone evaluation for unexplained cytopenia and had undergone FC and bone marrow morphological assessment between 3/2015-3/2020 at Mayo Clinic Rochester were included. Pts were excluded if a malignant hematological disorder was diagnosed prior to the time of FC. FC included evaluation of the following parameters: Abnormal expression of HLA-DR/CD13, CD2, CD7, CD45, and CD56 on blasts; and abnormal CD13/CD16 expression and side scatter on granulocytic cells. NGS panel up to 2018 included 34 genes, ASXL1, BCOR, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA1, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, MYD88, NOTCH1, NPM1, NRAS, PHF6, PTPN11, RUNX1, SETBP1, SF3B1, TERT, TET2, TP53, U2AF1, WT1, and ZRSR2; in 2018, BRAF was omitted and 12 genes were added, ANRD26, DDX41, ELANE, ETNK1, KDM6A, MYD88, NOTCH1, RAD21, SH2B3, SRP72, SMC3, and STAG2. Results: Characteristics: Of 490 consecutive pts, 238 (median age 69 years (range 19-92), 66% males) met our inclusion criteria as ICUS. 86 (36%) pts had CCUS (abnormal cytogenetics and/or tested positive for pathogenic mutations on NGS). After a median follow-up of 28 months (95% CI: 20 to 31 months), 21 (25%) patients developed MN and 23 (27%) died during follow-up. Comparing ICUS vs CCUS: upon comparing CCUS pts to ICUS, several factors were found to be significantly different: CCUS pts were older (p= .02); majority male (p= .04), had more abnormal HLA-DR/CD13 (p &lt;.0001), more side-scattered light by FC (p &lt;.0001), more pancytopenia on follow up (p= .02) and more morphologic atypia (&lt;.0001). Overall survival (OS) outcomes in CCUS: Several covariates were significant in univariate models, and model selection was used to generate a risk score based on abnormal CD7, abnormal CD13/CD16, abnormal HLA-DR/CD13, splenomegaly and history of prior chemotherapy or radiotherapy (range: 0 - 4; HR=2.58, [95 CI: 1.69 - 3.94], p&lt;.0001). Risk scores were grouped as low risk (score=0), intermediate risk (score=1), and high risk (score=2+), with estimated 2-yr-OS of 95%, 84%, 40%, respectively (Figure 1). An extended risk score model including NGS factors added ASXL1 and IDH1 mutation status to the previous model (range: 0 - 6; HR=2.72, [95 CI 1.82 - 4.06], p&lt;0.0001). MN-free survival (MNFS) in CCUS: 37 pts either progressed to MN and/or died with a median follow up time for MNFS of 22.4 months. Similar for OS, model selection approaches yielded a composite risk score: splenomegaly, BCOR mutation status, mutation in RAS signaling pathway, abnormal expression of flow markers CD13/CD16, HLA-DR/CD13 or CD7 (HR=3.23, [95 CI: 1.90 - 5.49], p=&lt;0.0001). Risk scores were grouped as low risk (score=0), intermediate risk (score=1), and high risk (score ≥ 2), with estimated 1-yr MNFS of 84%, 74%, and 31%, respectively (Figure 2). Conclusion: CCUS has unique features compared to ICUS. Several factors, including clinical characteristics, immune-phenotyping by FC, and somatic mutations have important impact on risk of progression to MN and on overall survival. Our findings serve as proof-of-concept that such integrated models could help identify CCUS patients at higher risks for progression to MN or death. They can guide treatment accordingly and should be evaluated further. Disclosures Shah: Dren Bio: Consultancy.

Objectives: We sought to evaluate the procedural safety and outcomes of high power (HP) versus conventional power (CP) radiofrequency (RF) ablation during pulmonary vein isolation (PVI). Methods: A systematic search was used via MEDLINE, EMBASE, and Cochrane databases between 01/1998 and 05/2020 for studies comparing the safety and efficacy between HP and CP during RF ablation for PVI using contact-force catheters (ThermocoolSmartTouch or TactiCath). The search terms used were “AF” AND “catheter ablation” OR “radiofrequency ablation”. Results: From eight comparative observational studies, we developed a cohort of 992 patients (478 in the HP and 514 in the CP group). The median maximum energy output used in the HP group was 50W vs 35W in the CP group. There was a statistically significant difference noted in acute pulmonary vein reconnection (APVR) in the HP group compared to the CP groups at16% vs 32.6%, respectively (RR: 0.53, 95% CI: 0.33 - 0.86, P = 0.01). Freedom from arrhythmia at 12 months follow-up was also significant and found to be 87.8% of cases in the HP group versus75.2% of cases in the CP group (RR: 0.46, 95%CI: 0.32 - 0.65, P <0.01). The mean RF ablation time was 20.1 minutes in the HP group vs 39.6 minutes in the CP group (P <0.01). The mean total procedural time was 103.5 minutes in the HP group compared to 135 minutes in the CP group (P <0.01). Two patients in the CP group experienced severe adverse events (1 cardiac tamponade and 1 myocardial infarction). No serious AEs were found in the HP group. Non-serious AEs (groin complications, pericardial effusion, and phrenic nerve injury) were reported in 0.35% and 0.51% of cases in the HP and CP group, respectively. Conclusion: This study suggests that HP PVI ablation can be associated with better ablation outcomes by reducing the rate of acute and late PV reconnection and atrial arrhythmia recurrence, with similar safety profiles, and shorter procedural times. These findings merit evaluation in a randomized controlled trial.