Greipp, Patricia T.

Abstract This retrospective analysis aimed to provide evidence-based risk stratification of TP53-mutated (TP53mut) myeloid neoplasms (MNs). Of 580 MNs harboring TP53mut with variant allele frequency (VAF) ≥2%, 219 (37.8%), 194 (33.4%), 92 (15.9%), and 75 (12.9%) were classified as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) with low blasts (MDS-LB), MDS with excess blasts (MDS-EB)-2, and -EB1 according to the revised fourth edition of the World Health Organization (WHO) classification, respectively. Hierarchical analysis identified the following 4 risk groups with distinct survival: (1) MDS-LB, (2) MDS-EB1/EB2/AML VAF <10%, (3) MDS-EB1/EB2 VAF ≥10%, and (4) AML VAF ≥10%. We next evaluated the impact of allelic status, VAF, and complex karyotype (CK). In our cohort, the significance of biallelic status was limited to MDS with <5% blasts and not for blasts 5% to 9%, as proposed by the International Consensus Classification (ICC), or 5% to 19%, as proposed by the fifth edition of the WHO (WHO-5). MDS-EB1 and -EB2 with VAF ≥10% had comparable survival (9.6 vs 7.2 months; P = .12), regardless of allelic status. Contrary to the ICC proposal, MDS-EB1/EB2 with VAF <10% and CK had poor survival compared with those without CK, comparable to MDS-EB1/EB2 with VAF ≥10% (5.6 vs 26.2 vs 6.3 months; P = .003). Survival of TP53mut AML was poor (median 3.9 months) regardless of allelic/CK status. Thus, using ICC or WHO-5 may underestimate prognosis of MDS with blasts 5% to 19% and 5% to 9%, respectively. Collectively, the hierarchical model acknowledges poor survival of 91.9% TP53mut MDS and AML compared with 36.5% and 80.7% by WHO-5 and ICC, respectively.

Abstract The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.

Abstract Given the heterogeneous clinical behavior of pancreatic neuroendocrine tumors (pNETs), improved prognostic markers are needed to guide management and post‐resection surveillance. Patients who underwent resection of large (≥3 cm) sporadic well‐differentiated pNETs from 2000 to 2019 were identified. The Ki‐67 proliferation index was determined using immunohistochemistry, and alternative lengthening of telomeres (ALT) status was assessed using fluorescence in situ hybridization. Recurrence‐free and overall survival were estimated using Kaplan–Meier analysis. Multivariable Cox regression analysis evaluated factors associated with recurrence‐free survival. A total of 106 patients were identified. ALT was positive in 57 (54%) and negative in 49 (46%). Ki‐67 was ≥3% in 74 (70%) and <3% in 32 (30%). Tumors with Ki‐67 ≥3% were more likely to be ALT positive (61% vs. 38%, p = .046). Stratifying by ALT status and Ki‐67 proliferation index, median recurrence‐free survival was 4.6 years for patients with ALT‐positive/Ki‐67 ≥3% tumors, 3.1 years for patients with ALT‐positive/Ki‐67 <3% tumors, 12.4 years for patients with ALT‐negative/Ki‐67 ≥3% tumors, and 20.2 years for patients with ALT‐negative/Ki‐67 <3% tumors ( p < .001). Initial recurrence was distant in 82% and locoregional in 18%. Across all groups, overall survival was similar ( p = .19). In multivariable analysis, advanced age, ALT positivity, perineural invasion, and lymph node metastases were associated with increased recurrence risk (all p < .05). ALT and Ki‐67 provide complementary information on post‐resection recurrence risk, which can guide subsequent surveillance and management strategies. These data support the incorporation of ALT testing into routine clinical practice.

Background: TP53-mutated (TP53mut) myeloid neoplasms (MN) have particularly poor survival. Discrepancies in defining TP53mut MN have impact on diagnostic work up, therapeutic decisions, and clinical trial enrolment. Methods: MN cases harboring TP53mut (variant allele frequency, VAF ≥2%) were classified based on bone marrow (BM) and peripheral blood (PB) blast % using the 4th revision of the WHO classification (WHO-4R). Biallelic loss was defined as (i) ≥2 mutations each with VAF ≥2%; (ii) single TP53mut VAF ≥2% plus 17p loss detected on karyotype, FISH, or SNP; or (iii) single TP53mut VAF ≥50%, whereas monoallelic loss was defined as single TP53mut VAF &lt;50% without 17p loss. Primary endpoint was overall survival (OS) from diagnosis. Conditional Inference Trees (CIT) analysis was used to determine the true effect of a predictor. Results: We identified 580 cases including WHO-4R defined acute myeloid leukemia (AML, BM/PB blasts ≥20%, n=219, 37.8%), myelodysplastic syndrome (MDS) with excess blasts-2 (EB-2, BM 10-19% or PB 5%-19%, n=92, 15.9%), MDS with excess blasts-1 (EB-1, BM 5-9% or PB 2-4%, n=75, 12.9%), and the remaining were MDS with low blasts (-LB, BM &lt;5% and PB ≤1%, n=194, 33.4%). Of the 578 cases evaluable for allelic status, 437 (75.6%) and 141 (24.4%) had biallelic and monoallelic TP53 loss, respectively. Higher frequency of biallelic loss was observed with increasing blasts. 63.2%, 73.3%, 78% and 86.3% of cases with MDS-LB, MDS-EB1, MDS-EB2, and AML had bi-allelic TP53 loss (P&lt;0.0001). In a multivariable analysis, WHO-4R categories, VAF ≥10%, and biallelic loss were independent predictors of poor survival. CIT analysis further stratified the cohort into 4 groups with distinct survival: (1) MDS-LB (n=194, 33.4%); (2) MDS-EB1/EB2 and AML with VAF &lt;10% (n=38, 6.6%); (3) MDS-EB1/EB2 with VAF ≥10% (n=149, 25.7%); and (4) AML with VAF ≥10% (n=199, 34.3%). MDS-LB cases could be further stratified based on allelic status and complex karyotype (CK): OS was poor for cases with biallelic TP53 loss and monoallelic TP53mut with CK compared to monoallelic TP53mut without CK, who had the most favorable survival (12.7 vs. 13 vs. 34.8 months, P&lt;0.0001).MDS-EB1/EB2/AML with VAF&lt;10% could also be stratified by CK: MDS-EB1/EB2/AML with VAF&lt;10% cases without CK had the favorable survival compared to their counterparts with CK and MDS-EB1/EB2 with VAF ≥10% cases (26.2 vs. 5.6 vs. 6.3 months, P=0.003).MDS-EB1/EB2 with VAF ≥10% was a homogenous subgroup: Biological characteristics including the proportion of cases with biallelic TP53 loss, CK (P&gt;0.9), monosomal karyotype (MK, P&gt;0.9), del 5q (P=0.6), del 7q (P=0.4), and del 17p (P=0.2) were comparable between MDS-EB1 and -EB2 with VAF ≥10%. Importantly, median OS of MDS-EB1 and EB2 with VAF ≥10% was comparable (9.6 vs. 7.2 months, P=0.12). OS in this group was comparable regardless of the blast %, allelic status, or presence of CK.AML with VAF ≥10% had extremely poor survival: Median OS was 3.9 months. Survival of AML was equally poor irrespective of the mono- or biallelic (3.6 vs. 3.9, P=0.89) and non-CK vs. CK (1.8 vs. 3.9 months, P=0.09). Combined, our model would acknowledge poor survival of 514 (89.1%) cases. In contrast, retrospective application of the 5th edition of the WHO classification (WHO-5) and International Consensus Classification (ICC) would classify only 211 (36.4%) and 468 (80.7%) cases as biallelic/multi-hit TP53mut MN, respectively. Finally, the Harrell's c-index of the proposed model, WHO-5, and ICC was 0.66, 0.571, and 0.617, respectively. Conclusion: We provide evidence for subsequent refinements in classifying MN harboring TP53mut. Our salient findings include: (i) acknowledgement of CK as ‘biallelic equivalent’ in MDS-LB; as well as EB1/EB2/AML with VAF 2 to &lt;10% cases; and (ii) demonstration of poor survival of MDS-EB1 and -EB2 with VAF ≥10% regardless of the allelic status. In conclusion, our proposed model acknowledged poor survival of a higher proportion of cases as TP53mut MN compared to the current models with a higher c- index.

Background: Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a heterogenous subtype of B-ALL defined by the presence of gene expression profiling similar to Ph+ ALL in the absence of a BCR::ABL1 fusion. Ph-like ALL has lower response rates to standard frontline therapies and carries a poorer prognosis when compared to other B-ALL subtypes. However, the role in which specific patient characteristics may impact responses is not well described. Our aim for this retrospective study was to evaluate the characteristics and outcomes of a real-world cohort of patients (pts) with Ph-like ALL across multiple institutions, including describing key patient characteristics, treatments, and factors that may contribute to minimal residual disease (MRD) status and treatment response. Methods: We conducted a retrospective review of adult pts with Ph-like ALL diagnosed and treated at the University of New Mexico, Mayo Clinic Phoenix, University of Chicago, and University of Michigan between 1/1/18 - 2/1/2024. Pts were eligible if they carried a diagnosis of B-ALL, and were determined to have Ph-like ALL according to each institutional diagnostic algorithm. Descriptive statistics, ANOVA, and Fisher's exact test were employed to summarize various clinical characteristics and their associations. Cox regression analysis was utilized to estimate the median survival time and assess the relationship between clinical characteristics and survival outcomes, including overall survival and progression-free survival. All statistical analyses were conducted using the R statistical software. Results: 67 pts were identified with a median age of 34.2 (IQR 28.5) and 35.8% were female. Twenty-eight pts identified as Hispanic or Latino (H/L) (43.1%), 25 (38.5%) identified as non-Hispanic White/Caucasian (NHW), 10 (15.4%) as American Indian/Alaska Native (AI/AN), and 2 (3.1%) as Asian/Pacific Islander. Thirteen pts (19.4%) had central nervous system (CNS) involvement at diagnosis, 22.4% of pts had extramedullary disease, and, in those who had NGS or cytogenomic microarray testing (n=49), 51% had an identified mutation/deletion in IKZF1. Initial treatment varied widely with pts receiving most commonly: Children's Oncology Group (COG) protocols (22.4%), CALGB 10403 (22.4%), HyperCVAD (11.9%), and CALGB 8811 (10.4%). Fifty-eight percent achieved a CR/CRi and 21% were refractory to initial therapy. Thirteen percent of pts received a Jak inhibitor and 6% of pts were treated with a TKI. Thirty pts (50.8%) underwent allogeneic stem cell transplant, with 8 of those pts (26.7%) experiencing a relapse post-transplant. Nine pts (13.4%) underwent treatment with CAR-T therapy with few pts experiencing grade 2 or higher cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Pts with CNS disease at diagnosis were less likely to achieve a CR/CRi compared to those without CNS disease at diagnosis (33.3% vs 64.0%; p=0.12). Pts identifying as AI/AN were more likely to be refractory to their first treatment compared to other racial/ethnic groups (75%, p=0.002). Forty two percent of pts never achieved MRD negativity (&lt; 0.01% by flow cytometry) during treatment; pts identifying as H/L and AI/AN had a higher rate of MRD positivity after induction compared to NHW pts (56% and 70% vs. 25%; p=0.02). In pts with IKZF1 mutation, 57.1% did not achieve MRD negativity compared to 21.7% in pts without a mutation (p=0.029). The median overall survival (OS) was 66.3 months (mos) and the median progression-free survival (PFS) was 15.7 mos. Pts who did not achieve MRD negativity after initial treatment had shorter OS compared to those who did achieve MRD negativity, 33.9 mos vs 66.3 mos (p=0.086). Progression-free survival (PFS) was significantly shorter for patients who did not achieve MRD negativity after initial treatment compared to those who did, 3.9 mos vs 43.9 mos (p=0.001). PFS was shorter in pts who identify as AI/AN compared to H/L and NHW pts (2 mos vs 35.7 mos and 35.7 mos; p=0.046). Conclusion: Pts with Ph-like ALL experience poor response rates to therapies used to treat B-ALL, highlighting the urgent need for novel therapies and treatment strategies. We identified race/ethnicity and CNS disease at diagnosis as risk factors for poor treatment response. In addition, race/ethnicity and the presence of an IKZF1 mutation was associated with worse rates of MRD negativity during treatment.

Introduction Genomic alterations are common in multiple myeloma precursor stages, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, commonly used stratification systems do not include somatic alterations that play a role in the disease. To address this clinical need, we generated a comprehensive genomic map of MM and precursors by harmonizing and analyzing mostly WGS data from 1,030 patients. We used these data to define a simple MM-like score, that is able to discriminate which premalignant patients are at risk to progress. Methods We collected, enriched, and performed WGS of tumor plasma cells and matched normals from 138 participants with MGUS or SMM, including those in low, intermediate, and high-risk groups. We combined our precursor dataset with genomic profiles from MM (n=20) and external sources of 872 individuals with MGUS (n=18), SMM (n=62), and MM (n=792) for a cohort of 1,030 individuals with MM or a precursor condition. In 16 patients, we could perform WGS serially from the bone marrow or circulating tumor cells (n=39) and reassess the presence of mutations. Results To develop a simple score that reflects the similarity of precursor genomes to full-blown multiple myeloma disease, we searched among the 107 common driver events (occurring in &gt;1% of patients) and initiating translocations for ones that are differently altered in precursor conditions versus MM. We found 26 differentially altered events: only MAF and MAFB translocations were enriched in MGUS/SMM whereas 24 events were enriched in MM, including known drivers MYC, KRAS, FAM46C, del(1p) and gain(1q). We then defined a simple “MM-like” score for each tumor as the number of MM-enriched drivers minus the number of MGUS-enriched drivers. As expected, the MM-like score in our cohort increased throughout MM development (MM-like score median of 1 in MGUS, 2 in SMM, and 3 in MM). Even among SMM patients, we found a gradual increase of the MM-like score from low- (median=1), to intermediate (median=2), to high-risk (median=3) groups that match the overall medians in MGUS, SMM and MM (p=2e-5). We tested whether the MM-like score can be used to estimate risk of progression. Among untreated SMM patients characterized with WGS, an MM-like score greater than 2 was associated with a higher likelihood of progression (HR=5.3, P=0.03). Using an independent dataset of 87 patients with SMM, we were able to validate that a MM-like score greater than 2 was indeed associated with a higher risk of progression (HR=3.3, P=5x10-5). 11 patients who did not progress and for whom we performed longitudinal WGS, has stable MM-like scores over time, while three patients clinically progressed and their MM-like score increased at the time of progression (due to newly detected mutations in KRAS and NRAS). For the two remaining patients, their MM-like score increased, and we observed growth of the subclone that acquired the additional MM-like driver. In the first patient with MGUS/low-risk SMM, a novel hyperdiploid clone was detected in addition to a TP53 bi-allelic hit and t(11;14) translocation and was shown to increase in clonal fraction with tumor burden (light chains +104% within three years). In the second non-progressor with an increasing MM-like score, a novel del(1p) was detected, and other subclones in the phylogenetic tree either shrank or were stable over three years. Finally, because the MM-like score can place tumors on a gradual axis of evolution towards a more genomically-mature tumor, we tested whether the MM-like score was also predictive of survival in patients treated with a newly diagnosed MM. To do so, we calculated the MM-like score in patients from the publicly available CoMMpass database. We found that an increased score significantly correlated with shorter progression-free survival (median PFS1: 3 years in high score, versus 5 years in low/intermediate score; p=1e-3) and overall survival (median OS: 4.5 years in high score, versus not reached in low/intermediate score; p=1e-5). Conclusion Overall, we demonstrate that it is possible to stratify precursor stages of MM by discovering drivers, detecting those that are associated with the stage of the disease, and defining a genomically-based score that can be used to assess risk of progression and is easy to implement in the clinic.

Background: Clonal cytopenia of undetermined significance (CCUS), a precursor of myeloid neoplasms (MN), is characterized by one or more persistent cytopenias, and acquired mutations in myeloid malignancy-associated genes. ZRSR2, located at Xp22.2, is one of the MN-associated genes and a member of the spliceosome family of genes. Aim: Describe the clinical characteristics, pattern of progression, and genetics of ZRSR2 mutation (ZRSR2m)-harboring CCUS patients. Methods: Next-generation sequencing (NGS) was performed for 9320 patients between 2016-2023 at Mayo Clinic. After obtaining IRB approval, clinical characteristics and results of bone marrow morphology, cytogenetics, and molecular studies were abstracted. Overall Survival (OS) was calculated using Kaplan-Meier, from the date of NGS until death or last follow-up. The ZRSR2m MN control cohort included 125 patients with myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and MDS/MPN overlap. BlueSky Statistics V10.3.1 was used for statistical analysis. Results: ZRSR2m was detected in 39 CCUS patients, all of whom were males. Concurrent hematological neoplasms were identified in 8 patients (21%). Five (13%) had plasma cell proliferative disorders including 3 multiple myeloma, 1 MGUS, and 1 AL amyloidosis. There were also 2 patients with chronic lymphocytic leukemia and 1 with VEXAS syndrome. Prior chemotherapy, with or without radiotherapy, was given to 4 patients (10.3%), whereas 13 patients (33%) had received previous immunotherapy. Abnormal cytogenetics were detected in 11 patients (29%), with the most common abnormality being +8 (n=5, 13%). In 23 patients (59%), an absolute monocyte count of ≥0.5 x 10^9/L was documented which could be classified as clonal cytopenia with monocytosis of unknown significance (CCMUS). ZRSR2 median gender-corrected VAF among CCUS patients was 32% (range, 1-45). Isolated ZRSR2m was found in 6 patients (15%), and 1 (3%) had multiple ZRSR2m. The median number of co-mutations was 1 (range, 0-3). Sequential NGS, available in 13 patients, showed that 1 patient developed 3 ZRSR2 mutations and 2 ZRSR2 VUS. TET2 was the most common co-mutation (n=25, 64%). Additionally, TET2 was an isolated co-mutation in 18 patients (46%). ASXL1 co-mutation was the second most common (n=8, 20.5%), while other less common co-mutations were IDH1, IDH2, SRSF2, SF3B1, TP53, GATA2, and KDM6A. Pre-ZF1 was the most commonly mutated region in ZRSR2 mutations (n=23, 59%). With a median follow-up of 32 months, 9 (23%) of the ZRSR2m CCUS patients progressed to MNs, none progressed to AML. Five (55.6%) progressed to MDS, 4 were subclassified as low blast (LB) and 1 as increased blast-1 (IB1). Four (44.4%) progressed to MDS/MPN overlap syndrome, with 3 subclassified as chronic myelomonocytic leukemia (CMML). None of the patients with isolated ZRSR2m progressed to MDS or CMML. None of the patients who received prior immunotherapy progressed to MDS. Thirty-six (92.3%) patients had high-risk CCUS (Malcovati et al, Blood 2017) while 3 had intermediate risk with no low-risk patients. None of the intermediate-risk patients progressed to MDS, while 5 patients of the high-risk (13.9%) progressed to MDS (p=1). Twelve (31%) patients died, and the median overall survival (mOS) was 56 months. Higher hemoglobin levels improved OS (HR=0.59, p=0.02), while higher adjusted ZRSR2 VAF worsened OS (HR=1.05, p=0.017). Patients with TET2 as isolated co-mutations showed better mOS than the rest of the cohort (not reached vs 41 months, p= 0.03). ZRSR2m CCUS patients showed a trend suggestive of better mOS than ZRSR2m with MNs including AML (56 vs 30 months, p=0.14), and with excluding AML (56 vs 39 months, p=0.24). On multivariate analysis, both Hgb (HR=0.61, p=0.03) and isolated TET2 co-mutation (HR=0.19, p=0.04) retained statistical significance. mOS was not affected by prior history of treatment, number of co-mutations, isolated ZRSR2, ASXL1 co-mutation, or MDS progression. Conclusion: ZRSR2m CCUS cohort was exclusively males. There was a significant number of patients with concurrent hematological malignancy or a history of prior chemo- and/or immuno-therapy (36%). Most patients had high-risk CCUS but showed a low rate of progression to MNs, especially in those with isolated ZRSR2. Additionally, patients with isolated TET2 co-mutation had better survival, indicating that TET2 confers a favorable prognosis among ZRSR2m CCUS patients.

Background: SETBP1 gene, located on 18q12.3, is a major oncogene in myeloid neoplasms. GATA2 gene, located on 3q21, is one of the six GATA transcription factors regulating gene expression via two conserved zinc finger domains (ZF). Previous data suggested that in patients with germline GATA2 mutation (m), acquisition of a somatic SETBP1 mutation (m) was associated with leukemic transformation among patients with excess blast MDS and CMML. Aim: To study the characteristics of patients with somatic SETBP1-GATA2 mutated myeloid neoplasms. Methods: This study is a retrospective study at Mayo Clinic. After obtaining IRB approval, we retrospectively reviewed the charts of patients who had myeloid NGS panel results between 2016-2023. All data were recorded at time of first NGS. Cohort 1 was defined as patients with SETBP1m and GATA2m, cohort 2; patients with SETBP1m and GATA2wt, and cohort 3; patients with SETBP1wt and GATA2m. Germline work-up was not performed in the majority of GATA2 cases. We stratified risk based on the European LeukemiaNet 2022 guidelines for AML, IPSS-M for MDS and MDS/MPN, and CPSS-M for CMML. Overall survival (OS) was calculated from date of NGS to date of last follow-up based on Kaplan-Meier estimates and Cox regression analysis. For statistical analysis, we used BlueSky Statistics V10.3.1. Results: General characteristics: 114 patients had SETBP1m (median VAF= 39%), and 63 patients had GATA2m (median VAF= 35%). Nine patients had co-occurring SETBP1m/GATA2m mutations (cohort 1). 4/9 patients in cohort 1 had MDS/MPN (44.4%), while only 13/105 in cohort 2 (12.4%) had MDS/MPN (P=0.02). AML was seen in 2 patients in cohort 1 (22.2%) compared to18 in cohort 2 (17.1%) (p=0.6). The median WBC count was 22.9 x 109 cells/L among cohort 1 compared to 9 x 109 cells/L among cohort 2 cases (p=0.09). BM blasts were higher in cohort 3 (7%) compared to cohort 1 (5%) and cohort 2 (3%) (p=0.09), while peripheral blasts tended to be lower in cohort 2 (1%) in comparison to cohort 1 (6%) and cohort 3 (4%) (p=0.48). Genetic characteristics: In cohort 1,7 GATA2m clustered in zinc finger 2 (ZF2) (77.8%), while the other two mutations were outside the ZF domains (22.2%). This was higher than the ZF2 mutated cases in cohort 3 (46.3%, p=0.1). Abnormal cytogenetics were seen in 66.7% of cohort 1 patients and 45% of cohort 2 (p= 0.3). Two cases with trisomy 8 were seen among patients in cohort 1 (22.2%), compared to only 4.9% in cohort 2 (p=0.09). Two incidences of isochromosome 17q [i(17q)] were seen in cohort 1 (22.2%), versus 5 cases in cohort 2 (4.8%) and 1 case in cohort 3 (1.9%) (p= 0.068). Co-mutations: The median number of co-mutationswas 3 in both cohort 1 and cohort 2 (p= 0.6). In cohort 1, ASXL1 and SRSF2 mutations were the most common (7/9, 77.8%) followed by NRAS (22.2%) and TET2 (22.2%). 77.8% of cohort 1 patients had SRSF2 co-mutation, compared to 44.8% in cohort 2 (p=0.08), and 27.8% in cohort 3 (p= 0.006). No isolated SETBP1m/GATA2m cases were found. Survival: Patients in cohort 1 had a numerically higher median OS compared to those in cohort 2 (19.4 vs 15.4 months, p= 0.3). When comparing with the cohort 3, patients in cohort 1 tended to have better outcomes (median OS= 19.4 vs 13.8 months, p=0.8). Among cohort 1, SRSF2 co-mutation was associated with worse survival outcomes compared to patients with SRSF2wt (median OS= 5.3 vs 19.4 months, p= 0.02); this association was not found in cohort 2 (12.5 vs 18.4 months, p= 0.3) and cohort 3 (13.2 vs 17.1 months, p= 0.4). Allogeneic hematopoietic cell transplantation was associated with favorable survival outcomes in all cohorts (cohort 1: 22.6 vs 7.8 months, p= 0.1; cohort 2: 20.9 vs 12.5 months, p= 0.04; cohort 3: 25.6 vs 13.1 months, p= 0.03). Conclusion: SETBP1m/GATA2m myeloid neoplasms included a significantly higher proportion of MDS/MPN overlap cases in comparison with the SETBP1m/GATA2wt group. The SETBP1m/GATA2m group had a higher proportion of ZF2 GATA2m and SRSF2 co-mutation compared to patients with SETBP1wt/GATA2m. Survival of SETBP1m/GATA2m patients was not worse compared to SETBP1wt/GATA2m or SETBP1m/GATA2wt.