Begna, Kebede H.

AbstractThe current study was approached with the assumption that response to induction chemotherapy, in acute myeloid leukemia (AML), overshadows pre‐treatment risk variables in predicting survival and therefore be used as an anchor for a simplified risk model. We considered 759 intensively‐treated patients with AML, not promyelocytic: median age 60 years; primary 66%, secondary 25%, and therapy‐related 9%; European LeukemiaNet cytogenetic risk category favorable 8%, intermediate 61%, and adverse 31%. Complete remission with (CR) or without (CRi) count recovery was achieved in 608 (80%) patients. After a median follow‐up of 22 months, 503 deaths, 272 relapses, and 257 allogeneic hematopoietic stem cell transplants (AHSCTs) were recorded. Multivariable analysis identified failure to achieve CR/CRi (HR 3.8, 95% CI 3.1–4.8), adverse karyotype (2.2, 1.8–2.8), and age >55 years (2.1, 1.6–2.7) as main risk factors for survival. HR‐weighted scoring resulted in four‐tiered risk stratification: low (0 points; N = 183), intermediate‐1 (1 point; N = 331), intermediate‐2 (2 points; N = 117), and high (≥3 points; N = 128), with respective median survival (5‐year rate) not reached (68%), 34 (37%), 13 (20%), and 5 (5%) months (p < .001). FLT3‐ITD mutation was associated with inferior survival in intermediate‐1 (p = .004) and TP53 in intermediate‐2 (p = .06) and high (p = .02) risk disease; the latter was fully accounted for by the close association between TP53 mutation and complex/monosomal karyotype while the observations regarding FLT3‐ITD were not affected by treatment with midostaurin. AHSCT had a favorable impact on survival, most apparent in intermediate‐1 (p < .001), intermediate‐2 (p = .03), and high (p = .01) risk disease. The proposed 3‐factor survival model offers a novel prototype that is amenable to further enhancement by molecular information and was validated in an external cohort of 1032 intensively‐treated AML patients.

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.

TPS7080 Background: Myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) are classified as a distinct category under the World Health Organization (WHO) classification of myeloid neoplasms. MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) and MDS/MPN, unclassifiable with > 15% bone marrow ring sideroblasts (MDS/MPN-U-RS) have similar clinical and pathological characteristics with symptomatic or transfusion-dependent anemia as the predominant morbidity. Luspatercept has been approved in myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/MPN overlap syndromes, based on the phase 3 MEDALIST clinical trial which primarily included MDS-RS patients with an objective erythroid response rate of approximately 40 per cent. In this trial, some MDS-RS patients also experienced an increase in neutrophil and platelet counts. This raises a safety concern for MDS/MPN patients with elevated platelet or WBC counts such as MDS/MPN-RS-T and MDS/MPN-U-RS. Previous studies have shown clinical and biological differences between MDS-RS and MDS/MPN-RS-T, with the latter group at a significantly elevated risk for thrombotic events. Additionally, several MDS/MPN-RS-T patients are on hydroxyurea which may blunt the erythroid response of luspatercept. Therefore, it is imperative to establish the safety and efficacy of luspatercept in this patient group. Methods: This is an investigator-initiated, prospective, phase II study of luspatercept in MDS/MPN overlap neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts with 2 arms; hydroxyurea-independent (cohort A) and hydroxyurea-dependent (cohort B). Hydroxyurea and/or aspirin use is allowed as per investigator discretion. The primary goal is to study the efficacy and safety of luspatercept in MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic anemia. The primary endpoint is to assess erythroid response rate as per the 2015 International Working Group MDS/MPN response criteria. Secondary endpoints include response duration, time to acute myeloid leukemia (AML) transformation, thrombosis rate, AML-free and overall survival. Inclusion criteria include newly diagnosed or relapsed/refractory adult patients with WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic or transfusion-dependent anemia and unlikely to respond (EPO level > 200 IU/L) or intolerant to erythropoiesis stimulating agent (ESA) therapy. Prior therapy with lenalidomide, hypomethylating agents or immunosuppressive therapy is allowed. The overall plan is to enroll 54 patients across the three Mayo Clinic sites, Minnesota, Arizona and Florida. Enrollment to the trial began in January 2022 with 1 patient enrolled at the time of abstract submission. Clinical trial information: NCT05005182.

AbstractTherapy‐related myeloid neoplasms (t‐MN) are aggressive malignancies in need of effective therapies. The BCL‐2 inhibitor venetoclax represents a paradigm shift in the treatment of acute myeloid leukemia. However, the effectiveness of venetoclax has not been studied in a large cohort of t‐MN. We retrospectively analyzed 378 t‐MN patients, of which 96 (25.4%, 47 therapy‐related acute myeloid leukemia, 1 therapy‐related chronic myelomonocytic leukemia, 48 therapy‐related myelodysplastic syndrome) received venetoclax. Median interval from t‐MN to venetoclax initiation was 2.9 (Interquartile range [IQR] 0.7–12) months, and patients received a median of 3 (IQR 1–4) cycles. The composite complete remission (CRc) rate, median progression‐free survival (PFS), and overall survival (OS) were 39.1%, 4.9 months, and 7 months, respectively. The upfront use of venetoclax and achieving CRc were associated with improved survival, whereas the presence of Chromosome 7 abnormalities was associated with an inferior survival. Neither the TP53‐status nor the percent bone marrow blast predicted the likelihood of CRc or survival. Paired genetic analysis performed at venetoclax initiation and failure did not show the evidence of the selection of the TP53‐mutated clone. In a propensity‐matched analysis, the use of venetoclax‐based regimen as the first‐line therapy was associated with a superior survival compared to hypomethylating agent (HMA)‐based first‐line therapy (9.4 vs. 6.1 months, p = .01). We conclude that the upfront use of venetoclax with HMA improved survival, though PFS and OS remain poor. As the phenotype at diagnosis or the percent blasts did not predict outcomes, venetoclax should be studied in all t‐MN phenotypes.