Distinct patterns of mutant ASXL1 over time and their implications for treatment failure (TF) and BCR::ABL1 mutation development in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) treated with asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS-TKI) in the ASC4FIRST study

ASC, an allosteric BCR::ABL1 inhibitor, was recently approved in several countries for use in newly diagnosed patients with CML-CP based on the results from the ASC4FIRST study (NCT04971226). The most frequent additional genomic alteration (AGA) at baseline (BL) reported in this study was ASXL1 mutation (ASXL1+). The allelic burden of ASXL1+ clones at BL was incidentally higher in pts receiving ASC (24% variant allele frequency [VAF]) vs IS-TKI (10% VAF). ASXL1+ at BL was associated with increased risk of TF (as per ELN 2020 criteria). Here, the authors report an exploratory analysis of the longitudinal changes of ASXL1+ from BL in relation to outcomes until week (wk) 96 follow-up. Presence of AGAs was determined using a DNA next-generation sequencing panel of 89 genes on diagnostic blood samples collected at BL, wk 48 and end of treatment (EOT). A multivariable Cox proportional hazards regression model with time-dependent covariates adjusted for age, sex and treatment (ASC or IS-TKI) was used to determine the prognostic and predictive value of AGAs considering their changes over time. Pts harboring AGAs were categorized as presenting persistent, eradicated or treatment-emergent clones.

Of 405 pts randomized, AGA analysis was performed at BL for 341 pts (ASC, n=169; IS-TKIs, n=172 [imatinib, n=83; second generation TKI, n=89]) with the available samples. AGAs were detected at BL in 21.1% (72/341) of pts (32/169 ASC vs 40/172 IS-TKI). The most frequent AGA detected was ASXL1+ in 11% (39/341) of pts at BL and in 15% (50/341) at any time until wk 96/EOT. Three patients with ASXL1+ at BL had no post-BL genomic data. Other AGAs detected were not included in the analysis due to low frequencies of events for individual mutated genes. On-treatment emergence of at least one new ASXL1+ clone was observed in 12 pts (6 ASC vs 6 IS-TKI). In 6 pts with an emergent ASXL1+ clone at wk 48 (VAF: 1%−10%), major molecular response (MMR) was achieved at the same time. In these 6 cases, clonal hematopoiesis (CH) in non-leukemic clones was suspected. For the other 6 pts, ASXL1+ emergence likely took place in leukemic clones. Eradication of BL ASXL1+ was observed in 74% (29/39) of pts irrespective of initial clonal burden (VAF: 1.2%–44%). ASXL1+ clones detectable at BL were persistent at the last evaluation in 6 pts (4 ASC vs 2 ISTKI). Pts with ≥1 persistent ASXL1+ clone had a higher probability of TF as compared to pts who had ontreatment eradication of BL ASXL1+ clones in either treatment arm. Summarized at pt level, TF was observed in 5/6 pts with persistent vs 4/29 pts with eradicated clones (Fisher test; p=0.03). Treatmentemergent BCR::ABL1 mutations were associated with persistent ASLX1+ in 5/6 cases vs 1/29 cases among pts who had on-treatment eradication of ASXL1+ clones. Overall, detectable ASXL1+ at any time during the study was a prognostic and a predictive factor for TF. For pts with no ASXL1 mutation at any time point (85%; 291/341 pts), the TF rate was considerably lower for ASC (8%; 12/145 pts) than for IS-TKI (28%; 41/146 pts). The overall TF rate was comparable between treatment arms (8/24 on ASC vs 9/26 on IS-TKI) among patients with detectable ASXL1+ at any time. Although the ASC arm showed a higher TF risk difference in ASXL1+ compared to ASXL1-negative pts, this may be due to the higher baseline ASXL1+ clonal burden in the ASC group. In the larger subset of ASXL1- negative pts, the MMR rate at wk 96 was 80% (116/145) for ASC and 51% (74/146) for IS-TKI, while the MMR rate was comparable for pts on ASC (13/24; 54%) vs IS-TKI (12/26; 46%) in the subset with detectable ASXL1+ at any time during the study.

ASXL1+ was the most frequent AGA in ASC4FIRST and was associated with higher rates of TF and BCR::ABL1 mutations. The number of emergent ASXL1 mutations on treatment was low and similar in both treatment arms. Most of the ASXL1+ clones were eradicated on treatment and the initial allelic burden at BL was not associated with persistence or eradication. TF risk was lower for pts with eradicated ASXL1+ clones. Data from this exploratory analysis in ASC4FIRST support the use of ASC in newly diagnosed CML-CP pts regardless of ASXL1 mutational status. Additional investigations in larger cohorts and longer follow-up are warranted to further elucidate the risks associated with different patterns of ASXL1+ over time and to develop optimized therapeutic strategies in this population.

Asciminib (ASC) demonstrates continued improvement in patient-reported outcomes (PROs) vs investigator-selected tyrosine kinase inhibitors (IS-TKIs) in newly diagnosed chronic myeloid leukemia (CML): ASC4FIRST week 96 analysis

Long-term TKI therapy for patients (pts) with CML is efficacious but is associated with adverse events (AEs) affecting quality of life (QOL). Even low-grade AEs can inhibit QOL, resulting in treatment nonadherence and subsequently poor clinical outcomes. Thus, effective management of CML requires assessing the impact of treatment-emergent AEs on QOL. ASC, the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket, is approved in several countries for pts with newly diagnosed CML in chronic phase (CP) based on superior clinical outcomes vs IS-TKIs in the pivotal phase 3 ASC4FIRST trial (NCT04971226). In the wk 48 ASC4FIRST PRO analysis, ASC vs IS-TKIs was associated with improved health-related QOL (HRQOL) and reduced symptom burden. Here, we present PROs from the wk 96 analysis (data cutoff: Oct 22, 2024). Adults with newly diagnosed CML-CP were randomized 1:1 to receive ASC or an IS-TKI, stratified by ELTS risk category and prerandomization-selected TKI (imatinib [IMA]/second-generation [2G] TKI). Wk 96 PRO secondary endpoints were change from baseline (BL) in scores and individual scales for EORTC QLQ-C30 and EORTC QLQ-CML24; improvement corresponded to a change from BL in functional/satisfaction and global health status/QOL scales (increase of >5) or symptom/item scores (decrease of >5). PRO-CTCAE items and FACIT-GP5 will be reported separately by Hughes et al. Pts completed questionnaires on electronic devices at BL and scheduled study visits.

A total of 405 pts were randomized to ASC (ASC IMA, n=101; ASC 2G, n=100) or IS-TKIs (IS-TKI IMA, n=102; IS- TKI2G, n=102); median duration of follow-up was 26.9 and 26.3 months per arm, respectively. Completion rates were balanced with ASC vs IS-TKI for EORTC QLQ-C30 (BL, 57.7% vs 59.0%; wk 96, 76.2% vs 65.2%) and EORTC QLQ-CML24 (BL, 56.2% vs 56.4%; wk 96, 75.5% vs 65.2%). Per EORTC QLQ-C30 at wk 96 vs BL, the following proportions of pts on ASC IMA and IS-TKI IMA and on ASC 2G and IS-TKI2G had improvement in the physical (31.3% and 17.6%; 43.5% and 40.0%), role (18.8% and 5.9%; 20.6% and 8.6%), cognitive (18.7% and 5.9%; 18.0% and 8.6%), social (25.0% and 17.7%; 33.3% and 22.9%), and emotional (40.7% and 23.5%; 35.9% and 34.2%) functional scales, respectively. The proportions of pts reporting improvement with ASC IMA and IS-TKI IMA and with ASC 2G and IS-TKI2G across symptoms included: fatigue (43.8% and 11.8%; 43.6% and 28.5%), nausea/vomiting (15.6% and 0.0%; 7.7% and 2.9%), diarrhea (18.8% and 17.6%; 10.3% and 11.4%), pain (15.7% and 5.9%; 33.4% and 14.3%), dyspnea (9.4% and 0.0%; 12.8% and 5.7%), insomnia (18.8% and 5.9%; 12.8% and 20.0%), appetite loss (25.0% and 5.9%; 25.6% and 11.4%), and constipation (18.8% and 11.8%; 7.7% and 20.0%), respectively. The proportion of pts on ASC IMA and IS-TKI IMA and on ASC 2G and IS-TKI2G who had improvement with financial difficulties was (18.8% and 29.4%; 23.1% and 20.0%). Overall, 37.5% vs 17.7% of pts receiving ASC IMA vs IS-TKI IMA and 58.9% vs 28.6% receiving ASC 2G vs IS-TKI2G, respectively, had improvements in global health status/QOL. Change from BL to wk 96 in EORTC QLQ-CML24 satisfaction/symptom scale scores with ASC IMA vs ISTKI IMA and with ASC 2G vs IS-TKI2G, respectively, showed that higher proportions of pts had improvements in symptom burden (27.5% vs 0.0%; 46.1% vs 20.6%), impact on daily life (62.0% vs 23.5%; 58.9% vs 47.1%), impact on worry/mood (48.2% vs 29.5%; 58.9% vs 41.2%), body image problems (27.6% vs 0.0%; 28.2% vs 11.8%), and satisfaction with care and information (41.4% vs 29.4%; 53.8% vs 29.4%). Improvement in satisfaction with social life was reported by 24.1% and 23.5% of pts on ASC IMA and ISTKI IMA, and 41.0% and 20.6% on ASC 2G and IS-TKI2G, respectively. Exploratory sensitivity analyses evaluating the impact of missing BL PRO data concluded that there was no substantial impact on observed PROs.

Overall, ASC continued to be associated with improved HRQOL and reduced symptom burden vs IS-TKIs, regardless of strata, in the wk 96 PRO analysis of ASC4FIRST. Considering the superior efficacy and favorable safety and tolerability of ASC in ASC4FIRST observed at wk 96, these PRO findings reinforce ASC as a standard of care for pts with newly diagnosed CML-CP. Longer follow-up of PRO evaluations is warranted and may support long-term QOL benefit of ASC in pts with CML-CP.

Improved long-term tolerability with asciminib (ASC) vs investigator-selected (IS) tyrosine kinase inhibitors (TKIs) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): Week 96 exploratory analysis of the phase 3 ASC4FIRST trial

Long-term CML treatment (Tx) requires assessing adverse event (AE) burden over time to optimize safety, tolerability, and efficacy. ASC4FIRST (NCT04971226) results demonstrated superior efficacy and favorable safety/tolerability of ASC vs IS-TKIs in newly diagnosed CML-CP. A prior report showed a lower risk of discontinuation due to AEs with ASC vs second-generation (2G) TKIs in a time to Tx discontinuation due to AEs (TTDAE) analysis (hazard ratio, 0.46; 95% CI, 0.215-0.997), suggesting better tolerability with ASC. The authors report exploratory post hoc analyses, including an innovative analysis of AE-free days, further evaluating the tolerability of ASC vs IS-TKI (imatinib [IMA]/2G TKIs) by the wk 96 analysis cutoff (Oct 22, 2024). Adults with newly diagnosed CML-CP were randomized 1:1 to receive ASC or IS-TKI (at label dose), stratified by ELTS risk category and prerandomization IS-TKI (IMA/2G TKIs). Dose modifications occurred per protocol for ASC and at investigator’s discretion for IS-TKIs. All reported AEs occurred on Tx or ≤30 days after last dose. Exploratory tolerability analyses included frequency/grade/type of AEs; relative dose intensity; rate of dose adjustment, interruption, or discontinuation; percentage of AE-free days (number of days pt was on Tx without any-grade AEs divided by Tx duration in days, censored at the wk 96 visit; a value of 100% indicates no AEs were experienced on Tx); and pt-reported outcome (PRO) measures (PRO-CTCAE and FACIT GP5).

Safety analyses included all pts who received Tx in IMA (ASC IMA [n=100]; IS-TKI IMA [n=99]) and 2G TKI (ASC 2G [n=100]; IS-TKI2G [n=102]) strata. Median follow-up was similar across groups (ASC IMA [25.1 mo]; IS-TKI IMA [24.3 mo]; ASC 2G [28.2 mo]; IS-TKI2G [27.7 mo]). More pts were continuing Tx at cutoff with ASC IMA (83.0%) vs IS-TKI IMA (52.5%) and ASC 2G (81.0%) vs IS-TKI2G (69.6%). More pts had relative dose intensity of >90% with ASC IMA (86.0%) vs IS-TKI IMA (79.8%) and ASC 2G (88.0%) vs IS-TKI2G (68.6%). The proportion of pts with dose reductions was lower with ASC IMA (n=19, 19.0%) vs IS-TKI IMA (n=23, 23.2%) and ASC 2G (n=18, 18.0%) vs IS-TKI2G (n=56, 54.9%). A similar number of pts with ASC IMA (47.0%) vs IS-TKI IMA (47.5%) and fewer pts with ASC 2G (46.0%) vs ISTKI2G (63.7%) had dose interruptions for any reason (included AEs, dosing/dispensing error, physician/pt decision, and technical problems); interruptions due to AEs were fewer with ASC vs IS-TKIs (ASC IMA [33.0%] vs IS-TKI IMA [37.4%]; ASC 2G [33.0%] vs IS-TKI2G [51.0%]). Less pts with ASC vs IS-TKIs had dose adjustment and/or interruption (ASC IMA [13.0%] vs IS-TKI IMA [18.2%]; ASC 2G [14.0%] vs IS-TKI2G [31.4%]) and discontinuation (ASC IMA [3.0%] vs IS-TKI IMA [6.1%]; ASC 2G [1.0%] vs IS-TKI2G [7.8%]) due to grade 1/2 nonhematologic AEs, most common (≥3%) being diarrhea, fatigue, COVID-19, nausea, and pleural effusion. A lower proportion of pts with ASC vs IS-TKIs discontinued due to grade ≥3 nonhematologic AEs (ASC IMA [2.0%] vs IS-TKI IMA [4.0%]; ASC 2G [2.0%] vs ISTKI2G [3.9%]). Dose adjustment and/or interruption due to grade ≥3 nonhematologic AEs occurred in 17.0% vs 8.1% of pts with ASC IMA vs IS-TKI IMA and 11.0% vs 17.6% with ASC 2G vs IS-TKI2G. Pts with ASC vs IS-TKIs had a higher median percentage of AE-free days by wk 96 (ASC IMA [15.7%] vs ISTKI IMA [3.5%]; ASC 2G [22.6%] vs IS-TKI2G [4.3%]) and vs individual 2G TKIs (nilotinib [13.5%]; dasatinib [4.2%]; bosutinib [0.1%]) in this arm. Pts with ASC had a higher proportion of symptomatic (nonhematologic, nonlaboratory AEs) AE–free days (ASC IMA [31.2%] vs IS-TKI IMA [9.9%]; ASC 2G [34.2%] vs IS-TKI2G [15.7%]; and vs individual 2G TKIs: nilotinib [30.3%]; dasatinib [8.5%]; bosutinib [0.1%]).

When analyzing maximum scores in PRO-CTCAE reported from baseline to wk 96, symptoms reported with ASC vs IS-TKIs were generally less frequent and less severe, with a smaller impact on daily life. At wk 96, more pts reported being not at all bothered by Tx side effects with ASC vs IS-TKIs per FACIT GP5 (67.0% vs 46.1%). Conclusions Pts with ASC had more days free from AEs, especially symptomatic AEs, and reported a lower symptom burden. Effective relative dose intensity (>90%) was higher with ASC vs IS-TKIs, with generally fewer pts requiring dose reduction, interruption, or discontinuation. These results from ASC4FIRST further support ASC’s favorable tolerability vs all current frontline TKIs.

Treatment cost per AE symptom-free day of asciminib and second-generation tyrosine kinase inhibitors in newly diagnosed patients with chronic myeloid leukemia

While the overall survival for patients with chronic myeloid leukemia (CML) has improved significantly after the introduction of tyrosine kinase inhibitors (TKI), tolerability of these treatments— including second generation (2G) tyrosine kinase inhibitors—remains a challenge for some patients, who experience a variety of adverse events. Asciminib is a BCR::ABL1 inhibitor that has demonstrated greater major molecular response and more favorable tolerability in newly diagnosed CML-Chronic Phase (CP) patients compared to 2G TKIs in a multicenter, phase III randomized controlled trial (ASC4FIRST, NCT04971226). Due to the high cost of TKI treatments, it is essential to not only measure clinical outcomes but also quantify the health economic value of any differences in outcomes. This study aims to bridge this knowledge gap by estimating the differences in outcome value between asciminib and 2G TKIs (bosutinib, dasatinib, and nilotinib) using a novel cost per adverse event (AE) symptom-free day metric. The study evaluated cost per AE symptom-free day for adult, newly diagnosed patients with CML-CP receiving asciminib or 2G TKIs (dasatinib, nilotinib, bosutinib). A day was defined as “AE symptom-free” if the patient was (i) on therapy and (ii) had no symptomatic adverse events (AEs), defined as a non-hematologic and non-laboratory AE. Cost per AE symptom-free day was calculated as the cost of treatment over a 96-week treatment period divided by the number of AE symptom-free days over the first 96 weeks of treatment. Median and mean number of AE symptom-free days for asciminib and aggregated 2G TKIs were estimated from ASC4FIRST. Treatment cost over 96 weeks was calculated by summing drug acquisition costs with AE management costs. Drug acquisition costs were calculated using US 2025 wholesale acquisition costs (WAC) and FDA label-based dosing. AE management costs were calculated as the average of medical and pharmacy costs for treating symptomatic AEs weighted by the observed frequency of the AEs among asciminib-treated and 2G TKI-treated patients in ASC4FIRST (Cortes et al. Blood 2024;144[1]: 475; Hochhaus et al. N Eng J Med 2024; 391[10]: 885). The 2G TKI costs were calculated as a weighted average of individual 2G TKI costs based on their relative prescribing frequency observed in the ASC4FIRST trial. Because generic dasatinib and nilotinib became available in 2024 and 2025, their cost was calculated as a weighted average of generic and branded WAC, with US market share of imatinib from one year after imatinib genericization as a proxy (branded: 42%, generic: 58%).

At 96 weeks, the median treatment duration was 673.0 days for both asciminib and 2G TKI cohorts. Asciminib-treated patients experienced a median of 172.0 AE symptom-free days vs. 67.0 days for 2G TKI-treated patients (Δ=105.0 days). Mean number of AE symptom-free days was 271.9 for asciminib-treated vs. 180.9 for 2G TKI-treated patients (Δ=91.0 days). Treatment cost over the 96-week treatment period was $528,798 for asciminib vs. $437,911 for 2G TKIs (Δ= $90,887). Cost per median AE symptom-free day was 53.0% lower with asciminib than 2G TKIs ($3,074 vs. $6,536, Δ=-$3,462). Cost per mean AE symptom-free day was also lower with asciminib than 2G TKIs ($1,945 vs. $2,421, Δ=-$476). Patients on asciminib experience more AE symptom-free days on treatment relative to 2G TKIs. Treatment cost per median and mean AE symptom-free day was lower for asciminib relative to 2G TKIs.

Indirect treatment comparison (ITC) of asciminib and dasatinib in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP)

First- and second-generation (1G and 2G) tyrosine kinase inhibitors (TKIs) have dramatically improved the outcomes of CML-CP, transforming it into a manageable chronic condition, with some patients achieving a near-normal life expectancy. Consequently, managing TKI side effects is key to maintaining adherence and response. Asciminib, the first BCR::ABL1 inhibitor to specifically target the ABL myristoyl pocket, has demonstrated superior efficacy and favorable tolerability against investigatorselected (IS) 1G and 2G TKIs (ASC4FIRST, [NCT04971226]) in newly diagnosed CML-CP. However, ASC4FIRST was not powered to show statistical significance in direct comparisons between individual 2G TKIs and asciminib. This study aimed to indirectly compare the efficacy of dasatinib and asciminib across randomized controlled trials (RCTs) using matching-adjusted indirect comparison (MAIC) to account for heterogeneous baseline characteristics between and within the RCTs. To inform the MAIC, a systematic literature review (through September 28 th , 2023) identified all Phase III RCTs with (1) adults newly diagnosed with CML-CP treated with asciminib (ASC) or dasatinib (DAS); (2) and assessed for clinical efficacy outcomes (i.e., MR2, major molecular response [MMR], MR4, MR4.5) by 48 and 96 weeks. Two trials were identified (ASC4FIRST and DASISION [NCT00481247]). Trial endpoints varied in timing (ASC4FIRST: 48 and 96 weeks, DASISION: 12 and 24 months), and DASISION utilized complete cytogenetic response rather than MR2. Patients were grouped into ASC and DAS cohorts by assigned treatment, irrespective of the trial in which they participated. To adjust for baseline cohort differences in relevant treatment effect modifiers and prognostic factors, a logistic model was built to predict treatment based on demographics (age, sex, race), clinical characteristics (WBC, platelet count), and severity at diagnosis (ECOG PS). Risk score adjustment was not feasible due to differing systems across trials. ASC patients were individually weighted via the logistic model such that their average characteristics were comparable to the DAS cohort’s, which were calculated as the weighted average of trial level DAS characteristics, weighted by trial patient count. DAS cohort outcomes were pooled across trials using inverse-variance weighted meta-analysis. All patients randomized to ASC in ASC4FIRST were included regardless of treatment strata (i.e., the comparator IS-TKI specified prior to randomization). Relevant limitations include heterogeneity between studies, including differences in risk score systems, endpoint timelines, evolved BCR::ABL1 assay methodologies and standardization, and the evolving landscape of approved therapies for CML during the study periods. Estimated weighted odds ratios (OR) and 95% confidence intervals (95% CI) are reported for all comparison between ASC 80 mg QD and DAS 100 mg QD.

ASC cohort included 200 patients (Effective Sample Size =142.01 after weighting), and DAS cohort included 301 patients. After weighting, characteristics were similar across cohorts, including age (mean±sd: ASC 46.50±14.92 vs DAS 46.5±14.92), proportion male (54.82% vs 54.82%), race (white: 55.13% vs 50.83%, black: 1.56% vs 0.7%, Asian: 42.52% vs 42.5%, other: 0.78% vs 5.9%), WBC ≤ 25.1% (47.2% vs 47.2%) platelet count ≤ 448 (48.5% vs 48.5%), and ECOG PS = 0 (81.73% vs 81.7%). By 48 weeks, patients in the ASC cohort had statistically significantly higher rates of MMR (OR [95% CI]: 2.58 [1.67, 3.98]), MR4 (3.64 [2.29, 5.79]), and MR4.5 (3.54 [1.94, 6.46]) than patients in the DAS cohort. This trend continued by 96 weeks (MMR: 2.16 [1.33, 3.51]; MR4: 2.14 [1.42, 3.23]; MR4.5: 2.11 [1.35, 3.30]). Rates of MR2 were numerically superior in the ASC cohort by 48 weeks (1.94 [0.95, 3.97]) and 96 weeks (1.94 [0.95, 3.97]). After controlling for available treatment effect modifiers and prognostic factors, asciminib patients experience significantly improved efficacy versus patients on dasatinib.

Asciminib (ASC) in chronic myeloid leukemia in chronic Phase (CML-CP): Interim analysis (IA) efficacy and safety results of the Phase 2 ASC2ESCALATE trial in the cohort of newly diagnosed (1L) patients (pts)

ASC, a BCR::ABL1 inhibitor that inhibits kinase activity by specifically targeting the ABL myristoyl pocket, has previously demonstrated efficacy, safety, and tolerability in 1L CML-CP and CML-CP after ≥1 tyrosine kinase inhibitor (TKI). ASC showed consistent safety across a wide dose range of 10-200 mg twice daily (BID) in CML-CP after ≥1 TKI. The ASC2ESCALATE (NCT05384587) trial evaluates ASC in 1L CML-CP and CML-CP after 1 prior TKI (2L). A dose-escalation strategy is being assessed for pts not meeting ELN2020 optimal response milestones at 6 and 12 mo. The authors report the first IA of ASC efficacy and safety in the cohort of pts with 1L CML-CP in the ASC2ESCALATE trial. ASC2ESCALATE is a phase 2, single-arm, open-label trial of ASC with dose escalation in adults with 1L or2L CML-CP without the T315I mutation in the US. All pts started treatment (Tx) with ASC 80 mg once daily (QD). Pts with BCR::ABL1 IS >1% at wk 24 had their dose increased to 200 mg QD. Pts with BCR::ABL1 IS >0.1% at wk 48 had their dose increased from 80 to 200 mg QD or from 200 mg QD to 200 mg BID or could be taken off study. In pts with grade 3/4 or persistent grade 2 toxicity refractory to optimal management, dose escalation was not considered, and the same dose of ASC was continued. The primary endpoint is major molecular response (MMR) at wk 48 in the 2L cohort; this endpoint will be repeated in the 1L cohort as a secondary endpoint.

This IA included all 95 pts with 1L CML-CP (cutoff: May 16, 2025; median follow-up: 11.0 [range 1.2-19.4] mo). Most pts were White (78.9%), male (64.2%), and 90% to 100%. Dose escalation from 80 to 200 mg QD occurred in a total of 16/95 pts (16.8%) due to suboptimal response at wk 24 (n=8) or 48 (n=8); 3 of 8 pts with dose escalation from 80 to 200 mg QD at wk 24 escalated to 200 mg BID at wk 48. Pts evaluable for all efficacy analyses at wk 12 (n=91), 24 (n=93), and 48 (n=75) completed assessments for the respective time point or discontinued earlier; 1 pt with undetectable BCR::ABL1 at baseline was excluded. At wk 12, 83 of 91 pts (91.2%) had BCR::ABL1 IS ≤10%. At wk 24 and 48, 73 of 93 (78.5%) and 54 of 75 (72.0%), respectively, had BCR::ABL1 IS ≤1%; 51 of 93 (54.8%) and 40 of 75 (53.3%), respectively, had MMR. Pts also had deep molecular responses at wk 48, including MR 4 (18/75 [24.0%]) and MR 4.5 (9/75 [12.0%]). The most common all-grade AEs (≥20%) were fatigue (35.8%), nausea (30.5%), diarrhea (25.3%), headache (24.2%), thrombocytopenia (22.1%), and hypertension (21.1%). Grade ≥3 AEs (≥5%) were hypertension (13.7%), thrombocytopenia (7.4%), and neutropenia (6.3%). AEs led to dose adjustment/interruption in 38 pts (40.0%). AEs led to discontinuation in 11 pts (11.6%); 1 of these 11 pts died due to multiple organ dysfunction syndrome; this was the only on-Tx death reported and was unrelated to ASC per the investigator. Arterial-occlusive events (AOEs) occurred in 4 pts (4.2%); ASC was discontinued due to grade 3 cerebrovascular accident in 2 pts; ASC was continued for 1 pt with grade 3 angina pectoris and 1 pt with grade 2 transient blindness. All AOEs resolved by the cutoff. ASC was discontinued in 1 pt with grade 3 acute pancreatitis which resolved by the cutoff. New AEs occurring in pts after dose escalation were mostly grade 1/2.

1L ASC demonstrated early and deep molecular responses with safety profile consistent with previous ASC data; no new or worsening safety signals were observed. After ≈1 year of median exposure, ASC was well tolerated with few AEs leading to discontinuation. These IA results support ASC as a standard-of-care Tx option in 1L CML-CP. The impact of dose escalation in pts not meeting response milestones continues to be explored. The trial is ongoing with results including additional pts and extended follow-up to be reported in the future.

A comparison of real-world outcomes of asciminib versus ATP-competitive tyrosine kinase inhibitors as second-line treatment in patients with chronic myeloid leukemia in chronic phase

Adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) are part of the current treatment landscape for Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP), approved by the FDA between 2006–2012 for newly diagnosed and previously-treated patients. Asciminib, a TKI that targets the ABL myristoyl pocket, received FDA approval in October 2024 for treatment of newly diagnosed or previously treated CML-CP following 2021 approval for third-line treatment or for those with T315I mutation. This study aimed to compare real-world outcomes of patients treated with asciminib versus ATP-competitive TKIs as second-line treatment (2L). This retrospective panel-based chart review study collected de-identified patient data via an online case report form between February-December 2024 (asciminib cohort), and May-June 2025 (comparison cohort) from eligible US oncologists and hematologists with experience treating CML. Adult patients with CML-CP were included if they had no T315I mutation and initiated asciminib (asciminib cohort) or a 1 st- or 2 nd -generation ATP-competitive TKI (comparison cohort) from January 2022–June 2023 (index) as 2L. Entropy balancing was used to adjust baseline characteristics between the two cohorts including demographics (age, sex, race/ethnicity, index year), severity at diagnosis (ECOG PS, Sokal score), first-line (1L) TKI characteristics (1 st- or 2 nd -generation TKI, reason for 1L TKI termination, last response on 1L TKI), and comorbidity profile at index (NCI comorbidity index). Time to discontinuation, and time to BCR::ABL1≤0.1% (MR3 or better) and BCR::ABL1≤0.01% (MR4 or better) were assessed using weighted Kaplan-Meier analyses; Wilcoxon tests were reported. Data collection is ongoing for the comparison cohort.

A total of 255 patients were included in the asciminib cohort, and an interim sample of 137 patients comprised the comparison cohort (dasatinib: 43.8%, nilotinib: 32.1%, bosutinib: 20.4%, imatinib: 3.6%). Data were collected from 76 physicians (community practice: 47.4%, academic center: 52.6%) for the asciminib cohort and 33 physicians (community: 36.4%, academic: 63.6%) for the comparison cohort, similarly distributed across all US census regions.

After balancing, characteristics were similar between the asciminib and comparison cohorts, including median age (62.0 vs 62.0), proportion female (43.5% vs 43.8%), race/ethnicity (white: 56.1% vs 56.2%, black: 20.8% vs 20.4%), ECOG ≥2 (17.3% vs 17.5%), intermediate-high Sokal scores (76.1% vs 75.9%), and NCI comorbidity index >0 (60.0% vs 59.9%). Similar proportions of patients discontinued their 1L TKI due to intolerance (43.5% vs 43.8%) or lack of efficacy (42.4% vs 42.3%) and had a last response of MR3 or better on 1L (28.2% vs 28.5%). All standardized mean differences were ≤0.01.

By 48-week post-index, 68.3% of the asciminib vs 58.1% of the comparison cohort achieved or maintained MR3 (p<0.05); and 40.6% vs 21.0% achieved or maintained MR4 (p<0.05). Median time to MR3 (MR4) was 30.7 (59.7) and 39.7 (74.0) weeks for the asciminib and comparison cohorts, respectively.

By 48-week post-index, 4.6% of the asciminib vs 13.0% of the comparison cohort had discontinued treatment for any reason (p<0.05). During that period, discontinuation due to intolerance occurred in 1.6% of patients in the asciminib vs 3.6% in the comparison cohort, and discontinuation due to resistance was observed in none and 4.4% of patients, respectively. Moreover, post-index, intolerance led to temporary treatment interruption in 4.3% of patients in the asciminib vs 8.8% in the comparison cohort, and to dose reduction in 2.0% and 5.8% of patients, respectively. Dose increase due to resistance was reported only in the comparison cohort, for 5.1% of patients. Patients with CML-CP who received asciminib as 2L achieved deeper and faster molecular responses, with higher rates of MR3 and MR4 and shorter time to MR3, in comparison to those treated with ATP-competitive TKIs. Moreover, asciminib-treated patients experienced fewer dose adjustments and discontinuations due to intolerance or resistance similar to previously reported data from ASC4FIRST and ASCEMBL. Findings from this large real-world study suggest that asciminib offers favorable tolerability and better efficacy compared to ATP-competitive TKIs in patients with CML-CP as 2L in the US clinical practice.

Asciminib (ASC) in chronic myeloid leukemia in chronic Phase (CML-CP): Efficacy and safety results of the Phase 2 ASC2ESCALATE trial in the cohort of patients (pts) with 1 prior tyrosine kinase inhibitor (TKI)

ASC previously demonstrated efficacy, safety, and tolerability in newly diagnosed (1L) CML-CP and CMLCP after ≥2 prior TKIs. ASC indications were updated in the US to include accelerated approval for 1L CML-CP and full approval for previously treated CML-CP. ASC2ESCALATE (NCT05384587) is a US trial evaluating ASC in CML-CP after 1 prior TKI (2L). A previous interim analysis (IA) of the 2L cohort reported ASC’s safety (n=101) and wk 24 efficacy (n=63). Here, the authors report updated IA safety (n=101) and wk 48 efficacy (n=72) results in the 2L CML-CP cohort in ASC2ESCALATE. ASC2ESCALATE is a single-arm, open-label study of ASC in adults with 1L or2L CML-CP without the T315I mutation that uses a dose-escalation strategy for pts not meeting response milestones. The 2L cohort– eligible pts discontinued prior treatment (Tx) due to warning or failure per ELN 2020 or intolerance with BCR::ABL1 IS >0.1% at screening. All pts started Tx with ASC 80 mg once daily (QD). Pts withBCR::ABL1 IS >1% at wk 24 had a dose increase to 200 mg QD. Pts with BCR::ABL1 IS >0.1% at wk 48 had a dose increase from 80 to 200 mg QD or from 200 mg QD to 200 mg twice daily (BID) or could be taken off study. In pts with grade 3/4 or persistent grade 2 toxicity refractory to optimal management, dose escalation was not considered and the same ASC dose was continued.

This IA included all 101 pts with 2L CML-CP. Prior TKIs included dasatinib (44.6%), imatinib (42.6%), nilotinib (9.9%), or bosutinib (5.0%). Pts received prior Tx for ≥12 mo (66.3%), ≥6 to <12 mo (16.8%), or <6 mo (16.8%) and discontinued due to lack of efficacy (56.4%; Tx failure [24.8%], warning response [31.7%]) or intolerance (43.6%). Baseline BCR::ABL1 IS levels included >0.1% to 1% (39.6%), >1% to 10% (30.7%), and >10% (29.7%). By the cutoff (May 16, 2025), 85 pts (84.2%) remained on ASC; 16 pts (15.8%) discontinued Tx due to adverse events (AEs; n=8), pt decision (n=4), loss to follow-up (n=2), physician decision (n=1), and unsatisfactory therapeutic effect (n=1). Median duration of ASC exposure was 51.3 (range, 6-126) wk. Median dose was 80 (range, 40-197) mg/day; most pts (78.2%) received a relative dose of >90% to 100%. Dose escalation from 80 to 200 mg QD occurred in 16/101 pts (15.8%) per response level at wk 24 (n=4) and 48 (n=12); 2 of 4 pts with dose escalation to 200 mg QD at wk 24 escalated to 200 mg BID at wk 48. Pts evaluable for all efficacy analyses at wk 24 (n=98) and 48 (n=72) completed assessments for the respective time point or discontinued earlier. At wk 24 and 48, 84/98 (85.7%) and 56/72 (77.8%) pts, respectively, had BCR::ABL1 IS ≤1%. Major molecular response (MMR) was achieved by 55/98 (56.1%) and 40/72 (55.6%) pts at wk 24 and 48, respectively; the MMR rate was numerically higher in those who discontinued prior Tx due to intolerance vs lack of efficacy at wk 24 (29/42 [69.0%] vs 26/56 [46.4%]) and 48 (18/31 [58.1%] vs 22/41 [53.7%]). Pts also achieved deep molecular responses at wk 24 and 48, including MR 4 (27/98 [27.6%] and 18/72 [25.0%]) and MR 4.5 (11/98 [11.2%] and 8/72 [11.1%]). Most AEs were grade 1/2. Most common all-grade AEs (≥20%) were headache (26.7%) and nausea (25.7%). Grade ≥3 AEs (≥5%) were hypertension (9.9%), thrombocytopenia (6.9%), and neutropenia (6.9%). AEs led to dose adjustment/interruption in 36 pts (35.6%). Discontinuation due to AEs occurred in 8 pts (7.9%) including 7 on-Tx (thrombocytopenia [n=2], and dyspepsia, neutrophil count decreased, tremor, vomiting and nausea, and weight decreased [n=1 each]) and 1 >30 days after last ASC dose (platelet count decreased [n=1]). Arterial-occlusive events occurred in 2 pts (2.0%: grade 2 cerebral infarction [n=1], grade 1 troponin T increased [n=1]); none led to dose reduction or discontinuation and all resolved by cutoff. No on-Tx deaths occurred. New AEs occurring in pts after dose escalation were mostly grade 1/2. In ASC2ESCALATE, the first prospective trial of ASC in 2L, ASC continued to demonstrate high molecular response rates and a safety profile consistent with previously established ASC data with no new or worsening safety signals. ASC was well tolerated with few AEs leading to discontinuation. These IA results support ASC as a Tx option in 2L CML-CP. The impact of dose escalation in pts not meeting response milestones continues to be explored. All 101 pts will be evaluated for safety and efficacy in the primary wk 48 analysis, which will be presented at ASH2025.

ASC4OPT 96-week results: Asciminib once or twice daily continues to be highly efficacious and demonstrates favorable safety in patients with chronic myeloid leukemia and suboptimal response, resistance or intolerance to two or more tyrosine kinase inhibitors

The primary results of the ASC4OPT study (NCT04948333), assessing asciminib 40 mg twice daily (BID) and 80 mg once daily (QD) in pretreated patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP), showed high efficacy and a favorable safety profile for both dosing regimens. Here we present longer-term results from ASC4OPT. This Phase 3b, international, non-comparative study in adults with CML-CP without the T315I mutation and previously treated with ≥2 tyrosine kinase inhibitors (TKIs) enrolled two different cohorts. The main cohort included pts not in major molecular response (MMR; treatment failure/warning categories as per European LeukemiaNet [ELN] 2020 or intolerant to their most recent TKI). Dose escalation to 200 mg QD was permitted for pts who did not achieve MMR at Week 48 or lost response between Weeks 48‒108. An exploratory cohort of pts intolerant to their most recent TKI and in MMR at baseline was also enrolled and analyzed separately. All pts were randomized 1:1 to each dosing regimen. The primary endpoint was MMR rate at Week 48 for pts in the main cohort; response rates were assessed separately for the exploratory cohort. Pt-reported outcomes were assessed with the MD Anderson Symptom Inventory (MDASI)-CML questionnaire.

169 pts were recruited to the main cohort. At data cutoff (11 February 2025, after the last pt completed their Week 96 visit), treatment was ongoing for 55.0% of pts, 18.3% had reached the end of the study at Week 144 and 26.0% had discontinued treatment; reasons for discontinuation included adverse events (AEs, 7.7%) and unsatisfactory therapeutic effect (5.3%). Four pts in the main cohort had a T315I mutation at baseline, which was detected after treatment start; these pts were excluded from efficacy analyses. MMR rates increased at Week 96 vs Week 48 (43.6% vs 39.4% overall; 45.8% vs 43.4% on 40 mg BID and 41.5% vs 35.4% on 80 mg QD, respectively). Deep molecular response (DMR) rates were maintained at Week 96 vs Week 48 (overall, MR 4 : 17.0% vs 17.0%; MR 4.5 : 10.9% vs 10.3%, respectively). Overall, 94.0% and 37.5% of pts in the main cohort experienced any-grade and Grade ≥3 AEs, respectively (94.0% and 32.1% on 40 mg BID, and 94.0% and 42.9% on 80 mg QD, respectively). The most frequent AEs included thrombocytopenia (16.7%), arthralgias (16.1%), COVID-19 and fatigue (13.1% each). AEs leading to discontinuation were reported in 7.1% of pts (40 mg BID, 8.3%; 80 mg QD, 6.0%). Forty pts (23.7%) in the main cohort had their asciminib dose escalated to 200 mg QD (40 mg BID, n=16; 80 mg QD, n=24); at data cutoff, 60.0% remained on treatment and 27.5% had reached the end of the study at Week 144. Among the 5 pts who discontinued treatment, the most common reason for discontinuation was disease progression/loss of response (n=2). At Week 96, 17.5% of these pts were in MMR. Among pts in the exploratory cohort (n=30), treatment was ongoing for 53.3%, 33.3% had reached the end of the study at Week 144 and 13.3% had discontinued treatment by data cutoff. Reasons for treatment discontinuation included AEs (n=2), physician decision and pt decision (n=1 each). At Week 96, 86.7% of pts maintained MMR (vs 93.3% at Week 48); 2 pts had discontinued treatment due to AEs (both on 80 mg QD) before Week 24 and were counted as non-responders. One more pt achieved MR 4 in Week 96 vs Week 48 (7/14 at both timepoints on 40 mg BID; 9/16 vs 8/16 on 80 mg QD, respectively). MDASI-CML Symptom and Interference Total scores decreased slightly and quickly at Weeks 4‒12, denoting some improvement in main cohort pts’ symptoms and reduced interference with their daily life activities; scores then stabilized. Similar results were observed for pts in the exploratory cohort, although with slightly larger reductions in scores. Two deaths were reported overall, assessed as not treatment related: one on treatment (in the 80 mg QD arm, main cohort, due to stroke) and one that occurred >30 days after the last treatment (in the 40 mg BID arm, exploratory cohort, due to hypoxemic respiratory failure). The 96-week results from the ASC4OPT study further strengthen asciminib as a standard of care for pretreated pts with CML-CP, regardless of dosing regimen, including those who are intolerant to previous TKIs: a considerable proportion of these pts maintained or deepened their response regardless of asciminib regimen.