Abaza, Yasmin

Abstract Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

AbstractVenetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real‐world data published on HMAs plus VEN have been either single‐center studies or using community‐based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real‐world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85–13.5), with OS significantly worse among patients with TP53‐mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30‐day and 60‐day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE‐A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

AbstractBackgroundAlthough the clinical outcomes of patients with TP53‐mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative‐intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53‐mutated AML.MethodsA multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53‐mutated AML (275 non‐Hispanic White [NHW] and 65 non‐Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients.ResultsThe median patient age was comparable between NHW and NHB patients (p = .76). A higher proportion of NHB patients had therapy‐related AML (31% vs. 20%; p = .08) and had co‐mutations (74% vs. 61%; p = .06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p = .02). Conversely, a higher proportion of NHB patients received low‐intensity chemotherapy (9% vs. 5.5%; p = .02) or best supportive care (22% vs. 7%; p < .001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p = .39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p = .02). The proportion of patients who were event‐free (18.5% vs. 8.5%; p = .49) or who remained alive (24.9% vs. 8.3%; p = .13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant.ConclusionsThe current study highlights disparities between NHW and NHB patients with TP53‐mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations.