We're bringing you highlights from the 67th ASH Annual Meeting with a summary of selected scientific sessions on CML

🌟 Oral Abstract Session: CML clinical & epidemiological - Therapeutic agents to enhance patient outcomes

Chairs: Elisabetta Abruzzese (Rome) - Vivian Oehler (Seattle)
This clinical session presented major advances in novel TKIs, frontline optimisation strategies, real-world outcomes in blast-phase CML, and next-generation approaches to achieving deeper and safer molecular responses. Across six presentations, investigators showcased: promising phase 1 data for TERN-701 and TGRX-678, updated results from a frontline asciminib combination trial, the largest US analysis of blast-phase management, a prospective study testing nilotinib vs. imatinib with early switch to improve TFR, and the first prospective trial of asciminib with dose escalation as second-line therapy. 

Collectively, the studies demonstrated:

• High efficacy and favourable safety of new agent seven in heavily pretreated or T315I-mutated patients,
• Asciminib’s expanding rolein both frontline combinations and second-line therapy,
• The persistent challenge and therapeutic needs of blast-phase CML,
• The importance of risk-adapted frontline selection to improve long-term TFR outcomes,
• And the feasibility of dose escalation strategies with asciminib to address suboptimal responders.

Our key takeaways from the presentations:

Presentation 1: 
CARDINAL: A Phase 1 study of TERN-701, a novel investigational allosteric BCR::ABL1 inhibitor for patients with previously treated CML

Speaker: Elias Jabbour (Houston)
“We observed encouraging efficacy across all dose levels, even in patients previously treated with asciminib or ponatinib.” – Elias Jabbour

Key points:

• Potent allosteric inhibitor: TERN-701 selectively targets the myristoyl pocket with >10,000-fold selectivity compared with ATP-site TKIs. 
• Heavily pretreated population: Patients had a median of 3 prior TKIs, 82% without baseline MMR, and 15% with BCR::ABL1 mutations. 
• Efficacy results: 24-week MMR 64% at all doses, 75% MMR and 36% DMR at RP2D (≥320 mg).
• Safety results: No dose-limiting toxicities, no maximum-tolerated-dose, low rates of grade ≥3 cytopenias (<10%), and only one treatment discontinuation due to adverse events (AEs). 
• Recommended doses: 320 mg and 500 mg QD selected for randomised expansion

Presentation 2:
Efficacy of TGRX-678, a potent BCR::ABL1 allosteric inhibitor, in CML-CP and CML-AP patients harbouring T315I mutation: Results from a phase 1 study

Speaker: Qian Jiang (Beijing)
“TGRX-678 achieved strong efficacy in both CML-CP and CML-AP patients with the T315I mutation.”– Qian Jiang

Key points:

• Designed for T315I mutation: TGRX-678 demonstrates potent activity against T315I BCR::ABL1 with high permeability and bioactivity. 
• Heavily pretreated population: Many patients had received ≥4 TKIs, including ponatinib/ olverembatinib; 80% carried isolated T315I. 
• Durable efficacy:  In chronic-phase (CP), 61% CCyR and 45% MMR at two years; accelerated-phase (AP) patients 32% CCyR
• Mutation dynamics: T315I clearance associated with MMR; emergent F359V/C/I and M244V mutations seen in non-responders. 
• Tolerability:Mostly mild, manageable AEs (neutropenia, hyperlipidemia); toxicity decreased over time.

Presentation 3:
Improved long-term tolerability and efficacy of asciminib-based combination therapies in newly diagnosed CML patients – the FASCINATION trial

Presenter: Thomas Ernst (Jena)
“After three years of follow-up, we see deep and durable molecular responses without unexpected toxicities, and patients are now entering TFR – which is the ultimate goal of frontline therapy.” – Thomas Ernst

Key points:

• Combination strategy: Asciminib combined with imatinib, dasatinib, or nilotinib as first-line treatment to accelerate deep responses and increase TFR eligibility. 
• Strong long-term efficacy: MR4 achieved in 49% at 24 months and 65% at 36 months; MMR reached in 91% at three years.
• Improved tolerability over time: Grade 3/4 AEs decreased substantially over time 
  (38% → 24% → 10% over three years). 
• NGS findings: 18% had additional mutations; ASXL1-mutated patients unexpectedly performed better, with 6/8 achieving MR4. 
• TFR eligibility: 37 patients entered TFR after 3 years, progressing to de-escalation per study design; no new safety signals emerged.

Presentation 4:
Management and outcomes of patients diagnosed with chronic myeloid leukemia in blast phase: 
A multicentre analysis by the H Jean Khoury CURE Consortium 

Presenter: Akriti Jain (Cleveland) 
“Despite therapeutic advances, blast phase CML continues to carry a poor prognosis. Age, disease phenotype, and timely access to allogeneic stem cell transplant are the strongest determinants of outcome in blast phase CML.”
– Akriti Jain

Key points:

• Large U.S. cohort: 288 BP-CML patients (2010–2025), 27% de novo BP; median age 50. 
• Treatment patterns: 65% received TKI + chemotherapy; dasatinib and ponatinib most used TKIs. 
• Survival outcomes: Median OS 19.7 months; better outcomes in patients <50 years, lymphoid phenotype, and those receiving transplant. 
• Transplant impact: Landmark analysis: OS 127.9 months in SCT recipients vs 16 months without SCT. 
• TKI generation effect: No significant difference between 2G vs 3G TKIs in OS or EFS. 
• Chemotherapy effect: On multivariate analysis, addition of chemotherapy did not make a significant difference in OS. Further studies are needed to confirm these analyses.

Presentation 5:
International, prospective study comparing nilotinib versus imatinib with early switch to nilotinib to obtain sustained treatment-free remission (TFR) in patients with chronic myeloid leukemia: 
The TFR rate at the end of follow-up

Presenter: Fabrizio Pane (Napoli) 
“If the final endpoint is TFR, an aggressive frontline strategy may be pursued in all patients.“  – Frabrizio Pane

Key points:

• Study design: 450 newly diagnosed CML patients randomised to frontline nilotinib vs imatinib with early switch if milestones not met. 
• Eligibility for TFR: One-third of patients in both arms became eligible for TFR at 4 years 
  (MR4 maintained). 
• TFR outcomes: TFR significantly higher in nilotinib-arm (65%) vs imatinib-arm (55%). 
• Risk stratification: Benefit of nilotinib most pronounced in low-ELTS; no major advantage in intermediate/high ELTS. 
• Safety results: Higher vascular/cardiac AEs in nilotinib recipients but overall manageable. 

Presentation 6:
Asciminib (ASC) in chronic myeloid leukemia in chronic phase (CML-CP): Efficacy and safety results of the Phase 2 ASC2ESCALATE trial in the cohort of patients (pts) with 1 prior tyrosine kinase inhibitor (TKI)

Presenter: Jorge Cortes (Augusta) 
“These primary analysis results further support asciminib as a treatment option in second line CML-chronic phase. The outcomes in patients with asciminib dose escalations continue to be explored.”– Jorge Cortes

Key points:

• Second-line patient cohort: CML-CP patients resistant or intolerant to one prior TKI, mostly imatinib or dasatinib. 
• Efficacy results: MMR at 48 weeks ≈60% (primary endpoint met), increasing to 70% at latest follow-up; MR4/MR4.5 deepening over time. 
• Dose escalation arm: 18 patients escalated (24 or 48 weeks); majority improved molecular responses and minimal added toxicity, showing feasibility. 
• Safety results: Only 8% discontinued due to AEs; hypertension was the most frequent grade ≥3 AE (12,9%).
• Post-baseline mutations: Post-baseline mutations were infrequent; the most common (A337T) has been previously observed in asciminib frontline and later studies 

🌟 Education Spotlight Session: The changing face of CML

Chairs: Gabriela Soriano Hobbs (USA)
This Education Spotlights Session provided a comprehensive, practice-oriented update on two central pillars of modern CML management:
(1) selecting optimal frontline therapy, and
(2) safely implementing treatment-free remission (TFR). 

Professor Jorge Cortes explored how evolving tyrosine kinase inhibitor (TKI) options, safety considerations, comorbidities, additional mutations (ASXL1), and patient goals shape first-line decision-making in 2025. 
Professor François-Xavier Mahon, a pioneer of TFR, presented the foundations, predictive factors, and long-term outcomes that guide treatment discontinuation today.

Together, the talks emphasised patient-centred care, biological heterogeneity, and the need for individualised strategies that optimise both survival and quality of life of patients with CML.

Our key takeaways from the presentations:

Presentation 1: 
Frontline treatment selection for CML in 2025 
Speaker: Jorge Cortes (Augusta)
“Patient-centred treatment goals must be the focus of our considerations - survival alone is no longer the only measure of success. Patients aim for better years of life, not just more years.“

Key points:

• Patient-centred treatment goals: Treatment choice should be guided primarily by patient-centred goals (survival, quality of life, TFR), comorbidities, and risk tolerance - not solely by ELTS/SOKAL scores. 
• TKI choice: Imatinib remains effective with the lowest cardiovascular risk, while second-generation TKIs offer faster and deeper responses; asciminib provides high response rates with a more favourable tolerability profile. 
• Genomic risk profile: Patients with ASXL1 or other pathogenic variants have worse outcomes, regardless of frontline TKI; newer strategies (e.g., asciminib combinations) may be needed. 
• Quality of life: Side effects are the main driver for patients wishing to stop therapy; long-term tolerability significantly influences TKI selection.
• Dosing strategy: TKI dosing should be flexible, including dose ramp-up (e.g. bosutinib), dose reduction, or minimal effective dosing in select scenarios. 

Presentation 2:
Can I stop taking my TKI yet? 
Speaker: François-Xavier Mahon (Bordeaux)
“TFR is a true paradigm shift in CML - About 25% of patients may become eligible, and long TKI exposure remains the strongest predictor of success.”

Key points:

• Definition & foundation: TFR is defined as maintaining molecular response after stopping TKIs; TFR requires sustained MR4/MR4.5 and high-quality, frequent PCR monitoring. 
• Predictive factors: The strongest predictors for successful TFR include duration of TKI therapy, duration of deep molecular response, early relapse kinetics, transcript type, NK-cell counts, and BCR::ABL positivity in granulocytes. 
• Relapses & safety: Most relapses occur within 6 months and respond rapidly and reliably to re-treatment; withdrawal syndrome is observed in ~25% and is usually mild and transient. 
• Long-term TFR: Some patients are detectable at a low level for decades - residual disease can persist without clinical consequence. Some are undetectable with a 15 year follow up, confirming a state of “operational cure”.
• Future directions: Defining biological predictors, and integrating dose-reduction to TFR strategies (e.g., DESTINY study) may improve TFR rates and safety. 

Q&A Highlights

Frontline treatment questions

• Family planning: For women with CML wishing to conceive, the preferred strategy is to achieve a deep response quickly, then stop the TKI before pregnancy.
• ASXL1 testing at diagnosis: Routine testing is not yet recommended by ELN/NCCN guidelines due to lack of prospective evidence, but mutations may justify earlier consideration of transplant after multi-TKI resistance.
• Imatinib → asciminib sequence: Switching from imatinib is possible, but “catch-up” strategies rarely achieve outcomes equivalent to starting with the most potent therapy first.

Treatment-Free remission questions

• Second TFR attempts: A second discontinuation attempt is feasible, with ~25% success, and is psychologically meaningful for patients whose first attempt failed.
• Which drug before second attempt? Re-treatment is generally recommended with the same TKI that previously achieved deep response, unless intolerance occurred.
• PCR access & costs: Frequent monitoring (especially first 6 months) is essential; availability and geographic distance remain barriers in some regions.
• Withdrawal symptoms: Typically managed with simple analgesics; symptoms are usually transient in nature.

 Additional clinical considerations

• Dose reductions: Lower-dose strategies may improve tolerability while maintaining efficacy; however, dose reduction should be used with careful consideration.
• Atypical transcripts: Asciminib should not be used in patients with rare transcripts such as b2a3/b3a3, which do not respond to myristoyl pocket inhibition.
• Long-term TFR biology: Duration of deep molecular response appears to correlate with recurrence risk reduction; a “ceiling” has not yet been defined.

🌟 Oral Abstract Session: CML clinical & epidemiological -
Decoding the molecular drivers of response and resistance

Chairs: Sin Tiong Ong (Singapore) - 
Naranie Shanmunagathan (Adelaide)
This session highlighted advances in understanding why patients with CML either respond well to TKIs, relapse after stopping therapy, or develop treatment failure. Across six presentations, scientists used genomic profiling, single-cell sequencing, transcriptomics, machine learning, clonal evolution studies, and integrated DNA/RNA MRD monitoring to decode mechanisms of resistance, relapse, and biological heterogeneity.
Key themes included ASXL1-driven risk, LSC signatures predicting relapse, genomic variants at diagnosis, AI-based TFR prediction, the distinct biology of minor BCR::ABL1, and DNA-based minimal residual disease (MRD) monitoring for safer TKI de-escalation.

Our key takeaways from the presentations:

Presentation 1:
Distinct patterns of mutant ASXL1 over time and their implications for treatment failure and BCR::ABL1 mutation development in newly diagnosed patients with CML in chronic phase treated with asciminib vs investigator-selected (IS) tyrosine kinase inhibitors in the ASC4FIRST study
Speaker: Susan Branford (Adelaide)
“Most ASXL1 clones presented at diagnosis were eradicated during therapy, but those that persisted or emerged were closely linked with poor outcomes.” – Susan Branford

Key points:

• ASXL1 prevalence: ASXL1 was the most frequent additional genomic alteration (11% baseline; 15% anytime), with most clones eradicated on therapy. 
• Risk patterns: Persistent or emergent ASXL1 variants were strongly associated with treatment failure and acquisition of BCR::ABL1 mutations. 
• Clonal interpretation: Emergent variants must be interpreted alongside BCR::ABL1 dynamics to distinguish CHIP clones, which lack leukemic relevance.
• Treatment comparison: ASXL1 patients without ASXL1 mutations had lower failure rates on asciminib, whereas ASXL1 positive patients had similar outcomes across both arms.
• Clinical implication: mutated ASXL1 is a risk factor, but not a treatment-selection biomarker between asciminib and IS-TKIs. 

Presentation 2:
A single-cell atlas of diagnostic bone marrow to uncover the origins of CML relapse following therapy cessation
Speaker: Vaidehi Krishnan (Singapore)
“LSC signatures at diagnosis can predict relapse after stopping TKIs.” – Vaidehi Krishnan

Key points:

• Predictive LSC states:Diagnostic leukemic stem cells (LSCs) already carry relapse-specific transcriptional signatures, independent of cell composition. 
• Two relapse subtypes: Relapse divides into MYC/mTOR-driven (proliferative) and TNFα/NF-κB-driven (immune) subtypes.
• Immune microenvironment: Relapse-I patients showed heightened cell - cell interactions, particularly TNFα signalling to LSCs. 
• Novel biomarkers: PRSS21 and SPAG6 emerged as candidate diagnostic TFR biomarkers requiring validation. 
• Clinical insight: Remission LSCs occupy a hybrid intermediate state, potentially explaining TKI sensitivity and durable TFR.

Presentation 3:
Somatic mutations at diagnosis in patients with chronic phase CML receiving frontline imatinib are associated with a higher rate of treatment failure: First analysis from the international CML Foundation (iCMLf) Genomics Alliance on the HARMONY platform

Presenter: Susan Branford (Adelaide)
“This is the largest genomic analysis of frontline imatinib-treated patients, and it highlights the clear clinical relevance of pathogenic variants at diagnosis.” – Susan Branford

Key points:

• Global data integration:The iCMLf Genomics Alliance, in partnership with the HARMONY big-data platform, aggregates international genomic and clinical datasets to enable the largest, standardised analysis of pathogenic variants in frontline CML, strengthening the evidence base for genomics-guided risk stratification. 
• Pathogenic variants: 20% of patients carried pathogenic mutations at diagnosis - most commonly ASXL1 (11%) - and these variants were associated with higher treatment failure, more BCR::ABL1 mutations, and lower MMR rates.
• Progression risk: Variant-positive patients showed a trend toward higher progression to AP/BP, though not always statistically significant due to mixed cohort selection.
• Validation:Variant frequencies and clinical associations were consistent with previously published single-centre studies, reinforcing the robustness of the pooled dataset.
• Future work: Ongoing expansion of the dataset and separation of retrospectively sequenced cases will support refined risk models and multivariable analyses.
  
  

Presentation 4:
A machine learning approach identifies a transcriptomic signature predicting treatment-free remission in chronic myeloid leukemia
Presenter: Vincent Alcazar (Lyon)
“To date, there is no tool capable of predicting treatment-free remission at the individual level — our model aims to change that.” – Vincent Alcazar
Key points:

• Predictive signature: A 50-gene blood-based signature predicted TFR with AUC 0.72–0.76 in external validation. 
• Biological pathways: High-signature patients showed glycolysis/ROS and antigen-processing activation, while low-signature patients displayed MYC targets, genomic instability, and T-cell exhaustion.
• Model independence: Prediction was independent of TKI duration and DMR duration, meeting current TFR prerequisites.
• Clinical application: On going prospective study to develop a tool for prediction at the individual level. 
• Future steps: Moving to targeted RNA sequencing for a practical clinical TFR test applicable across TKIs.

Presentation 5:
Molecular landscape and clonal evolution in minor versus major BCR::ABL1 chronic myeloid leukemia under tyrosine kinase inhibition: A Study from the French group fi-LMC
Presenter: Benjamin Podvin (Lille)
“Minor BCR::ABL1 CML is a rare subtype with a distinct clinico-biological and molecular profile.“ – Benjamin Podvin

Key points:

• Minor subtype: Minor BCR::ABL1 CML represents a biologically specific subtype with a myelomonocytic phenotype and deeper cytopenias. 
• High mutational burden: Minor cases showed frequent ASXL1, TET2, DNMT3A, and multi-hit epigenetic lesions, indicating a pre-mutated myeloid background.
• Clonal architecture: In ~1/3 of cases, the BCR::ABL1 fusion was a secondary event, arising on top of pre-existing myeloid clones. 
• Single-cell profilingMulti-omic single-cell profiling demonstrated broad myeloid involvement with sparing of T-cells and clarified primary vs secondary acquisition patterns. 
• Clinical relevance: Minor BCR::ABL1 behaves more like a CMML-like myeloid neoplasm, supporting tailored monitoring and therapeutic strategies. 

Presentation 6:
DNA-based MRD monitoring enhances risk stratification during TKI dose reduction in CML: Evidence from the clinical trial
Presenter: Katerina Machova Polakova (Prague)
“DNA-based MRD helps distinguish truly deep responders from those with silent residual disease —
a critical step for safe TKI tapering.” – Katerina Machova Polakova

Key points:

• MRD stratification model: Combined DNA and RNA MRD stratification accurately predicted relapse risk during both dose reduction and post-cessation. 
• Risk groups: Double-positive patients had the highest relapse rates; DNA+/RNA- showed intermediate risk; double-negative had ~90% relapse-free survival. 
• MRD dynamics: MRD status evolved over time, with RNA re-emergence during de-escalation serving as an early warning signal. 
• Clinical guidance: Double-negative patients may qualify for less intensive monitoring, while DNA-positive, RNA-negative, and red double-positive groups require adjusted dosing or delayed cessation.
• Clinical impact: DNA-guided de-escalation may reduce relapse, improving safety and precision in TKI stopping strategies.