ABL Inhibitors Research Articles

Beyond IC50-A computational dynamic model of drug resistance in enzyme inhibition treatment.

Resistance to therapy is a major clinical obstacle to treatment of cancer and communicable diseases. Drug selection in treatment of patients where the disease is showing resistance to therapy is often guided by IC50 or fold-IC50 values. In this work, through a model of the treatment of chronic myeloid leukaemia (CML), we contest using fold-IC50 values as a guide for treatment selection. CML is a blood cancer that is treated with Abl1 inhibitors, and is often seen as a model for targeted therapy and drug resistance. Resistance to the first-line treatment occurs in approximately one in four patients. The most common cause of resistance is mutations in the Abl1 enzyme. Different mutant Abl1 enzymes show resistance to different Abl1 inhibitors and the mechanisms that lead to resistance for various mutation and inhibitor combinations are not fully known, making the selection of Abl1 inhibitors for treatment a difficult task. We developed a model based on information of catalysis, inhibition and pharmacokinetics, and applied it to study the effect of three Abl1 inhibitors on mutants of the Abl1 enzyme. From this model, we show that the relative decrease of product formation rate (defined in this work as "inhibitory reduction prowess") is a better indicator of resistance than an examination of the size of the product formation rate or fold-IC50 values for the mutant. We also examine current ideas and practices that guide treatment choice and suggest a new parameter for selecting treatments that could increase the efficacy and thus have a positive impact on patient outcomes.

Targeted Degradation of SOS1 Exhibits Potent Anticancer Activity and Overcomes Resistance in KRAS-Mutant Tumors and BCR-ABL-Positive Leukemia.

SOS1 is an essential guanine nucleotide exchange factor for RAS that also plays a critical role in the activation of the small GTPase RAC mediated by BCR-ABL in leukemogenesis. Despite this, small molecule inhibitors targeting SOS1 have shown limited efficacy in clinical trials for KRAS mutant cancers, and their potential as a therapeutic approach for chronic myeloid leukemia (CML) remains largely unexplored. In this study, we developed a potent SOS1 PROTAC SIAIS562055, which was designed by connecting a CRBN ligand to an analogue of the SOS1 inhibitor BI-3406. SIAIS562055 exhibited sustained degradation of SOS1 and inhibition of downstream ERK pathways, resulting in superior anti-proliferative activity compared to small molecule inhibitors. SIAIS562055 also potentiated the activity of both KRAS inhibitors in KRAS-mutant cancers and ABL inhibitors in BCR-ABL+ CML. In KRAS-mutant xenografts, SIAIS562055 displayed promising antitumor potency as a monotherapy and enhanced ERK inhibition and tumor regression when combined with KRAS inhibitors, overcoming acquired resistance. In CML cells, SIAIS562055 promoted the active uptake of BCR-ABL inhibitors by upregulating the carnitine/organic cation transporter SLC22A4. SIAIS562055 and BCR-ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary CML patient samples. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an effective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR-ABL-harboring leukemia.

Asciminib in Advanced-Line Treatment of Chronic Myeloid Leukemia.

Asciminib, a novel allosteric BCR::ABL1 inhibitor, targets the ABL1 myristoyl pocket to potentially reduce toxicity and enhance efficacy. It is approved for Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) in patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs) or those with the T315I mutation. This retrospective analysis evaluated patients with CML treated with asciminib under a managed-access program across eight Israeli centers from July 2019 to August 2022. We assessed treatment responses, toxicities, event-free survival (EFS), and overall survival (OS) using Kaplan-Meier methods. The study included 30 patients who had received a median of three prior TKIs, with 73% starting asciminib due to intolerance. After a median follow-up of 7.1 months, 85% of those without prior complete cytogenetic response (CCyR) achieved CCyR, and 60% previously not in major molecular response (MMR) attained MMR. Resistance was rare (10%), with no cardiovascular events reported despite high baseline comorbidity (73%). Median EFS was 47 months; median OS was not reached. Asciminib demonstrates significant efficacy and tolerability in heavily pretreated patients with CML-CP, with no new cardiovascular events observed. Further long-term studies are necessary to explore its full cardiovascular impact.

Pharmacological effects of small molecule BCR-ABL tyrosine kinase inhibitors on platelet function.

Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein, such as imatinib (Gleevec), have revolutionized targeted cancer therapies. However, drug resistance and side effects, particularly those affecting hemostasis, continue to pose significant challenges for TKI therapies. As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo Our study included standard-of-care agents (e.g., imatinib and nilotinib), and second-generation ABL inhibitors including ponatinib and bosutinib designed to mitigate drug resistance. Additionally, we explored the effects of allosteric inhibitors targeting the myristoyl pocket of ABL (e.g., asciminib and GNF-2), and novel agents in preclinical development, including ELVN-919, which uniquely exhibits high specificity for the ABL kinase active site. Our findings reveal that while ABL inhibitors such as ponatinib and bosutinib impede platelet activity, highly specific new-generation ABL inhibitors, including first-in-class therapeutics, do not impact platelet function ex vivo Overall, these new insights around the effects of ABL TKIs on platelet function could inform the development of targeted therapies with reduced hematologic toxicities. Significance Statement This study examines the effects of clinically relevant small molecule BCR-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (e.g., imatinib, ponatinib) with well-characterized effects on platelet function, to discern potential anti-platelet and other effects of BCR-ABL TKIs and inform clinical safety.

Real-World Evaluation of Treatment Patterns and Clinical Outcomes among Patients With Chronic Myeloid Leukemia in Chronic Phase Treated With Asciminib in Clinical Practice in the United States: Real-world asciminib treatment outcomes in CML-CP

BackgroundTyrosine kinase inhibitors (TKIs) are the mainstay treatment for chronic myeloid leukemia in chronic phase (CML-CP). Asciminib, an ABL/BCR::ABL1 inhibitor which binds to the myristoyl pocket, was recently approved in the US for patients with CML-CP previously treated with ≥2 TKIs or with the T315I mutation. This study described treatment patterns and real-world clinical outcomes among patients with CML-CP treated with asciminib in US clinical practice. MethodsElectronic health record data from adult patients with CML-CP who initiated asciminib after ≥2 prior TKIs, without the T315I mutation, were obtained from the Flatiron Health database. Time-to-treatment discontinuation and molecular response (MR; time-to-BCR::ABL ≤0.1% and time-to-BCR::ABL1 ≤1%, separately) were evaluated from asciminib initiation (index date) using Kaplan–Meier analyses. ResultsOverall, 97 patients initiated asciminib (median age: 63 years, 50.5% female, 64.9% White) after either 2 (47.4%) or 3 (24.7%), or ≥4 (27.8%) prior TKIs. In total, 85.7% and 78.1% of patients remained on asciminib by 12- and 24-weeks postindex, respectively. Among patients with ≥1 MR assessment postindex, 31.3% (95% confidence interval [CI]: 21.6%, 43.9%) and 49.7% (95% CI: 38.1%, 62.6%) achieved or maintained BCR::ABL1 ≤0.1%, while 51.3% (95% CI: 40.1%, 63.6%) and 64.2% (95% CI: 52.6%, 75.6%) achieved or maintained BCR::ABL1 ≤1%, by 12- and 24-weeks, respectively. ConclusionsResults of this real-world study describing clinical outcomes among patients with CML-CP treated with asciminib after ≥2 prior TKIs in the US demonstrated that asciminib was well-tolerated and effective. These findings were consistent with results from the ASCEMBL trial.

CML-399 CARDINAL: A Phase 1, Multicenter, Open-Label, Dose-Escalation and Dose-Optimization Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of TERN-701 in Chronic Myeloid Leukemia

ObjectiveDespite improvements in outcomes achieved with BCR::ABL1 active-site-targeting tyrosine kinase inhibitors (TKIs) for treatment of chronic-phase (CP) chronic myeloid leukemia (CML), many patients need to switch treatments due to disease progression, intolerance, or resistance. Because active-site TKIs utilize similar mechanisms of action, novel treatment options are needed for patients. TERN-701 is a highly selective, oral, investigational, allosteric BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket. Preclinical data suggest that TERN-701 is highly potent against native BCR::ABL1 and most common BCR::ABL1 mutations, including T315I, acquired with use of second-generation active-site TKIs. CARDINAL (NCT06163430) is an open-label, global, 2-part, phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of TERN-701 in patients with previously treated CP-CML. MethodsEligible patients are ≥18 years old with an Eastern Cooperative Oncology Group performance status of 0–2, a confirmed diagnosis of BCR::ABL1-positive CP-CML, with or without the T315I mutation, and treatment failure/intolerance of ≥1 prior second-generation TKI (dasatinib, nilotinib, or bosutinib). Patients intolerant of asciminib without overt resistance are eligible. Patients with CML in accelerated or blast phase are ineligible. Patients will receive TERN-701 orally once daily in continuous 28-day cycles. Part 1 (dose escalation) has been initiated and will include ≈24–36 patients assigned to sequential dose-escalation cohorts, starting at 160 mg, and optional backfill cohorts; dose escalation will be guided by a Bayesian optimal interval algorithm. Primary endpoints of Part 1 include incidence of dose-limiting toxicities during the first treatment cycle and other measures of safety and tolerability; secondary endpoints include PK and efficacy measures, such as hematologic and molecular responses. Based upon the results of Part 1, ≥2 TERN-701 dose levels will be selected for further evaluation in Part 2. In Part 2 (dose expansion), ≈40 patients will be randomized to one of the selected dose levels. Part 2 primary endpoints will measure efficacy (hematologic response, molecular response, and best categorical shift in BCR::ABL1 transcript levels from baseline); secondary endpoints include safety, tolerability, and PK. The study is being conducted in the US, Europe, Australia, and South Korea.

Asciminib monotherapy as frontline treatment of chronic-phase chronic myeloid leukemia: results from the ASCEND study

AbstractAsciminib is a myristoyl site BCR::ABL1 inhibitor approved for patients with chronic-phase chronic myeloid leukemia (CP-CML) failing ≥2 prior lines of therapy. The Australasian Leukaemia and Lymphoma Group conducted the Asciminib Evaluation in Newly Diagnosed CML study to assess efficacy of asciminib for newly diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily. Patients with treatment failure, defined as BCR::ABL1 of >10% at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib, or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1% to 10% at 6 months, >0.1% to 1% at 12 months, or >0.01% to 1% at 18 months, the asciminib dose was increased to 80 mg twice daily. With a median follow-up of 21 months (range, 0-36), 82 of 101 patients continue asciminib. Most common reasons for treatment discontinuation were adverse events (6%), loss of response (4%), and withdrawn consent (5%). There were no deaths; 1 patient developed lymphoid blast crisis. The coprimary end points were early molecular response (BCR::ABL1 of ≤10% at 3 months), achieved in 93% (96% confidence interval [CI], 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI, 70-87%), respectively. Cumulative incidence of molecular response 4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline CP-CML therapy leads to high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. This trial was registered at https://www.anzctr.org.au/ as #ACTRN12620000851965.

Asciminib: the next-generation bullet for first-line treatment of chronic myeloid leukemia

The standard of care for chronic myeloid leukemia (CML) involves tyrosine kinase inhibitors (TKIs), which suppress tyrosine kinase activity of BCR::ABL1. Hochhaus etal. reported that asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, showed superior efficacy and favorable safety compared with TKIs in the phase 3 ASC4FIRST trial in patients with newly diagnosed chronic-phase CML.1.

The BCR::ABL1 tyrosine kinase inhibitors ponatinib and nilotinib differentially affect endothelial angiogenesis and signalling.

BCR::ABL1 inhibitors, the treatment of choice for the majority of patients with chronic myeloid leukaemia (CML), can cause vascular side effects that vary between agents. The exact underlying mechanisms are still poorly understood, but the vascular endothelium has been proposed as a site of origin. The present study investigates the effects of three BCR::ABL1 inhibitors, ponatinib, nilotinib and imatinib, on angiogenesis and signalling in human endothelial cells in response to vascular endothelial growth factor (VEGF). The experiments were performed in endothelial cells isolated from human umbilical veins. After exposure to imatinib, ponatinib and nilotinib, the angiogenic capacity of endothelial cells was assessed in spheroid assays. VEGF-induced signalling pathways were examined in Western blotting experiments using different specific antibodies. RNAi technology was used to downregulate proteins of interest. Intracellular cGMP levels were measured by ELISA. Imatinib had no effect on endothelial function. Ponatinib inhibited VEGF-induced sprouting, while nilotinib increased spontaneous and VEGF-stimulated angiogenesis. These effects did not involve wild-type ABL1 or ABL2, as siRNA-mediated knockdown of these kinases did not affect angiogenesis and VEGF signalling. Consistent with their effects on sprouting, ponatinib and nilotinib affected angiogenic pathways in opposite directions. While ponatinib inhibited VEGF-induced signalling and cGMP formation, nilotinib activated angiogenic signalling, in particular phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2). The latter occurred in an epidermal growth factor receptor (EGFR)-dependent manner possibly via suppressing Fyn-related kinase (FRK), a negative regulator of EGFR signalling. Both, pharmacological inhibition of Erk1/2 or EGFR suppressed nilotinib-induced angiogenic sprouting. These results support the notion that the vascular endothelium is a site of action of BCR::ABL1 inhibitors from which side effects may arise, and that the different vascular toxicity profiles of BCR::ABL1 inhibitors may be due to their different actions at the molecular level. In addition, the as yet unknown pro-angiogenic effect of nilotinib should be considered in the treatment of patients with comorbidities associated with pathological angiogenesis, such as ocular disease, arthritis or obesity.

Scaffold-Hopped Compound Identification by Ligand-Based Approaches with a Prospective Affinity Test.

Scaffold-hopped (SH) compounds are bioactive compounds structurally different from known active compounds. Identifying SH compounds in the ligand-based approaches has been a central issue in medicinal chemistry, and various molecular representations of scaffold hopping have been proposed. However, appropriate representations for SH compound identification remain unclear. Herein, the ability of SH compound identification among several representations was fairly evaluated based on retrospective validation and prospective demonstration. In the retrospective validation, the combinations of two screening algorithms and four two- and three-dimensional molecular representations were compared using controlled data sets for the early identification of SH compounds. We found that the combination of the support vector machine and extended connectivity fingerprint with bond diameter 4 (SVM-ECFP4) and SVM and the rapid overlay of chemical structures (SVM-ROCS) showed a relatively high performance. The compounds that were highly ranked by SVM-ROCS did not share substructures with the active training compounds, while those ranked by SVM-ECFP4 were mostly recombinant. In the prospective demonstration, 93 SH compounds were prepared by screening the Namiki database using SVM-ROCS, targeting ABL1 inhibitors. The primary screening using surface plasmon resonance suggested five active compounds; however, in the competitive binding assays with adenosine triphosphate, no hits were found.

Representing mutations for predicting cancer drug response.

Predicting cancer drug response requires a comprehensive assessment of many mutations present across a tumor genome. While current drug response models generally use a binary mutated/unmutated indicator for each gene, not all mutations in a gene are equivalent. Here, we construct and evaluate a series of predictive models based on leading methods for quantitative mutation scoring. Such methods include VEST4 and CADD, which score the impact of a mutation on gene function, and CHASMplus, which scores the likelihood a mutation drives cancer. The resulting predictive models capture cellular responses to dabrafenib, which targets BRAF-V600 mutations, whereas models based on binary mutation status do not. Performance improvements generalize to other drugs, extending genetic indications for PIK3CA, ERBB2, EGFR, PARP1, and ABL1 inhibitors. Introducing quantitative mutation features in drug response models increases performance and mechanistic understanding. Code and example datasets are available at https://github.com/pgwall/qms.

Asciminib in Patients With CML-CP Previously Treated With ≥ 2 Tyrosine Kinase Inhibitors: 96-Week Results From the Japanese Subgroup Analysis of the ASCEMBL Study

Asciminib is a first-in-class BCR::ABL1 inhibitor that Specifically Targets the ABL1 Myristoyl Pocket (STAMP). It is approved worldwide and in Japan for chronic myeloid leukemia in chronic phase (CML-CP) with resistance or intolerance to previous tyrosine kinase inhibitor (TKI) therapy. In the Phase 3 ASCEMBL study, patients with CML-CP who received ≥ 2 prior ATP-competitive TKIs were randomized (2:1) to asciminib 40 mg twice-daily or bosutinib 500 mg once-daily. Here, we report the 96-week results of the subgroup analysis of Japanese patients (asciminib, n = 13; bosutinib, n = 3) in the ASCEMBL study. The MMR rate at Week 96 was 46.2% in asciminib-treated patients, increasing from Weeks 24 and 48. Patients who achieved MMR at Week 24 remained in MMR up to the Week 96 cutoff. While a high proportion of patients treated with asciminib remained on treatment at cutoff, none randomized to bosutinib were on treatment at Week 96. Despite the longer duration of exposure to asciminib, its safety and tolerability continued to be favorable with no new or worsening safety findings. Overall, the efficacy and safety outcomes in the Japanese subgroup were comparable with the ASCEMBL global study population, which supports the use of asciminib in Japanese patients with previously treated CML-CP.

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia

BackgroundPatients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs).MethodsIn a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum.ResultsA total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, −5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).ConclusionsIn this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).

Abstract 6056: Identification of first-in-class, orally bioavailable SOS1 bifunctional degraders for the treatment of KRAS- and RTK-driven cancers

Abstract Monotherapies which target nodes within the RTK-RAS-MAPK pathway often display early potency in the clinic, but their preliminary response is limited as tumors begin to regrow due to adaptive and acquired resistance mechanisms. Disrupting proteins that mitigate either type of resistance mechanism in combination with oncogene-targeted agents could help extend and enhance the clinical potential of these drugs. Son of Sevenless 1 (SOS1), a RAS guanine nucleotide exchange factor, is a highly attractable protein to target given its role in transducing inputs from upstream receptor tyrosine kinases (RTKs) to downstream RAS proteins to regulate signaling pathways involved in cell proliferation and survival. Additionally, SOS1 is subject to MAPK-mediated negative feedback inhibition and drugs targeting upstream and downstream nodes relieves SOS1 from this inhibition resulting in pathway reactivation. To address this need, we have developed orally bioavailable SOS1 bifunctional degraders for cancers driven by KRAS and RTKs. Our top two lead molecules demonstrate CRBN- and proteasomal-mediated SOS1 degradation with DC50s &amp;lt; 10nM and maximum degradation &amp;gt; 90%. Consistent with this notion, SOS1 degradation inhibited downstream signaling marker phopshoERK with IC50s &amp;lt; 5nM and were 26- or 53-fold more potent when compared to the clinical SOS1 inhibitor. Notably, the SOS1 degraders exhibited weaker SOS1 binding compared to other SOS1 inhibitors highlighting that the potency is heavily driven by the catalytic nature of degradation rather than occupancy-driven events. Both SOS1 degraders displayed CRBN- and SOS1-dependent antiproliferative activity in KRAS- and EGFR- mutant, solid tumor cell lines as well as in BCR-ABL driven, CML cells with IC50 values ranging from 0.5-10nM. Consistent with our in vitro data, oral administration of our SOS1 degraders in mice harboring H358 (KRAS G12C) and H441 (KRAS G12V) xenografts resulted in SOS1 degradation, phosphoERK reduction and significant tumor growth inhibition. While SOS1 degrader monotherapy demonstrated in vitro and in vivo potency, combination of mutant or allele specific EGFR and KRAS inhibitors and ABL inhibitors with our proof-of-concept degraders prevented pathway reactivation associated with these inhibitors and lead to a more durable response. These combinations also yielded synergistic effects in in vitro proliferation assays as well as enhanced tumor growth inhibition in KRAS-mutant xenograft models. Together, our SOS1 degraders alone and in combination with other targeted agents demonstrated anti-tumor activity in a variety of KRAS- and RTK-driven cancer cell lines and xenograft models. These results support the potential of orally bioavailable SOS1 degraders to help mitigate pathway reactivation for enhanced efficacy and prolonged response duration. Citation Format: Kyle Begovich, Angela Schoolmeesters, Navin Rajapakse, Elena Martinez, Qiao Liu, Arvind Shakya, Akinori Okano, Venkat Mali, Shenlin Huang, Aparajita Chourasia, Leah Fung. Identification of first-in-class, orally bioavailable SOS1 bifunctional degraders for the treatment of KRAS- and RTK-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6056.

Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials

Ponatinib, the only approved all known-BCR::ABL1 inhibitor, is a third-generation tyrosine-kinase inhibitor (TKI) designed to inhibit BCR::ABL1 with or without any single resistance mutation, including T315I, and induced robust and durable responses at 45 mg/day in patients with CP-CML resistant to second-generation TKIs in the PACE trial. However, cardiovascular toxicities, including arterial occlusive events (AOEs), have emerged as treatment-related AEs within this class of TKIs. The OPTIC trial evaluated the efficacy and safety of ponatinib using a novel, response-based, dose-reduction strategy in patients with CP-CML whose disease is resistant to ≥2 TKIs or who harbor T315I. To assess the dose-response relationship and the effect on the safety of ponatinib, we examined the outcomes of patients with CP-CML enrolled in PACE and OPTIC who received 45 mg/day of ponatinib. A propensity score analysis was used to evaluate AOEs across both trials. Survival rates and median time to achieve ≤1% BCR::ABL1IS in OPTIC were similar or better than in PACE. The outcomes of patients with T315I mutations were robust in both trials. Patients in OPTIC had a lower exposure-adjusted incidence of AOEs compared with those in PACE. This analysis demonstrates that response-based dosing for ponatinib improves treatment tolerance and mitigates cardiovascular risk.

Expectations and challenges for clinical application of cancer genome panels in acute myeloid leukemia

The blood cancer field has played a pioneering role in advancing precision medicine, with milestones such as development of ABL1 inhibitors for chronic myeloid leukemia. The significance of gene mutation information in AML treatment has increased, evident in classifications and guidelines from organizations such as WHO and ELN. This article examines the anticipated roles of cancer genome panels (CGPs) in AML treatment from three perspectives: diagnosis, risk stratification, and treatment selection. Use of CGPs enables more accurate diagnosis and risk stratification. In treatment selection, CGPs not only complements but also substitutes existing companion diagnostics, and is expected to be a crucial information source for future drug adoption and investigation of tumor-agnostic therapies. However, various challenges remain to be addressed, including the purpose and timing of CGPs, the time required for the tests, and how to utilize expert panels.

Tyrosine Kinase Inhibitors with Intensive Chemotherapy in AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1: Time to Reconsider Prognostic Risk? a Study from the Dataml Registry

Introduction De novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 is now a distinct entity of the ICC and WHO 2022 classifications within the group of AML with defining genetic abnormalities. This entity is distinguished from cases with history of chronic myeloid leukemia (CML) and ≥ 20% blasts, which are classified as CML in myeloid blast phase (CML-BP), although the distinction between both entities could be challenging. In the 2022 ELN classification, AML with BCR::ABL1 belong to the adverse risk group. However, this entity is very rare and generally excluded from clinical trials. Thus, there is little data on outcome especially since the era of BCR::ABL1 inhibitors (Orsmark-Pietras C et al.). In this study, we thought to describe treatments and outcome of patients (pts) with de novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 in comparison with CML-BP and ELN 2017 intermediate (Int) or adverse (Adv) risk AML. Methods Inclusion criteria were: pts aged ≥ 18y, included in the DATAML registry between 2000 and 2021, with either de novo BCR::ABL1 AML defined as no previous history of CML, no previous treatment with TKI and ≥ 20% blasts in bone marrow/blood or CML-BP defined as the occurrence of ≥ 20% blasts following the diagnosis of CML in chronic phase. Outcomes of pts with de novo BCR::ABL1 AML were compared with those of CML-BP pts and AML with ELN 2017 Int (n=643) or Adv (n=863) risk treated with intensive chemotherapy (IC) over the same period. A 50-gene NGS panel was retrospectively performed on available samples. Results We identified 20 pts with de novo BCR::ABL1 AML among 5819 AML (0.3%). We only studied the 18 pts who received IC. Their main characteristics were: female to male ratio (55.6%), median age (54y), extramedullary disease (47%) including splenomegaly (35%); high WBC at diagnosis; isolated t(9;22) (67%); p210 isotype (78%), mutations in ASXL1, RUNX1, NPM1, TET2, BCOR, BCORL1, DNMT3A, EZH2, IDH1, KDM6A, NF1, SMC1A, SRSF2, WT1. Comparisons with the 24 pts CML-BP who were treated with IC are shown in the Table. The main differences between both groups was a higher WBC and the presence of NPM1 mutation in de novo pts whereas ABL1 mutations were found in CML-BP only. Induction chemotherapy was mainly cytarabine and daunorubicin (45-90 mg/m²) combined with imatinib (median dose 600 mg, range 400-800). Only 2 patients did not receive imatinib because the drug was not available in 2000-2003. Those 2 pts achieved complete remission (CR) but subsequently relapsed and died from progression. Overall, 17 pts (94.4%) achieved CR or CR with incomplete hematologic recovery (CRi) after one or two induction cycles, one pt failed and there was no early death. Consolidation was mainly high dose cytarabine with imatinib and 12 pts received an allogeneic hematopoietic cell transplantation (alloHCT) in first CR/CRi with myeloablative or reduced intensity conditioning in 7 and 5 pts, respectively. Five pts received maintenance therapy with imatinib (n=4) or nilotinib (n=1). Of note, 4 of the 5 CR/CRi pts who were not transplanted in CR1 did not relapse. With a median follow-up of 76.3 months, median RFS was not reached and 2y-RFS was 82.4% (95%CI, 55-94). Median OS was not reached and 2-y OS was 77.4% (95%CI, 50.3-90.9). Of note, there were 3 late deaths at 48, 60 and 84 months unrelated to AML (1 lung cancer, 1 pancreatic cancer, 1 infection). CR/CRi rate was significantly higher in pts with de novo BCR::ABL1 AML(94.4%) compared with CML-BP (79.2%), AML with ELN 2017 Int (83.4%) or Adv (68.5%) risk (P&amp;lt;0.0001). RFS (median, CML-BP: 100.5 months, IQR 19.7-NR; ELN-Int: 20.6 months, IQR 7.2-115.3; ELN-Adv: 10.3 months, IQR 4.4-48.1; P&amp;lt;0.0001) and OS (median, CML-BP: 33.9 months, IQR 14.6-NR; ELN-Int: 26.9 months, IQR 10.3-117.3; ELN-Adv: 11.8 months, IQR 4.7-40.0; P&amp;lt;0.0001) were also significantly improved. 2-y OS was 77.4%, 57.0%, 53.7% and 33.4% in de novo BCR::ABL1 AML, CML-BP, AML with ELN2017 Int and Adv, respectively (P&amp;lt;0.0001) (Figure). Conclusion De novo AML with t(9;22)(q34.1;q11.2)/ BCR::ABL1 is a very rare event in AML classifications (&amp;lt;1%) with particular features. Pts treated with IC and imatinib have a high rate of CR, very low incidence of relapse and a remarkable OS rate that do not support the ELN2022 risk classification . Pts may have prolonged RFS and OS without alloHCT. Further studies are needed to confirm these results and reclassify these AMLs in the intermediate or even favorable group of the ELN 2022 classification.

Asciminib (ASC) Add-on to Imatinib (IMA) Demonstrates Sustained High Rates of Ongoing Therapy and Deep Molecular Responses (DMRs) with Prolonged Follow-up in the ASC4MORE Study

CONCLUSIONS As tyrosine kinase inhibitors (TKIs) have led to a life expectancy close to that of the general population for responding patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP), there is increased emphasis on quality of life and potential for treatment (Tx)-free remission (TFR). However, Tx strategies enabling more pts to safely achieve durable DMRs as entry criteria for TFR are needed in early therapy lines. :ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP). Preclinical studies of ASC combined with ATP-competitive TKIs showed suppression of BCR::ABL1 mutants, suggesting the potential for enhanced BCR::ABL1 inhibition via combination therapy. In the primary (wk 48) analysis of the ASC4MORE (NCT03578367) study, ASC add-on to IMA led to rapid and deep responses, with no new or worsening safety findings vs those observed with ASC alone. Here, we report results of ASC add-on to IMA vs continued IMA vs switch to nilotinib (NIL) and of pts who crossed over from continued IMA to ASC add-on after 96 wks of Tx in pts not achieving DMR with ≥1 y of IMA as their first TKI (cutoff: 6 Mar 2023). Eligible adults with CML-CP were randomized 1:1:1:1 to receive ASC (40 or 60 mg once daily [QD]) add-on to IMA 400 mg QD, continue IMA 400 mg QD, or switch to NIL 300 mg twice daily in this qualitative trial. Pts must have received only IMA 400 mg QD for ≥1 y as their first TKI with BCR::ABL1IS &amp;gt;.01% to ≤1% at randomization with no DMR at any point and no Tx failure per European LeukemiaNet 2013 criteria. Molecular response (MR) 4.5 (MR 4.5, BCR::ABL1IS ≤.0032%) rate at wks 48 and 96 were the primary and secondary endpoints, respectively. Pts not achieving MR 4.5 at wk 48 with IMA could add on ASC 60 mg QD. The safety and efficacy of ASC monotherapy vs ASC add-on to IMA will be evaluated in future analyses. Pts (N=84) were randomized (n=21 in each Tx arm). With median (range) durations of exposure of 141.7 (27-203), 124.3 (1-192), 53.4 (50-186), and 110.1 (1-189) wks for pts receiving ASC 40 mg add-on, ASC 60 mg add-on, IMA, and NIL, respectively, 85.7%, 76.2%, 19.0%, and 52.4% of pts completed randomized Tx. The top reasons for discontinuation were pt decision (9.5% with ASC 40 mg add-on), adverse events (AEs; 14.3% and 33.3%, with ASC 60 mg add-on and NIL, respectively), and physician decision (66.7% with IMA, all of whom crossed over to ASC 60 mg add-on). At wk 96, 19.0%, 19.0%, 4.8%, and 9.5% of pts in the 40-mg ASC add-on, 60-mg ASC add-on, IMA, and NIL arms, respectively, were in MR 4.5, with 38.1%, 23.8%, 9.5%, and 28.6%, respectively, in MR 4 ( BCR::ABL1IS ≤.01%) (Figure). Cumulative MR 4.5 rates at wk 96 were 28.6%, 28.6%, 9.5%, and 19.0%, respectively. MR 4.5 was achieved by 14.3%, 21.4%, and 14.3% of pts at wks 24, 48, and 96 post crossover, respectively, for pts crossing over from IMA to ASC 60 mg add-on. With longer follow-up, there were no new or worsening safety findings with ASC add-on to IMA (Table). Despite longer median durations of exposure with ASC add-on, fewer pts experienced AEs leading to discontinuation with ASC 40 mg (4.8%) and 60 mg (14.3%) add-on vs switching to NIL (33.3%). Rates of discontinuation with ASC add-on did not increase with longer follow up compared with the primary analysis. An arterial-occlusive event (AOE) occurred in 1 pt in the NIL arm; no AOEs occurred with ASC add-on. Serious AEs occurred more frequently with NIL (23.8%) than with ASC 40 mg (14.3%) and 60 mg (19.0%) add-on. No new deaths occurred since the primary analysis. Among pts not achieving DMR after ≥1 y on IMA, more pts achieved MR 4.5 with ASC add-on to IMA than with continuing IMA or switching to NIL at wk 96. Pts crossing over from IMA to ASC 60 mg add-on were still able to achieve DMRs. ASC add-on to IMA was well-tolerated, with no new or worsening safety findings compared with those known for ASC alone. The high rate of pts completing randomized Tx with ASC add-on (&amp;gt;75%) after &amp;gt;2 y on study is particularly notable and contrasts with the completion rate observed when switching to NIL (52.4%). The high rates of DMRs in these pts are promising and warrant further study. Future analyses from this study involving the ASC monotherapy arm will assess whether ASC alone can provide similar responses as ASC add-on to IMA.

Tern-701 (HS-10382) Is a Potent Inhibitor of BCR::ABL1 and Is Synergistic with Active Site Tyrosine Kinase Inhibitors

CONCLUSIONS Although tyrosine kinase inhibitors (TKIs) targeting the ATP-binding site of the BCR::ABL1 oncoprotein are effective therapeutics for chronic myeloid leukemia (CML), patients often develop drug resistance due to ATP-site mutations that inhibit drug binding. TERN-701 is a potent and highly selective inhibitor of BCR::ABL1 that is designed to bind the allosteric myristoyl site on the kinase, circumventing resistance to active site mutations, with potential for synergistic combination with active site TKIs. Competition binding screens were used to assess the selectivity of TERN-701 on more than 450 targets spanning the human kinome. The potency of TERN-701 against the proliferation of wild type and mutant CML cell lines, as well as a panel of 102 cancer cell lines, was assessed using CellTiter-Glo®. Synergy between TERN-701 and active site TKIs was assessed in vitro with interactions quantified using Bliss, combination, and curve-shift analyses. Prospective mutagenesis experiments were conducted by treating BaF/3 cells engineered to overexpress the BCR::ABL1 kinase with various concentrations of both TERN-701 and the TKI imatinib, followed by observation of clonal outgrowth of treated cells over time. We have previously shown that TERN-701 is a potent inhibitor of native CML cell lines such as K562. Here, we show that TERN-701 inhibited cell proliferation in various clinically relevant mutant CML cell lines (including T315I) with IC 50s ranging from 5 to 26 nM and 70 to 1200 nM against active site and myristoyl site mutations, respectively. TERN-701 was highly selective for BCR::ABL1, with no appreciable activity (&amp;gt;50%) against &amp;gt;450 purified kinase targets. Against a panel of cancer cell lines, TERN-701 was more selective than the comparator allosteric BCR::ABL1 inhibitor asciminib while maintaining similar potency. In vitro combination studies previously revealed that TERN-701 works synergistically with multiple TKIs in the non-mutant K562 cell line. Here, expanded studies using KCL22-s and BCR::ABL1-T315I mutant cell lines identified strong synergistic interactions between TERN-701 and active site TKIs, including ponatinib and dasatinib. Furthermore, prospective mutagenesis studies showed that the combination of TERN-701 and imatinib resulted in greater inhibition of the outgrowth of resistant clones relative to either compound alone. TERN-701 is a potent and highly selective allosteric inhibitor of BCR::ABL1 that can act synergistically with active site TKIs in vitro, even against the T315I gatekeeper mutation that confers resistance to all approved active site TKIs except ponatinib, which has known safety liabilities. These data support the continued development of TERN-701 for the treatment of CML using both monotherapy and combination approaches.

Excellent Early and Major Molecular Responses Observed with Asciminib Treatment for CP-CML: Results from the ALLG CML13 Ascend-CML Study

ATP-competitive BCR::ABL1 inhibitors are effective in many patients with CP-CML patients. However, a significant minority experience treatment failure with currently available drugs due to resistance or toxicity. Asciminib, a first-in-class myristoyl site BCR::ABL1 inhibitor, is now indicated in many jurisdictions for CP-CML after ≥2 prior lines of treatment. The Australasian Leukaemia and Lymphoma Group (ALLG) CML13 ASCEND-CML trial assessed its tolerability and efficacy in the frontline setting, where data are scarce. ALLG CML13 is a prospective open-label phase II study that completed enrolment in Dec 2022 at 14 sites. Patients commenced asciminib 40mg twice a day (BID) at time of diagnosis, and were assessed according to optimal 2020 ELN targets ( BCR::ABL1 ≤10%, ≤1% &amp; ≤0.1% at 3, 6, 12 months respectively); and ≤0.01% at 18 months. Patients in Major Molecular Response (MMR; BCR::ABL1 ≤0.1%) at 12 months were switched to 80mg QD for ease of administration. Patients with treatment failure ( BCR::ABL1 &amp;gt;10% at 3 or 6 months; BCR::ABL1 &amp;gt;1% at 12 or 18 months) continued asciminib, with additional imatinib or dasatinib or nilotinib, according to physician preference. Patients with a suboptimal response at 6, 12, or 18 months, but without treatment failure, continued asciminib but with the dose doubled to 80mg BID. This is a pre-specified analysis of the co-primary end points: i) final analysis of Early Molecular Response (EMR, BCR::ABL1 ≤10% at 3 months) and ii) interim analysis of MMR by 12 months. By data cut-off in May 2023, 101 patients had median follow-up of 20 (0-29) months (including 1 patient who enrolled but never started therapy due to elevated lipase at baseline). Grade 3/4 adverse events (AEs) included neutropenia and thrombocytopenia, (reported in 6% and 5% of patients, respectively); increased lipase/amylase reported in 8% (clinical pancreatitis reported in 2%), anaemia (2%), infection (2%) and 1% each of increased AST/ALT, back, abdominal and chest pain from pulmonary embolism. The only treatment emergent vascular event was a stroke, reported in a male patient aged 73 with pre-existing diabetes and hypertension, after 20 months of asciminib. Fifteen patients discontinued asciminib: 6 due to AEs (2 with persistent cytopenia requiring an allograft, 3 with recurrent asymptomatic lipase elevation, 1 with pancreatitis); 3 lost to follow-up; and 6 due to resistant disease (1 confirmed loss of MMR at 9 months, without ABL1 mutation; 1 transformed to lymphoid blast crisis at 6 months with myristoyl site mutations A337T/V and P465S; 1 loss of MMR at 6 months with A337T mutation; 1 loss of MR2 with V506L; and 2 with failure to achieve EMR - below). No other transformation occurred. During the first 3 months of treatment, 85% of patients had an assigned dose density of &amp;gt;90%; 9% of patients dose reduced to &amp;lt;66%. EMR was achieved by 94/101 patients (93.1%; 96% CI 86-97%): 1 patient never started treatment, 1 patient missed this assessment, 3 patients had withdrawn by this timepoint, and 2 had BCR::ABL1 of 24% and 210%, respectively. Neither of the EMR failure patients had myristoyl site mutations; both were subsequently intolerant of combination TKI/asciminib therapy because of cytopenia and headaches, respectively and are now on dasatinib monotherapy. Six patients dose escalated and remain on asciminib 80mg BID: 3 after failing to achieve MMR by 12 months, &amp; 3 failing to achieve MR4 after 18 months; 2 have since achieved their targets. By 3 months, 48/101 (48%) patients achieved MMR and 12 (11.9%) achieved MR4. Considering only patients with &amp;gt;12 months of follow up, the interim rate of MMR by 12 months is 62/75 patients (82.7%; 98% CI 70-92%). With “off-protocol for any reason” as the competing risk, the cumulative incidences of MMR &amp; MR4.5 by 12 months were 81.1% &amp; 32.3% respectively (Figure). ASCEND is one of the first studies using frontline asciminib, with excellent achievement of EMR and MMR, and low transformation rate. Rates of MMR at 12 months are comparable to those reported with second generation TKIs, though achievement of deeper responses appears more rapid with asciminib. Treatment was well tolerated in general: majority of AEs were grade I/II events that did not result in treatment discontinuation, and only one vascular event was observed. Early achievement of MMR and MR4 may accelerate eligibility for, &amp; increased success of, treatment-free remission attempts.