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Asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), is approved worldwide for the treatment of adults with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (CML-CP) treated with ≥2 prior tyrosine kinase inhibitors (TKIs). In ASCEMBL, patients with CML-CP treated with ≥2 prior TKIs were randomized (stratified by baseline major cytogenetic response [MCyR]) 2:1 to asciminib 40 mg twice daily or bosutinib 500 mg once daily. Consistent with previously published primary analysis results, after a median follow-up of 2.3 years, asciminib continued to demonstrate superior efficacy and better safety and tolerability than bosutinib. The major molecular response (MMR) rate at week 96 (key secondary endpoint) was 37.6% with asciminib vs 15.8% with bosutinib; the MMR rate difference between the arms, after adjusting for baseline MCyR, was 21.7% (95% CI, 10.53–32.95; two-sided p = 0.001). Fewer grade ≥3 adverse events (AEs) (56.4% vs 68.4%) and AEs leading to treatment discontinuation (7.7% vs 26.3%) occurred with asciminib than with bosutinib. A higher proportion of patients on asciminib than bosutinib remained on treatment and continued to derive benefit over time, supporting asciminib as a standard of care for patients with CML-CP previously treated with ≥2 TKIs.

Context: In CML-CP, the BCR::ABL1 T315I mutation confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs), except ponatinib and olverembatinib. In a previous analysis of the phase I, dose-escalation trial X2101, asciminib—a BCR::ABL1 inhibitor that binds to the ABL myristoyl pocket—demonstrated efficacy and a favorable safety profile in heavily pretreated patients with T315I-mutated CML. We report updated efficacy and safety data in patients with CML-CP with the T315I mutation (data cutoff: January 6, 2021). Objective: Provide updated safety and efficacy data for patients with T315I-mutated CML-CP after added exposure. Design: Patients with T315I-mutated CML-CP and treated with ≥1 prior TKI were enrolled and received asciminib 200mg twice daily (BID). Results: 48 patients were included; 25 patients (52.1%) received ≥3 prior TKIs. At data cutoff, treatment was ongoing in 27 patients (56.3%). 45 of 48 patients were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR); 3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable patients, 19 (42.2%) achieved MMR by week 24 and 22 (48.9%) by week 96. Evaluable patients included 26 ponatinib-pretreated and 19 ponatinib-naive patients; 34.6% and 68.4%, respectively, achieved MMR by week 96. The probability of maintaining MMR for ≥96 weeks was 84% (95% CI, 68.1%-100.0%). 23 of 37 patients (62.2%) with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by week 96. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added exposure (median duration of exposure, 2.08 years; range, 0.04-4.13 years). The most common (≥10%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations) and thrombocytopenia (14.6%). Arterial occlusive events occurred in 4 patients (8.3%); none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation occurred in 5 patients (10.4%). Only 2 study deaths, both due to COVID-19, occurred in this patient population. Conclusions: After a median exposure of >2 years, asciminib monotherapy 200mg BID exhibited a sustained, favorable safety profile and clinical efficacy in patients with T315I-mutated CML-CP—a population with high unmet medical need. This updated analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP, including those previously treated with ponatinib.

7004 Background: Asciminib is the first BCR::ABL1 inhibitor to specifically target the ABL Myristoyl Pocket (STAMP). In the ASCEMBL primary analysis, asciminib had superior efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. After a median follow-up of 2.3 years (16.5 months’ additional follow-up since primary analysis), we report efficacy and safety results (cutoff: October 6, 2021). Methods: Eligible pts were adults with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 European LeukemiaNet. Pts were randomized 2:1 to asciminib 40 mg twice daily or BOS 500 mg once daily, stratified by major cytogenetic response (MCyR) status (Ph+ metaphases ≤35%) at baseline. The key secondary endpoint was major molecular response (MMR) rate at wk 96. Results: 233 pts were randomized to asciminib (n=157) or BOS (n=76). At cutoff, treatment was ongoing in 84 (53.5%) and 15 (19.7%) pts, respectively; the most common reason for discontinuation was lack of efficacy in 38 (24.2%) and 27 (35.5%) pts, respectively. MMR rate at wk 96 (per ITT) was higher on asciminib (37.6%) than BOS (15.8%). The difference, adjusting for baseline MCyR, was 21.7% (95% CI, 10.5%-33.0%; 2-sided P=.001). More pts on asciminib than BOS, respectively, had BCR::ABL1IS ≤1% (45.1% vs 19.4%) at wk 96. The probability of maintaining MMR and BCR::ABL1IS ≤1% for ≥72 wk was 96.7% (95% CI, 87.4%-99.2%) and 94.6% (95% CI, 86.2%-97.9%), respectively, on asciminib and 92.9% (95% CI, 59.1%-99.0%) and 95.0% (95% CI, 69.5%-99.3%), respectively, on BOS. Median duration of exposure was 103.1 (range, 0.1-201.1) wk on asciminib and 30.5 (range, 1.0-188.3) wk on BOS. Despite the longer duration of asciminib exposure, safety/tolerability of asciminib continued to be better than that of BOS (Table). No new on-treatment deaths were reported since the primary analysis. Most frequent (>10%) grade ≥3 adverse events (AEs) on asciminib vs BOS were thrombocytopenia (22.4%, 9.2%), neutropenia (18.6%, 14.5%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). Conclusions: After >2 years of follow-up, asciminib continued to show superior efficacy and better safety/tolerability vs BOS. Responses were durable, with more pts on asciminib in MMR. Additionally, more pts on asciminib had BCR::ABL1IS ≤1%, a milestone response in later lines associated with improved survival. These results continue to support the use of asciminib as a new CML therapy, with the potential to transform standard of care. Clinical trial information: NCT03106779. [Table: see text]

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). In adults, 5 TKIs are approved: imatinib, dasatinib, nilotinib, bosutinib and ponatinib. In the pediatric population, however, only imatinib, dasatinib and nilotinib are approved. Pediatric pts have similar cytogenetic and molecular response rates to first-line (1L) imatinib and 1L second-generation TKIs nilotinib and dasatinib as adults. While the safety profiles for TKIs are similar in adult and pediatric pts, growth retardation has been reported specifically in the pediatric population. Therefore, safer and more efficacious options are needed for pediatric pts. Asciminib is an investigational drug that inhibits BCR-ABL1 by specifically targeting the ABL myristoyl pocket (STAMP inhibitor). Asciminib has shown promising efficacy and safety in adults with CML-CP in phase I-III trials, given without food for 1 hour prior and 2 hours after taking asciminib (fasted). In the phase I asciminib monotherapy trial in heavily pretreated adult pts, 48% and 28% without and with T315I mutations, respectively, achieved or maintained major molecular response (MMR) by 12 months. In the phase III ASCEMBL trial for adults with CML-CP who are resistant to or intolerant of ≥2 TKIs, 25.5% of pts on asciminib vs 13.2% of pts on bosutinib achieved MMR at 24 weeks. Here we present the phase Ib/II trial evaluating asciminib monotherapy in pediatric pts. OBJECTIVE: The primary objectives of this study are to characterize the pharmacokinetic (PK) profile of asciminib in pediatric pts and identify a pediatric formulation dose (taken with food) leading to an asciminib exposure comparable to that of 40 mg twice daily (BID) in adult pts (fasted). DESIGN: This is a multicenter, open-label, phase Ib/II study (NCT04925479, Figure 1). Eligible pts have Philadelphia chromosome-positive CML-CP resistant to or intolerant of ≥1 prior TKI, do not bear T315I mutations and are aged ≥1 to In part 1 (dose-determining cohort), 4 to 6 pts aged ≥1 to In part 2 (expansion cohort), the body weight-adjusted dosing determined in part 1 will be used, and the total pts enrolled on pediatric formulation will be increased to 30, including those from part 1 (15 pts aged 1 to The total duration of the study treatment period is 5 years. The primary analysis (primary PK endpoints, safety, and pharmacodynamics) will be assessed after all pts have been on study for 52 weeks or discontinued earlier. A final analysis will be completed after all pts have been on study for 5 years or discontinued earlier. Pts who discontinue the study early will be followed up for survival until the study is complete. MAIN OUTCOMES MEASURES: The primary endpoints include PK parameters. Secondary endpoints include treatment-associated AEs, hematologic and molecular responses, and acceptability and palatability of asciminib (Table 1). CONCLUSIONS: Data from this study will be used to support a strategy of full extrapolation from adult data to use in the pediatric setting. This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Hijiya: Novartis: Consultancy; Stemline Therapeutics: Consultancy. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Descamps: Novartis: Current Employment. Bayar: Novartis: Current Employment. Ramscar: Novartis: Current Employment.

T-cell acute lymphoblastic leukemias (T-ALLs) are aggressive hematologic tumors that result from the malignant transformation of T-cell progenitors. T-ALLs are classified immunologically into immature (pro- and pre-T), cortical and mature T-ALL. ETP-ALL is a recently described subtype of immature T-ALL. T-ALL is characterized by overexpression of oncogenic transcription factors that drive the malignancy: TAL1, TAL2, LYL1,LMO1, LMO2; TLX1, TLX3, NKX2.1, NKX2.2, NKX2.5, MEF2C and HOX genes. This study was conducted to understand the landscape of protein-coding genes using RNAseq in immature, cortical and mature T-ALL patients in India. This was a prospective study done on 134 T-ALL cases. The T-ALL patients were divided into 2 cohorts: discovery (n=35; immature 13, cortical 17, mature 5) and validation cohort (n=99; immature 45, cortical 44, mature 10). Total RNA seq was done in the discovery cohort. Clinical and prognostic relevance of lesions identified in the discovery cohort were studied in validation cohort. On RNAseq, a total of 2,318 genes were most differentially expressed between the 3 subtypes. In immature T-ALL cases, transcription factors controlling early hematopoiesis (MEF2C, TP63, HHEX, RUNX2, HOXA10, HOXA9, RUNX1T1 and ZBTB16) were highly expressed. LYN, a tyrosine kinase gene was also highly expressed. BAALC and MN1 genes, previously reported in acute myeloid leukemia, but not emphasized in reported genomics studies in the West, were overexpressed. Interestingly, LMO2 was overexpressed in the absence of significant overexpression of LYL1, a gene reported to be critical for oncogenic functions of Lmo2. In cortical T-ALL, the cortical thymocyte-defining CD1A gene was overexpressed. Homoebox domain genes NKX2-1, TLX1, TLX3, involved in T-cell development were overexpressed. In addition, FAT1, FAT3, EREG, CD1C, AKAP-2, IL-4, PRTG, TCL-6, ZP1 and TRAV genes were overexpressed. On examining CD1a+/sCD3+ and CD1a+/sCD3- groups, we found that in contrast to reported literature, TLX1 was highly expressed in the former group and TLX3 in the latter. In mature T-ALL, APC2, BCL3, CCR4, CDKN2A, EML4, HIST1H4G, HIST2H2B, NCOR2, ST20 and TRAV22 genes were overexpressed. Conventional drivers of T-ALL leukemogenesis - LYL1, TAL1 and LMO1 were not differentially expressed in our patients suggesting a difference between Indian and Western T-ALL patients. The clinical significance of expression of MEF2C, BAALC, HHEX, LYL1, TAL1 and FAT1 genes was studied in validation cohort by real-time PCR. High expression of MEF2C and BAALC gene was associated with immature immunophenotype (IPT) as compared to cortical and mature IPT (p=0.009; 0.008, respectively). Patients with ETP-ALL had higher expression of MEF2C and BAALC gene (p=0.018; 0.014, respectively). High MEF2C and BAALC expression were associated with CD34 positivity (p=0.004; 0.032, respectively). High BAALC expression was also associated with aberrant expression of the myeloid markers (p=0.021). Although not statistically significant, high HHEX expression was associated with immature IPT (p=0.072) and ETP-ALL IPT (p=0.06). Although LYL1 expression did not correlate with immature IPT, ETP-ALL was associated with higher LYL1 expression (p=0.039). Higher expression of FAT1 gene was associated with cortical IPT (p=0.026). Low XIST expression was more frequently associated with non-ETP-ALL IPT (p=0.017). TAL1 expression did not correlate with IPT. On survival analysis, only MEF2C gene expression was associated with EFS and OS. Compared to low MEF2C expressors, patients with high MEF2C had a lower event free survival (EFS) (73.58% vs 51.38%, p=0.01). High expression was found to be a significant predictor of overall survival (OS) (81.11% vs 96.43%, p=0.012). MEF2C emerged as driving oncogene in our T-ALL patients which can be used as predictor of EFS and OS. Expression of BAALC, HHEX, LYL1, TAL1, FAT1 and XIST genes did not correlate with EFS and OS. In this first study correlating T-ALL IPT with transcriptome profile in Indian T-ALL patients, we noted interesting differences from the West, potential subjects of further study. MEF2C gene expression emerged as the predictor of poor EFS and OS in T-ALL patients. Lastly, increased expression of LYN gene in our patients suggests that our immature T-ALL patients may benefit from tyrosine kinase inhibitors targeting Lyn. Disclosures No relevant conflicts of interest to declare.