CML-047 Post Hoc Analysis of Responses to Ponatinib in Patients With Chronic-Phase Chronic Myeloid Leukemia (CP-CML) by Baseline BCR::ABL1 Level and Baseline Mutation Status in the OPTIC Trial

International audienceObjectives: OPTIC (NCT02467270) is a Phase 2 trial evaluating the safety and efficacy of ponatinib in patients with CP-CML resistant to ≥2 TKIs or have a T315I mutation. We present a post hoc analysis of patient responses by baseline BCR::ABL1 level and mutation status. Methods: Patients with CP-CML resistant to ≥2 TKIs or with the T315I mutation were randomized to ponatinib starting doses of 45 mg, 30 mg, and 15 mg once daily. Doses were reduced to 15 mg after achievement of ≤1% BCR::ABL1IS in the 45-mg and 30-mg cohorts. The primary endpoint is ≤1% BCR::ABL1IS at 12 months. In this analysis, outcomes are analyzed by baseline T315I mutation status and baseline BCR::ABL1 level in the intent-to-treat (ITT) population. Results: 283 patients were randomized (45-mg/30-mg/15-mg cohorts: n=94/95/94). At baseline, 84.1% of patients had >10% BCR::ABL1IS; 23.8% had T315I mutation. Subanalysis showed that patients with T315I mutations in the 45-mg cohort had the highest ≤1% BCR::ABL1IS response rates (60%) by 3 years versus other cohorts. Across cohorts, 97 patients without T315I mutations achieved ≤1% BCR::ABL1IS. Median duration of response (mDoR) for patients with a T315I mutation at baseline was 27 months in the 45-mg cohort (n=15) and 12 months in the 30-mg cohort (n=5). For patients without T315I mutations, the mDoR was not reached. Across cohorts, 79% of patients who achieved ≤1% BCR::ABL1IS maintained this response during the study. The most common nonhematologic treatment-emergent adverse events (TEAEs) and hematological TEAEs in the ITT population for all cohorts combined were arterial hypertension (28%), headache (18%), lipase increase (17%), thrombocytopenia (40%), neutropenia (26%), and anemia (19%). Overall, 6.0% of patients experienced a treatment-emergent arterial occlusive event (TE-AOE); 4.6% experienced a Grade ≥3 TE-AOE. Conclusions: The OPTIC post hoc analysis showed clinical benefit across dosing regimens regardless of T315I mutation status at baseline; the 45-mg cohort showed the highest response rates regardless of baseline BCR::ABL1IS levels. Regardless of T315I mutation status, most patients were able to maintain their response after dose reduction upon achieving BCR::ABL1IS ≤1%. This abstract is an encore from the American Society of Hematology 2021 Annual Meeting

A mixed-method approach on digital educational games for K12:Gender, attitudes and performance

Research on the influence of gender on attitudes towards and performance in digital educational games (DEGs) has quite a long history. Generally, males tend to play such games more engagingly than females, consequently attitude and performance of males using DEGs should be presumably higher than that of females. This paper reports an investigation of a DEG, which was developed to enhance the acquisition of geographical knowledge, carried out on British, German and Austrian K12 students aged between 11 and 14. Methods include a survey on initial design concepts, user tests on the system and two single-gender focus groups. Gender and cultural differences in gameplay habit, game type preferences and game character perceptions were observed. The results showed that both genders similarly improved their geographical knowledge, although boys tended to have a higher level of positive user experience than the girls. The qualitative data from the focus groups illustrated some interesting gender differences in perceiving various aspects of the game

CML-046 Dose Modification Dynamics of Ponatinib in Patients With Chronic-Phase Chronic Myeloid Leukemia From the PACE and OPTIC Trials

International audienceObjective: In the PACE trial (NCT01207440), patients with resistant/intolerant chronic-phase chronic myeloid leukemia (CP-CML) demonstrated lasting responses to ponatinib 45 mg once daily (QD). The OPTIC trial (NCT02467270) prospectively evaluated a response-based dose-reduction strategy to optimize the dosing schedule of ponatinib in patients with CP-CML resistant to second-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) therapy or with a T315I mutation. Our objective was to analyze dosing dynamics between the 2 trials and compare efficacy and safety outcomes. Methods: In PACE, patients received an initial dose of ponatinib 45 mg QD. In OPTIC, patients were randomly assigned (1:1:1) to an initial oral dose of ponatinib 45 mg, 30 mg, or 15 mg QD. In PACE, proactive dose reductions were mandated as arterial occlusive events (AOEs) emerged as notable adverse events (AEs). In OPTIC, patients in the 45-mg and 30-mg cohorts in OPTIC achieving ≤1% BCR::ABL1IS had their doses reduced to 15 mg QD; doses were also reduced to manage AEs. Data from patients with CP-CML in PACE and from the 45-mg starting dose cohort in OPTIC were analyzed. Efficacy outcomes include ≤1% BCR::ABL1IS, progression-free survival (PFS), and overall survival (OS). Safety outcomes include treatment-emergent (TE) AEs and TE-AOE rates. Results: A total of 364 CP-CML patients had ≥1 prior second-generation TKI or a T315I mutation and received a starting dose of ponatinib 45 mg (PACE, n=270; OPTIC, n=94). The percentages of patients with vascular disorders were 44% in PACE and 32% in OPTIC. The median follow-ups were 57 months (PACE) and 32 months (OPTIC). The ≤1% BCR::ABL1IS responses by 24 months were 52% (PACE) and 56% (OPTIC), 2-year PFS was 68% (PACE) and 80% (OPTIC), and 2-year OS was 86% (PACE) and 91% (OPTIC). Dose reductions due to AEs occurred in 82% (PACE) and 46% (OPTIC) of patients. Per 100 patient-years, exposure-adjusted TE-AOEs were 15.8 (PACE) and 7.6 (OPTIC) at 0 to <1 year. Conclusions: The response-based dose-reduction strategy in OPTIC resulted in comparable or better efficacy outcomes and fewer AE-related dose reductions and exposure-adjusted TE-AOEs, further demonstrating the benefit of the response-based dosing regimen used in OPTIC. This abstract is an encore from the European Hematology Association 2022 Annual Meeting

Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial

International audienceIn PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270