Achieving successful outcomes in chronic phase‐chronic myeloid leukemia (CP‐CML) requires careful monitoring of cytogenetic/molecular responses (CyR/MR). SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor use and management patterns in patients with CP‐CML receiving first‐line imatinib (n = 416), dasatinib (n = 418) or nilotinib (n = 408) in the US and 6 European countries in routine clinical practice. Twelve‐month follow‐up data of 1242 prospective patients (enrolled October 01 2010‐September 02 2015) are reported. 81% of patients had baseline comorbidities. Treatment selection was based on perceived efficacy over patient comorbidity profile. There was a predominance of imatinib‐treated patients enrolled earlier in the study, with subsequent shift toward dasatinib‐ and nilotinib‐treated patients by 2013/2014. Monitoring for either CyR/MR improved over time and was documented for 36%, 82%, and 95% of patients by 3, 6, and 12 months, respectively; 5% had no documentation of CyR/MR monitoring during the first year of therapy. Documentation of MR/CyR testing was higher in Europe than the US (P < .001) and at academic versus community practices (P = .001). Age <65 years, patients being followed at sites within Europe, those followed at academic centers and patients no longer on first‐line therapy were more likely to be monitored by 12 months. SIMPLICITY demonstrates that the NCCN and ELN recommendations on response monitoring have not been consistently translated into routine clinical practice. In the absence of appropriate monitoring practices, clinical response to TKI therapy cannot be established, any needed changes to treatment strategy will thus not be implemented, and long‐term patient outcomes are likely to be impacted.

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.

INTRODUCTION: Asciminib is the first BCR-ABL1 inhibitor that potently inhibits kinase activity of the BCR-ABL1 oncoprotein by Specifically Targeting the ABL Myristoyl Pocket (STAMP). The primary analysis from ASCEMBL, a randomized, phase 3 trial, demonstrated that asciminib has superior efficacy and a better safety and tolerability profile than bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after ≥2 prior ATP-binding tyrosine kinase inhibitors (TKIs). The major molecular response (MMR) rate at wk 24 was 25.5% with asciminib vs 13.2% with BOS; the difference in MMR rates, after adjusting for major cytogenetic response status at baseline, was 12.2% (95% CI, 2.19-22.30; 2-sided P=.029). Grade ≥3 adverse events (AEs) were reported in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively, and AEs leading to discontinuation in 5.8% and 21.1%, respectively. After a median follow-up of 19.2 months (or 7.5 months' additional follow-up since the primary analysis), we report updated efficacy and safety results from ASCEMBL. METHODS: Adults with CML-CP treated with ≥2 prior TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Eligible pts must have experienced treatment failure (lack of efficacy) per 2013 European LeukemiaNet recommendations for second-line TKI therapy or intolerance of the most recent TKI at screening. Pts intolerant of their most recent TKI were eligible only if they had BCR-ABL1 on the International Scale &gt;0.1% at screening. Pts with known BOS-resistant T315I or V299L mutations were ineligible. The cutoff date for the current analysis was January 6, 2021. RESULTS: A total of 233 pts were randomized to receive either asciminib (n=157) or BOS (n=76). At cutoff, all randomized pts had completed their wk 48 visit or had discontinued earlier. Treatment was ongoing in 89 (56.7%) and 17 (22.4%) pts on asciminib and BOS, respectively; the most common reason for treatment discontinuation was lack of efficacy in 37 (23.6%) and 27 (35.5%) pts, respectively (Table 1). By wk 48, the cumulative incidence of MMR was 33.2% with asciminib and 18.6% with BOS, showing that the difference between the 2 treatment arms observed by wk 24 in the primary analysis was maintained with longer follow-up (Figure 1). The cumulative incidence of BCR-ABL1IS ≤1% by wk 48 in patients without this level of response at baseline was 50.8% with asciminib and 33.7% with BOS. The difference in deep molecular responses (MRs) favoring asciminib vs BOS persisted by wk 48: MR 4 (BCR-ABL1IS ≤0.01%) and MR 4.5 (BCR-ABL1IS ≤0.0032%) rates were 14.0% and 9.6% with asciminib and 6.6% and 2.6% with BOS, respectively. With a longer duration of exposure in the asciminib arm, the safety and tolerability profile in the current analysis remains similar to that at the primary analysis. Median duration of exposure was 67.1 wk (range, 0.1-162.1 wk) for asciminib and 29.7 wk (range, 1.0-149.3 wk) for BOS. By the cutoff date, 91.0% of pts on asciminib and 97.4% of pts on BOS reported ≥1 all-grade AE; 54.5% and 67.1% of pts, respectively, reported ≥1 grade ≥3 AE. No additional fatal events were reported since the primary analysis. Fewer pts in the asciminib (7.1%) than BOS (25.0%) arm experienced AEs leading to treatment discontinuation (Table 2). The most common AEs leading to treatment discontinuation included thrombocytopenia (3.2%) and neutropenia (2.6%) in the asciminib arm and increased alanine aminotransferase (5.3%) and neutropenia (3.9%) in the BOS arm. CONCLUSIONS: Resistant/intolerant CML-CP after 2 lines of TKI treatment remains BCR-ABL1 dependent. The novel STAMP inhibitor asciminib demonstrates continued superior efficacy and a limited adverse event profile; myelosuppression, while more prominent, appears to be early and disease related. Secondary resistance based on loss of MMR is rare. Overall, after a median follow-up of 19.2 months, the positive benefit-risk profile of asciminib vs BOS continues to support the use of asciminib as a new therapy in this heavily pretreated pt population. This study is sponsored by Novartis. Figure 1 Figure 1. Disclosures Mauro: Sun Pharma / SPARC: Research Funding; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy. Minami: Takeda: Honoraria; CMIC: Research Funding; Astellas: Honoraria; Ono: Research Funding; Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Voloshin: Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Pfizer: Consultancy; Biacad: Consultancy, Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes: Sun Pharma: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Fogliatto: AstraZeneca: Speakers Bureau. Kim: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Paladin: Honoraria, Research Funding; Bristol-Meier Squibb: Research Funding. le Coutre: Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squibb: Honoraria. Saussele: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Honoraria; Roche: Honoraria. Hughes: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte: Honoraria. Chaudhri: Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Garcia Gutierrez: Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Kapoor: Novartis: Current Employment, Current equity holder in publicly-traded company. Allepuz: Novartis: Current Employment, Current equity holder in publicly-traded company. Quenet: Novartis: Current Employment. Bédoucha: Novartis: Current Employment. Boquimpani: Pinth Pharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jansen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Introduction: Asciminib, unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action. BOS, an ATP-competitive TKI, has shown clinical efficacy in pts who received ≥2 TKIs and in newly diagnosed CML, in prospective clinical trials. We asked if asciminib could provide superior efficacy to BOS beyond 2nd line, based on the clinical activity of asciminib monotherapy in heavily pretreated pts with CML in a phase 1 study. Methods: Adults with CML-CP previously treated with ≥2 TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Randomization was stratified by major cytogenetic response (MCyR; Ph+ metaphases ≤35%) status at baseline. Pts intolerant of their most recent TKI were eligible if they had BCR-ABL1IS &gt;0.1% at screening (19 pts with BCR-ABL1IS &lt;1% enrolled). Pts with treatment failure (per 2013 European LeukemiaNet recommendations) on BOS are permitted to switch to asciminib per investigator judgement. Pts with known bosutinib-resistant T315I or V299L mutations were excluded. The primary endpoint was major molecular response (MMR) rate at 24 wks. We report primary efficacy and safety results from ASCEMBL (cutoff: May 25, 2020). Results: A total of 233 pts with CML-CP was randomized to receive asciminib 40 mg BID (n=157) or BOS 500 mg QD (n=76). Fewer pts on asciminib discontinued their last TKI due to lack of efficacy and fewer received ≥3 prior lines of TKI therapy (Table 1). At cutoff, treatment was ongoing in 97 (61.8%) and 23 (30.3%) pts, respectively; the most common reason for treatment discontinuation was lack of efficacy (asciminib, 33 [21.0%] pts; BOS, 24 [31.6%]) (Table 1). Lack of efficacy was most frequently BCR-ABL1 &gt;10% or Ph+ &gt;65% after 6 months of therapy (asciminib 10.8%, BOS 25.0%). Among the 24 pts who discontinued BOS due to lack of efficacy, 22 switched to asciminib. At baseline, ≥1 BCR-ABL1 mutation was present in 12.7% pts on asciminib (most common: F359C/V) and 17.1% on BOS (most common: M244V, F317L). Median duration of follow-up was 14.9 months from randomization to cutoff. Median duration of exposure was 43.4 wks (range, 0.1-129.9) for asciminib and 29.2 wks (range, 1.0-117.0) for BOS; median relative dose intensity was 99.7% (87-100) and 95.4% (74-100). MMR rate at 24 wks was 25.5% with asciminib and 13.2% with BOS, meeting the primary objective. The between-arm common treatment difference for MMR at 24 wks, after adjustment for MCyR status at baseline, was 12.2% (95% CI, 2.19-22.3: 2-sided P=.029). Among those pts who achieved MMR, median time to MMR was 12.7 wks and 14.3 wks with asciminib and BOS, respectively. At 24 wks, more pts on asciminib (17 [10.8%] and 14 [8.9%]) than on BOS (4 [5.3%] and 1 [1.3%]) achieved deep molecular response (MR4 and MR4.5, respectively). CCyR rate at 24 wks was 40.8% with asciminib vs 24.2% with BOS. Preplanned subgroup analysis showed that the MMR rate at 24 wks was superior with asciminib than BOS across most major demographic and prognostic subgroups, including in pts who received ≥3 prior TKIs, in those who discontinued the prior TKI due to treatment failure, and regardless of baseline cytogenetic response (Figure). Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively. The proportion of pts who discontinued treatment due to AEs was lower with asciminib (5.8%) than BOS (21.1%). Grade ≥3 AEs and AEs requiring dose interruption and/or adjustments were reported less frequently with asciminib than BOS (Table 2). Most frequent grade ≥3 AEs (occurring in &gt;10% of pts in any treatment arm) with asciminib vs BOS were thrombocytopenia (17.3%; 6.6%), neutropenia (14.7%; 11.8%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). On-treatment deaths occurred in 2 pts (1.3%) on asciminib (ischemic stroke and arterial embolism, 1 pt each) and 1 pt (1.3%) on BOS (septic shock). Conclusions: In this first controlled study comparing treatments for resistant/intolerant (R/I) pts with CML, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with BOS (primary objective), deeper MR rates, and a favorable safety profile. These results support the use of asciminib as a new treatment option in CML, particularly in R/I pts who received ≥2 prior TKIs. Disclosures Hochhaus: Novartis: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Boquimpani:Novartis: Speakers Bureau. Rea:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Minami:Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria. Lomaia:Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Voloshin:Novartis: Honoraria, Speakers Bureau. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Sun Pharma.: Research Funding. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Sun Pharma: Research Funding. Abdo:Novartis: Honoraria; Takeda: Honoraria. Kim:Paladin: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding. le Coutre:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chee:Novartis: Other: Travel support for attendance at investigator meeting. García Gutiérrez:Novartis Pharma AG: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding; Pfizer: Honoraria, Other: travel/accommodations/expenses, Research Funding; Incyte: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding. Sasaki:Pfizer Japan: Consultancy; Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Aimone:Novartis: Current Employment. Allepuz:Novartis: Current Employment. Quenet:Novartis: Current Employment. Bédoucha:Novartis: Current Employment. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding.

Data from the large, prospective, multinational, phase 3b JUMP study were analyzed to identify factors predictive of spleen and symptom responses in myelofibrosis patients receiving ruxolitinib. Factors associated with higher spleen response rates included International Prognostic Scoring System (IPSS) low/intermediate-1 risk vs intermediate-2/high risk (43.1% vs 30.6%; adjusted OR [aOR] 0.65 [95% CI 0.44-0.95]), ruxolitinib as first-vs second-or later-line therapy (40.2% vs 31.5%; aOR 0.53 [95% CI 0.38-0.75]), and a ruxolitinib total daily dose at Week 12 of >20 mg/day vs 20 mg/day (41.3% vs 30.4%; aOR 0.47 [95% CI 0.33-0.68]). No association was seen between baseline characteristics or total daily dose at Week 12 and symptom response. Ruxolitinib led to higher spleen response rates in patients with lower IPSS risk, and when used earlier in treatment. Higher doses of ruxolitinib were associated with higher spleen response rates, but not with symptom improvement. TRIAL REGISTRATION INC424 for patients with primary myelofibrosis, post polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis (JUMP).