Saliba, Antoine N.

AbstractThe intricate interplay of anemia and iron overload under the pathophysiological umbrella of ineffective erythropoiesis in non-transfusion-dependent β-thalassemia (NTDT) results in a complex variety of clinical phenotypes that are challenging to diagnose and manage. In this article, we use a clinical framework rooted in pathophysiology to present 4 common scenarios of patients with NTDT. Starting from practical considerations in the diagnosis of NTDT, we delineate our strategy for the longitudinal care of patients who exhibit different constellations of symptoms and complications. We highlight the use of transfusion therapy and novel agents, such as luspatercept, in the patient with anemia-related complications. We also describe our approach to chelation therapy in the patient with iron overload. Although tackling every specific complication of NTDT is beyond the scope of this article, we touch on the management of the various morbidities and multisystem manifestations of the disease.

TPS7089 Background: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN) that can be further divided into MD (WBC < 13 x 109/L) and MP (≥13 x 109/L) subtypes. MP-CMML is enriched in RAS pathway mutations ( NRAS, CBL, KRAS, PTPN11 and NF1), has a shorter median survival (19 vs 36 months), has a higher rate of acute myeloid leukemia (AML) transformation (40% vs 10%) and has a unique transcriptomic and epigenetic composition. These RAS pathway mutations promote selective PLK1 overexpression, a mitotic checkpoint kinase. Given the relative inefficacy of hypomethylating agents (HMA) in MP-CMML and previously demonstrated in vitro and in vivo efficacy data for PLK1 inhibition on MP-CMML with RAS pathway mutations, we designed a phase 1 clinical trial testing the safety of onvansertib, a novel, orally bioavailable, PLK1 inhibitor in relapsed/refractory MP-CMML. Methods: This is an investigator-initiated, prospective, open-label, phase I study of onvansertib in MP-CMML relapsed/refractory (RR) or intolerant to existing therapies including HMA and hydroxyurea. The primary endpoint is characterization of safety. Secondary endpoints include efficacy as defined by the 2015 MDS/MPN International Working Group criteria, volumetric spleen response and symptom response via assessment with MPN-SAF-TSS. Inclusion criteria include MP-CMML RR following hydroxyurea or at least 4-cycles of HMA or intolerance of treatment with either, platelets ≥ 20,000/m3 and Cockcroft-Gault creatinine clearance ≥ 60 mL/min/m2. Hydroxyurea may continue for the first 28 days on study. Onvansertib will be given orally on days 1 through 21 of a 28-day cycle with a Bayesian optimal interval design to assess the safety and recommended phase II dose. Exploratory end points include targeting efficacy, impact of PLK1 and KMT2A expression and interactions with ASXL1 and TET2 mutations. Twenty-five patients will be enrolled at Mayo Clinic in Minnesota, with enrollment open since November 2022. Clinical trial information: NCT05549661 .

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.

Abstract We conducted a multi-center study to analyze factors predicting survival among patients with TP53-mutated (m) AML receiving allogeneic hematopoietic stem cell transplant (allo-HSCT) in the recent era. Among 370 patients, 68 (18%) patients were bridge to allo-HSCT. The median age of the patients was 63 years (range, 33–75), 82% of patients had complex cytogenetics and 66% of patients had multi-hit TP53m. Forty three percent received myeloablative conditioning (MAC) and 57% received reduced intensity conditioning (RIC). The incidence of acute graft versus host disease (GVHD) was 37% and chronic GVHD was 44%. The median event-free survival (EFS) from the time of allo-HSCT was 12.4 months (95% CI: 6.24–18.55) and median overall survival (OS) was 24.5 months (95% CI: 21.80-27.25). In multivariate analysis utilizing variables that showed significance in univariate analysis, complete remission at day 100 post allo-HSCT retained significance for EFS (HR: 0.24, 95% CI: 0.10–0.57, p = 0.001) and OS (HR: 0.22, 95% CI: 0.10–0.50, p = < 0.001). Similarly, occurrence of chronic GVHD retained significance for EFS (HR: 0.21, 95% CI: 0.09–0.46, p = < 0.001) and OS (HR: 0.34, 95% CI: 0.15–0.75, p = 0.007). Our report suggests that allo-HSCT offers the best opportunity to improve long-term outcome among patients with TP53m AML.