CML Session Summaries from EHA2026 Congress

Go to the EHA2026 Congress Platform to view the sessions in full and to find other content related to the congress. 

Oral Session: Biology and Translational Research

Session summary

This session highlighted major advances in understanding the biological mechanisms underlying disease progression and treatment resistance in CML. Using single-cell technologies, genomic and transcriptomic profiling, and functional studies, investigators provided new insights into the origins of blast crisis, identified biomarkers capable of detecting high-risk chronic phase disease before transformation, uncovered mechanisms of resistance to asciminib, and refined the biological classification of accelerated phase CML. Together, these findings emphasise that disease progression begins long before overt blast crisis develops and demonstrate how translational research may enable earlier intervention and more personalised treatment strategies.

Our key takeaways from the presentations:

Presentation 1

Single-cell genetic lineage tracing reveals pre-existing blast crisis-initiating clones at chronic-phase CML diagnosis

Speaker: Elaine Cao (Singapore)

‘Lymphoid and myeloid blast crisis follow distinct evolutionary routes’

Key points:

• Blast crisis clones originate during chronic phase: In 6 of 7 patients, the cell of transformation could be traced back to chronic phase disease, demonstrating that progression-associated clones are already present months to years before overt blast crisis develops. The single exception was a patient with a germline TP53 background, in whom the relevant clones were not detectable in chronic phase.
• Different origins for lymphoid and myeloid blast crisis: The cell of transformation was consistently identified as Pro-B cells in lymphoid blast crisis, whereas myeloid blast crisis originated from more primitive HSC/MPP populations with multilineage involvement. 
• Blast crisis signatures are already detectable at diagnosis: Established blast crisis transcriptional programs were confirmed in all three lymphoid cases and in three of four myeloid cases, indicating that transformation-associated programs emerge early.
• Inflammatory pathways are a common feature: NF-κB-driven inflammatory signatures were consistently enriched in all three lymphoid blast crisis cases and in three of four myeloid blast crisis cases, suggesting inflammation as a common driver of progression. This inflamed progenitor state was described as a feature of the transforming clone not previously characterised.
• Myeloid transformation is biologically heterogeneous: Unlike the convergent lymphoid pathway, myeloid blast crisis displayed diverse genetic alterations and more variable transcriptional programs.
• Single-cell lineage tracing overcomes limitations of bulk analyses: Simultaneous assessment of copy number alterations, somatic mutations and gene expression at single-cell resolution enabled direct identification of transformation-initiating clones.

Presentation 2

Single-cell transcriptomic-guided flow cytometric analysis of inflamed megakaryocytic and lymphoid progenitors at diagnosis identifies chronic-phase CML at high risk for blast crisis transformation

Speaker: S. Tiong Ong (Singapore)

‘Single-cell omics can be translated into clinically useful tests.’

Key points:

• Single-cell omics enabled development of protein-based biomarkers: Transcriptomic analyses identified lineage-specific inflammatory signatures that were translated into practical multiparameter flow cytometry assays.
• Distinct progenitor expansion patterns predict transformation: Patients progressing to lymphoid blast crisis demonstrated lymphoid progenitor expansion, while both lymphoid and myeloid blast crisis patients showed expansion of megakaryocytic progenitors.
• Inflammation precedes cellular expansion: Phospho-STAT1-positive inflammatory signals in progenitor cells were detectable before overt expansion, suggesting that inflammatory activation may be an early event in transformation.
• Flow cytometry identified high-risk patients with high accuracy: The optimised assay achieved 95–100% sensitivity and over 90% specificity in the most recent validation cohort. The assay was statistically superior to the Sokal score and trended to superiority over the ELTS score, and is positioned as complementary to ELTS rather than a replacement.
• Very high-risk patients may benefit from earlier intervention: Earlier identification could allow more intensive monitoring, use of more potent TKIs and timely referral for transplantation before blast crisis develops.
• More potent frontline TKIs may be preferable in selected patients: The data suggested that patients with isolated MKP expansion without accompanying inflammatory signalling (phospho-STAT1 negative) may particularly benefit from second-generation or later TKIs frontline.

Presentation 3

Influence of non BCR::ABL1 somatic mutations on tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia

Speaker: Michele Ciboddo (Helsinki)

‘Not all resistance mechanisms are shared across TKIs – BCOR loss confers resistance to asciminib but not to imatinib.’

Key points:

• CROP-seq identified pathways associated with primary TKI resistance: Single-cell CRISPR screening revealed transcriptional signatures involving mTOR signalling, unfolded protein response and apoptosis regulation.
• BCOR loss specifically mediates asciminib resistance: BCOR knockout cells retained sensitivity to imatinib but became resistant to asciminib, highlighting a mutation-specific resistance mechanism.
• Findings were validated experimentally: The differential sensitivity pattern was reproducible in the K562 cell-line model used throughout.
• BCL-XL emerged as a key mediator: BCOR-deficient cells displayed higher baseline BCL-XL protein levels and maintained elevated expression after asciminib treatment.
• Combination therapy restored sensitivity: BCOR knockout cells showed increased susceptibility to combined treatment with asciminib and the oral BCL-XL inhibitor A-1331852.
• Results may guide future therapeutic strategies: Understanding mutation-specific resistance mechanisms could enable rational combination approaches to overcome resistance.

Presentation 4

Molecular mechanisms of ZDHHC19-mediated JAK1 palmitoylation driving TKI resistance in CML leukemia stem cells

Speaker: Teng Wang (Chongqing)

‘Metabolic rewiring through JAK1 palmitoylation represents a novel therapeutic vulnerability in TKI-resistant CML.’

Key points:

• Alterations in the bone marrow adipocyte compartment were observed in CML: Patients demonstrated reduced adipocyte numbers and increased circulating palmitic acid levels, particularly in TKI-resistant disease.
• Palmitic acid promoted TKI resistance in leukemia stem cells: Functional experiments showed enhanced resistance following exposure to palmitic acid.
• Resistance was mediated through protein palmitoylation: Elevated palmitoyl-CoA levels promoted activation of the JAK1–STAT3 pathway rather than simply serving as an energy source.
• ZDHHC19 was identified as the responsible enzyme: Integrated transcriptomic and palmitoylation analyses identified ZDHHC19 as a key regulator of JAK1 palmitoylation, with ZDHHC19 knockdown reducing JAK1 palmitoylation and downstream STAT3 activation.
• Blocking palmitoylation restored TKI sensitivity: Inhibition with the broad-spectrum palmitoylation inhibitor 2-bromopalmitate reduced proliferation, induced apoptosis and improved responses in mouse models. Enzyme specificity was supported separately by the ZDHHC19 knockdown experiments above rather than by 2-bromopalmitate alone.
• Targeting lipid metabolism may represent a new therapeutic avenue: Development of selective ZDHHC19 inhibitors may offer novel strategies to eradicate resistant leukemia stem cells.

Presentation 5

Integrated genomic and transcriptomic analyses reveal biological heterogeneity of accelerated-phase chronic myeloid leukemia and identify a blast-phase like subgroup

Speaker: Xiaoshuai Zhang (Beijing)

‘Evolved accelerated phase spans a biological continuum between chronic phase and blast phase.’

Key points:

• De novo accelerated phase resembles newly diagnosed chronic phase: Genomic and transcriptomic analyses demonstrated that de novo AP shares features with chronic phase rather than blast phase disease.
• Clinical AP features do not necessarily indicate blast-phase biology: Even blast-enriched AP subtypes remained molecularly distinct from de novo blast phase.
• Evolved AP represents a biological continuum: Patients with evolved AP exhibited characteristics intermediate between TKI-resistant chronic phase and blast phase disease.
• Two molecular subgroups were identified: Transcriptomic profiling separated evolved AP into CP-like AP and BP-like AP subgroups.
• BP-like AP was associated with poor prognosis: Patients with BP-like AP had outcomes similar to blast phase CML and significantly worse survival than CP-like AP patients.
• BP-like AP was characterised by genomic instability and stemness activation: Increased mutational burden, leukemia stem-cell signatures and activation of cell cycle and DNA repair pathways distinguished this subgroup.
• Analysis was performed on bulk RNA-seq of total leukocytes rather than sorted blasts, and blast-phase patient numbers were limited.
   

Education Session – Chronic myeloid leukemia

Chair: Kateřina Machová Poláková (Prague)

The EHA2026 Education Session on CML provided a broad overview of the biological mechanisms that underlie leukemic stem cell persistence, immune control and treatment-free remission (TFR), and the increasingly individualised approach to frontline therapy. 
The presentations highlighted the importance of the bone marrow niche and inflammatory pathways in maintaining residual disease, the central role of immune surveillance, particularly natural killer (NK) cells, in successful TFR, along with the need to tailor treatment strategies according to disease biology, patient characteristics, and therapeutic goals. Together, the talks reinforced the concept that future progress in CML will depend not only on more potent BCR::ABL1 inhibition, but also on targeting the microenvironment, understanding immune mechanisms, and addressing the heterogeneity of the disease. 

Our key takeaways from the presentations:

Presentation 1:

The crosstalk between CML and the niche

Speaker: Mirle Schemionek (Aachen)

“Leukemic stem cell persistence is not solely an intrinsic property of the cell, but is strongly influenced by a permissive and dynamically changing microenvironment.”
– Mirle Schemionek

Key points:

• Inflammatory signalling sustains leukemic stem cell persistence
  Leukemic stem cells survive despite complete BCR::ABL1 inhibition, with inflammatory pathways such as JAK/STAT and NF-κB contributing to treatment resistance. Preclinical studies showed that targeting these pathways enhances stem cell eradication.
• The bone marrow niche actively supports residual disease
  CML remodels the stromal and vascular microenvironment, creating a permissive niche that maintains quiescent, TKI-resistant stem cells. Mesenchymal stromal cells and adipogenic progenitors play key roles in this process.
• Myelofibrosis at diagnosis predicts poorer treatment-free remission outcomes
  Patients presenting with bone marrow fibrosis were more likely to experience molecular relapse after TKI discontinuation, suggesting that fibrosis reflects a niche favourable to leukemic stem cell persistence.
• Megakaryocytes emerge as active niche-remodelling cells
  CML-associated megakaryocytes promoted angiogenesis and fibrosis-associated changes and showed increased production of TGF-β, indicating that they may contribute to both stem cell quiescence and disease persistence.
• Spatial organisation of the bone marrow changes during disease progression
  Recent spatial and single-cell studies demonstrated profound alterations in vascular architecture and stem cell localisation, emphasising that the niche evolves throughout disease development.
• Niche-directed therapies may complement TKIs in the future
  Emerging clinical data with anti-inflammatory approaches and preclinical studies targeting stromal interactions suggest that combining TKI therapy with niche-targeted strategies could improve eradication of residual disease.

Presentation 2:

Immune surveillance and treatment-free remission in CML

Speaker: Satu Mustjoki (Helsinki)

“Treatment-free remission is not simply determined by residual leukemia cells, but by the interaction between leukemic cells and the immune system.”– Satu Mustjoki

Key points:

• CML patients exhibit a distinct immune profile at diagnosis
  Increased immune suppressor populations and altered checkpoint molecule expression distinguish CML from other leukemias and may influence treatment responses.
• Immune composition changes during TKI therapy
  Treatment restores immune function, including normalisation of NK-cell activity and reduction of inhibitory checkpoint expression, suggesting that TKIs have important immunomodulatory effects.
• Immune parameters correlate with molecular response and TFR success
  The number and phenotype of immune cells are closely linked to treatment outcomes, and immune biomarkers may outperform traditional clinical predictors in identifying patients likely to achieve deep responses.
• Natural killer cells appear central to successful treatment discontinuation
  Multiple studies consistently showed that higher numbers of mature and functionally active NK cells are associated with sustained TFR, highlighting innate immunity as a key component of disease control.
• Additional mutations beyond BCR::ABL1 may influence TFR outcomes
  Mutations in epigenetic modifier genes were more common in patients who relapsed after treatment discontinuation, suggesting that leukemia biology and immune surveillance jointly determine TFR success.
• Future strategies may focus on boosting immune responses
  Approaches involving interferon, checkpoint inhibition, vaccines, and NK-cell activating therapies are being explored to enhance immune control of residual leukemia and improve TFR rates.

Presentation 3:

Choosing wisely from different treatment options

Speaker: Delphine Réa (Paris)

“CML is not a homogeneous disease, and treatment decisions should reflect both biological and clinical heterogeneity.” – Delphine Réa

Key points: 

• CML is a biologically and clinically heterogeneous disease
  Prognosis is influenced not only by traditional risk scores but also by transcript type, additional cytogenetic abnormalities, and mutations beyond BCR::ABL1. Future management will require a more refined definition of high-risk disease using both baseline and dynamic parameters.
• Treatment selection should be individualised according to disease and patient characteristics
  Age, comorbidities, treatment priorities and quality-of-life considerations should all be incorporated into frontline treatment decisions, emphasising a personalised approach to therapy.
• More potent TKIs improve molecular responses and may increase opportunities for TFR
  Second-generation TKIs and asciminib offer deeper molecular responses and lower risks of resistance, particularly in patients with intermediate- and high-risk disease, although longer follow-up is required for asciminib.
• Safety, tolerability and quality of life are essential components of treatment decisions
  Chronic toxicities and off-target effects influence long-term adherence and patient satisfaction. Dose optimisation and careful management of comorbidities are critical to maintaining treatment success.
• The ultimate goal should extend beyond lifelong disease control
  The question "Why should CML remain a chronic condition?" highlights the need to pursue deeper responses and curative strategies rather than accepting indefinite therapy as the endpoint for all patients. Better identification of patients unlikely to achieve deep molecular remission or successful TFR is needed.
• Future clinical trials should address the unmet needs of distinct patient subgroups
  Rather than applying the same strategy to all patients, future studies should focus on populations at high risk of resistance, failure to achieve deep molecular response, or unsuccessful TKI discontinuation.
   

Specialized Working Group Session: Blast Phase CML

 Chair: Andreas Hochhaus (Jena)

This Specialized Working Group session focused on one of the major remaining challenges in CML: blast phase disease. Despite the success of tyrosine kinase inhibitors in chronic phase CML, outcomes after progression remain poor. Presentations highlighted learnings from international registries, the role of genomic abnormalities in predicting disease progression, and innovative patient-derived xenograft models that may enable more individualised therapeutic approaches. A recurring message throughout the session was that preventing blast phase through improved risk stratification is just as important as developing better therapies for patients who progress.

Our key takeaways from the presentations:

Presentation 1:

Blast crisis: Lessons from real-world registries

Speaker: Kendra Sweet (Tampa)

“Overall survival remains extremely poor in this disease, and we have a lot of work in front of us if we want to improve long-term outcomes.” – Kendra Sweet

Key points:

• Poor outcomes persist despite modern therapies:
  Across the ELN, H. Jean Khoury Cure CML Consortium and MD Anderson registries, median overall survival for patients in blast phase remained only 12–24 months. Outcomes were particularly poor for patients progressing from chronic phase, emphasising that blast phase CML remains a major unmet need.
• Substantial biological heterogeneity complicates treatment:
  Blast phase CML is highly heterogeneous with regard to phenotype, prior treatment history and molecular characteristics. No standard chemotherapy regimen or preferred TKI has emerged from registry data.
• Allogeneic transplantation remains the most important treatment strategy:
  AlloSCT resulted in deeper molecular responses and improved overall survival and should be pursued whenever possible in patients who achieve a second chronic phase. Post-transplant maintenance strategies remain an area of ongoing investigation.
• The need for intensive chemotherapy remains uncertain:
  Data is conflicting on the need for chemotherapy plus TKI versus TKI monotherapy. Registry analyses suggested that the benefit of adding chemotherapy to TKI therapy may be less important in patients who subsequently undergo allogeneic transplantation. 
• Validated prognostic models can identify high-risk patients:
  The ELN blast phase prognostic score, incorporating age, blast percentage, platelet count, phenotype, extramedullary disease and de novo versus transformed disease, successfully stratified patients according to outcome and has now been independently validated.
• Collaborative studies and clinical trials are urgently needed:
  Larger international datasets and prospective clinical trials will be essential to determine optimal treatment strategies and develop more effective therapies for blast phase disease.

Presentation 2:

Somatic mutations and chromosomal aberrations as predictors of blast crisis

Speaker: Thomas Ernst (Jena)

“Genomic profiling may improve risk stratification, enable early identification of high-risk patients, and guide future targeted and combination therapies.” – Thomas Ernst

Key points:

• Genomic abnormalities are present from diagnosis:
  Mutations and cytogenetic abnormalities can be detected already at diagnosis and provide important information on disease biology and long-term clinical outcomes.
• Accumulation of genetic lesions drives progression to blast phase:
  Increasing genomic complexity is strongly associated with disease evolution and transformation. Additional mutations and chromosomal abnormalities accumulate during progression and appear to be major mediators of blast crisis development.
• Specific cytogenetic abnormalities identify high-risk disease:
  High-risk additional chromosomal abnormalities include 3q26.2 rearrangements, 
  11q23 abnormalities, chromosome 7 abnormalities, isochromosome 17q and complex karyotypes. These lesions are associated with inferior survival whether present at diagnosis or acquired later.
• ASXL1 and other recurrent mutations are associated with adverse outcomes:
  Mutations involving ASXL1, TP53, RUNX1 and IKZF1 emerged as particularly important high-risk lesions. ASXL1 mutations were associated with inferior molecular responses and outcomes comparable to those seen with complex karyotypes.
• Combination therapies may overcome adverse genomic features:
  Early results from the German FASCINATION study suggest that asciminib-based combination approaches may mitigate the negative prognostic impact of ASXL1 mutations and improve molecular responses.
• Genomic profiling may enable precision medicine approaches: 
  Incorporating genetic information into routine risk assessment could improve early identification of high-risk patients and guide individualized treatment strategies, including targeted combinations and risk-adapted therapy. 

Presentation 3:

PDX models to predict response to drug combinations in blast crisis

Speaker: Adam Laznicka (Prague)

“The heterogeneity observed between PDX models underlines the necessity of personalised therapeutic approaches.” – Adam Laznicka

Key points: 

• Patient-derived xenograft (PDX) models capture the complexity of blast phase CML:
  PDX models preserve clonal diversity and biological heterogeneity, allowing a more accurate representation of human blast phase disease and improving prediction of treatment response.
• PDX models can identify effective therapeutic combinations:
  Multiple models demonstrated activity of novel drug combinations, even in highly resistant disease, supporting their use as a platform for translational research.
• Marked heterogeneity supports personalised treatment approaches:
  Different models exhibited distinct resistance mechanisms and therapeutic sensitivities, emphasising that individualised treatment strategies will likely be required for blast phase CML.
• Ponatinib-based combinations showed consistent activity:
  Across several models, combinations involving ponatinib with venetoclax or ponatinib with asciminib prolonged mouse survival and overcame resistance observed with single-agent therapy. These findings provide a rationale for prioritising these combinations in future clinical studies.
• Resistance mechanisms are influenced by co-occurring mutations:
  Mutations such as NRAS affected sensitivity to venetoclax, illustrating how genomic context may influence response and highlighting the need for biologically informed treatment selection.
• Further clinical studies are required to optimise therapy:
  Additional trials are needed to determine the optimal drug combinations, dosing schedules and treatment sequences to improve outcomes for patients with blast phase CML.

Oral Session: Chronic Myeloid Leukemia – Clinical

Chairs: Tim Henrik Brümmendorf (Aachen) and Delphine Réa (Paris)

This session showcased important advances in the clinical management of CML, with a strong focus on improving molecular responses, expanding opportunities for treatment-free remission (TFR), and developing new therapeutic options for patients across different treatment settings. Long-term follow-up data from ASC4FIRST reinforced the emerging role of asciminib as a frontline therapy, while two independent studies demonstrated that a second TFR attempt is achievable in selected patients. Additional presentations explored novel strategies to deepen molecular responses through asciminib-based combination therapy and highlighted encouraging early results from the highly selective next-generation BCR::ABL1 inhibitor ELVN-001. 

Our key takeaways from the presentations:

Presentation 1:

ASC4FIRST week 144 analysis: Continued superior efficacy and favourable safety of asciminib versus investigator-selected tyrosine kinase inhibitors in newly diagnosed chronic myeloid leukemia

Speaker: Timothy Hughes (Adelaide)

“Asciminib continues to demonstrate a favourable benefit-risk profile compared with current standard-of-care TKIs. The difference in MR4.5 at three years may prove particularly important as a pathway towards treatment-free remission.”– Timothy Hughes

Key points:

• Superior molecular responses: At 144 weeks, asciminib maintained significantly higher rates of major molecular response (MMR) and deep molecular response compared with both imatinib and investigator-selected second-generation TKIs. 
• Higher rates of deep molecular remission: Deep molecular responses continued to improve with longer treatment duration. At week 144, MR4.5 rates reached 41% with asciminib compared with 29% for second-generation TKIs, reinforcing the potential of asciminib to increase future treatment-free remission opportunities.
• Improved treatment persistence: More patients remained on asciminib therapy after three years compared with either imatinib or second-generation TKIs. Lower rates of treatment failure and fewer discontinuations due to adverse events contributed to superior long-term treatment retention.
• Favourable resistance profile: No new BCR::ABL1 mutations emerged during the third year of follow-up. Importantly, previously observed asciminib-resistant mutations remained manageable through subsequent treatment with second-generation TKIs.
• Future TFR potential: The study is ongoing, and analyses to assess the potential for TFR eligibility and success are planned.  

Presentation 2:

Ponatinib consolidation and discontinuation in chronic myeloid leukemia patients after failed first treatment-free remission attempt: Updated TFR outcomes and CHIP mutation analysis from ReStop Trial

Speaker: Gonzalo Carreño Gómez-Tarragona (Barcelona)

“Ponatinib consolidation achieved high TFR rates in patients who had failed previous TKI discontinuation attempts.”– Gonzalo Carreño Gómez-Tarragona

Key points:

• High rates of second treatment-free remission: Ponatinib consolidation followed by a second discontinuation attempt resulted in encouraging TFR outcomes in patients who had previously relapsed after their first stop attempt. One year after ponatinib discontinuation, 68.2% of patients remained treatment-free, exceeding outcomes previously reported in many second-attempt TFR studies.
• Effective molecular consolidation strategy: Patients received two years of ponatinib consolidation before re-attempting treatment discontinuation. The findings suggest that intensifying therapy with a potent TKI may help restore durable treatment-free remission in selected patients.
• No disease progression observed: No cases of progression to advanced-phase disease were reported during the study. Most patients who successfully completed the consolidation phase maintained molecular remission throughout the first year of treatment discontinuation.
• Manageable but important safety considerations: Adverse events were consistent with the established ponatinib safety profile, including hypertension and vascular events. These findings highlight the need for careful patient selection and cardiovascular risk assessment when considering this strategy.
• Potential impact of CHIP mutations: Patients carrying CHIP mutations appeared more likely to maintain TFR than non-carriers, although the differences were not statistically significant due to the small sample size. The observation warrants further investigation in larger cohorts.
• No increased cardiovascular risk associated with CHIP: Importantly, CHIP mutations were not associated with a worse cardiovascular or overall safety profile in ponatinib-treated patients. This provides reassurance that CHIP status alone should not necessarily exclude patients from this approach.

Presentation 3:

High rates of successful second stop attempts in patients with chronic myeloid leukemia: Results of the NAUT trial
Speaker: Susanne Saussele (Mannheim)

“The NAUT trial demonstrates that a relevant proportion of patients after a second discontinuation can achieve successful TFR. Longer retreatment before a second stop attempt may be an important contributor to success.”– Susanne Saussele

Key points: 

• Second TFR attempts can be successful: The NAUT trial demonstrated that a substantial proportion of patients can successfully discontinue treatment after a previous unsuccessful stop attempt. Molecular recurrence-free survival reached 58% at 12 months, exceeding the study’s predefined expectations.
• Extended retreatment may improve outcomes: Patients underwent two years of nilotinib consolidation before attempting treatment discontinuation again. The findings suggest that prolonged retreatment and re-establishment of stable deep molecular responses may be critical factors for successful second TFR attempts.
• Rapid regain of response after relapse: Most molecular relapses occurred early, with a median time to relapse of just over three months. Nearly all patients who restarted therapy rapidly regained deep molecular responses, confirming the safety of close molecular monitoring.
• No new safety signals identified: The safety profile observed during nilotinib treatment was consistent with previous experience and no unexpected adverse events emerged. No disease progression or CML-related deaths were reported during the study.
• Cardiovascular events require monitoring: More than 40% of patients experienced cardiovascular adverse events, although most were low-grade and largely related to hypertension. Serious cardiovascular complications remained relatively uncommon in this carefully selected population.
• A realistic option for selected patients: The results support offering a second treatment discontinuation attempt to appropriate patients who regain stable deep molecular responses. These findings add to growing evidence that TFR may remain achievable even after an initial unsuccessful attempt.

Presentation 4:

Efficacy and safety of adding low-dose tyrosine kinase inhibitors for patients with CML who don't achieve optimal response or a deep molecular remission 
(ALERT-CML)

Speaker: Jay Yang (Chicago)

“The addition of low-dose TKI to asciminib was feasible and safe in patients who failed to achieve deep molecular remission. Combination therapy improved responses in 66% of patients.”– Jay Yang

Key points: 

• Strong frontline activity with asciminib: Asciminib monotherapy continued to generate rapid and deep molecular responses, with 42% of patients achieving MR4 at 12 months. Responses continued to deepen over time, supporting the growing body of evidence for asciminib as an effective frontline therapy.
• Combination therapy for suboptimal responders: Patients with treatment failure, warning responses, or insufficient molecular depth were offered low-dose TKI therapy in addition to asciminib. This strategy aimed to overcome residual disease and further enhance molecular responses.
• Improved molecular responses in most patients: Two-thirds of patients receiving combination therapy achieved improved molecular responses after the addition of low-dose dasatinib. Importantly, no patient experienced deterioration of their molecular response following treatment intensification.
• Potential to increase deep remission rates: Both patients who entered the study arm because they had not achieved MR4.5 after two years of asciminib subsequently reached MR4.5 after low-dose TKI addition. These findings suggest a possible role for combination therapy in expanding future TFR eligibility.
• Favourable safety profile maintained: Combination treatment was generally well tolerated, with most adverse events being mild. No cardiovascular events, thrombotic complications, pleural effusions, or QT prolongation signals were observed during follow-up.
• Promising strategy requiring longer follow-up: Although patient numbers remain small and follow-up is relatively short, the results provide early evidence that asciminib-based combination therapy may benefit patients with slower or suboptimal molecular responses.

Presentation 5: 

ENABLE: Updated efficacy and safety results of ELVN-001, a novel selective ATP-competitive inhibitor of BCR::ABL1 in patients with previously treated CP-CML

Speaker: Dennis Kim (Toronto)

“Encouraging MMR rates were observed even in heavily pre-treated patients and after asciminib failure.” – Dennis Kim

Key points: 

• Highly selective next-generation inhibitor: ELVN-001 is a highly selective ATP-competitive inhibitor of BCR::ABL1 that minimizes off-target kinase inhibition. Its unique binding properties may help reduce toxicities associated with currently available TKIs and offer activity against several resistance mutations, including those emerging after allosteric inhibition.
• Favourable safety and tolerability profile: Longer-term follow-up confirmed a favourable safety profile, with only around 6% of patients discontinuing treatment because of adverse events. Rates of arterial occlusive events were low, and no new safety concerns emerged despite treatment in a heavily pre-treated population.
• Encouraging efficacy in heavily pre-treated patients: Among patients who had not achieved MMR prior to ELVN-001 treatment, 48% attained MMR, while all patients who entered the study with MMR maintained their response. Responses occurred rapidly, with many patients achieving MMR within the first 24 weeks of therapy.
• Deep molecular responses continued to develop: At week 24, approximately 30% of patients receiving the biologically active 80 mg once-daily dose achieved MR4. Molecular responses were either maintained or improved over time, with no evidence of worsening response during treatment.
• Activity after asciminib failure: ELVN-001 demonstrated clinically meaningful activity in patients previously treated with asciminib. MMR rates reached 67% in patients who had failed asciminib after one or two prior lines of therapy and remained approximately 33% even in patients who had received asciminib in later treatment lines.
• Advancing towards Phase 3 development: Based on safety, pharmacokinetic and pharmacodynamic analyses, 80 mg once daily was selected as the optimal biological dose. The pivotal Phase 3 ENABLE-2 study is expected to begin in the second half of 2026.

A link to the ELVN-001 P1 EHA Oral Presentation is provided by Enliven and can found here