Arellano, Martha

Background Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported. Methods Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×10⁶ CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided. Results Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7–58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups. Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22). Conclusions In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

AbstractBackgroundPatients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.MethodsThis was a multicenter, open‐label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two‐stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1–10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1–5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.ResultsThe composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%–26.8%) and 30.8% (95% confidence interval, 9.1%–61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.ConclusionsThe combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.

7053 Background: Mutations in isocitrate dehydrogenase 1 ( IDH1) occur in ̃3% of patients (pts) with MDS and are associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO), an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, is FDA approved for m IDH1 R/R AML and m IDH1 newly diagnosed AML in pts ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human study of IVO in pts with m IDH1 advanced hematologic malignancies (NCT02074839), 12 pts with R/R MDS received IVO 500 mg once daily (QD). Based on encouraging safety and efficacy findings, including an investigator-assessed overall response rate (ORR) of 75%, with median response duration of 21.4 months, the FDA granted Breakthrough Therapy designation to IVO in m IDH1 R/R MDS and the study was amended to enroll additional pts. We report updated results. Methods: This substudy of the single-arm, open-label study of IVO evaluated pts with R/R MDS after documented failure or relapse following prior standard therapy including intensive chemotherapy and hypomethylating agents. Other key eligibility criteria included: high disease burden based on IPSS or IPSS-R risk at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and no prior IDH1 inhibitor therapy. Pts received IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: As of 08May2021, 16 pts with R/R MDS were enrolled: 5 (31%) pts remained on treatment and free from leukemic transformation; 11 (69%) had discontinued including 6 for disease progression, 1 for allogeneic stem cell transplantation, and 1 owing to an adverse event (AE) of sepsis (the only fatal AE; reported by investigator as not related to IVO). AEs are summarized in the Table. 2 pts each experienced differentiation syndrome (grade 2) and QTcF prolongation (grade 1 and 2). 7/16 pts achieved complete response (CR, 44%; 95% CI, 20%, 70%), 1 achieved partial response (6%), and 5 achieved marrow CR (31%), resulting in an ORR of 81% (95% CI, 54%, 96%). Hematologic improvement in ≥1 lineages was achieved by 11/16 (69%) pts. The Kaplan-Meier estimate of duration of CR+PR at 12 months was 60%. 3 pts experienced CRs lasting 24.0, 63.7, and 65.4 months, which remain ongoing. 5/7 pts (71%) who were transfusion dependent at baseline became independent of red blood cell or platelet transfusions for 56 or more consecutive days on treatment. Additional translational data are being analyzed. Conclusions: In pts with m IDH1 R/R MDS, IVO monotherapy was tolerable and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for pts with m IDH1 R/R MDS. Clinical trial information: NCT02074839. [Table: see text]