Session Summaries from the ESH-iCMLf 28th Annual John Goldman Conference on CML: Biology and Therapy - Session 4

Scientific Session: Clinical trials

Chair: Ehab Atallah (Milwaukee)

This Scientific Session on clinical trials explored the evolving landscape of CML treatment, highlighting emerging tyrosine kinase inhibitors (TKIs), new clinical trial results and strategies to improve long-term patient outcomes. Presentations covered promising efficacy and safety data for novel ATP-competitive and allosteric inhibitors, the sustained benefits of asciminib, and patient-guided dose reduction as an approach to improving quality of life.

A central message was that the future of CML treatment is not only about achieving deeper molecular responses, but also about reducing long-term toxicity, supporting treatment-free remission (TFR) and individualising treatment according to patients’ needs and preferences. The session also addressed the importance of cognitive health and patient-reported outcomes as survival continues to improve.

Our key takeaways from the presentations:

Keynote presentation

New, newer and newest TKI: what is their role in the treatment of CML in the next decade
Speaker: Andreas Hochhaus (Jena)

“TFR should not be just a bystander effect, nice to have. It should be a very clear developmental objective in clinical trials.” - Andrea Hochhaus

Key points:

• Expectations: CML treatment goals have evolved from improving survival to achieving deep molecular responses, enabling TFR and improving quality of life. New TKIs must deliver meaningful improvements in both efficacy and tolerability.
• Safety: Long-term tolerability must become as important as efficacy, with new treatments minimising chronic and organ-specific toxicity while improving patients’ quality of life.
• Individualisation: Treatment strategies should reflect patients’ age, comorbidities, molecular characteristics and individual priorities, including TFR, fertility, independence and treatment burden.
• Trial design: Future trials should use contemporary active comparators, assess MMR and MR4.5 kinetics alongside patient-reported outcomes and provide sufficient follow-up to evaluate cumulative toxicity and durability of response.
• Biology and TFR: Prospective mutation profiling, clonal evolution and predefined pathways towards TFR should be incorporated into clinical trials. Eligibility should cover BCR::ABL1-positive CP-CML patients, including those without a detectable Philadelphia chromosome, where appropriate.
• Future standards: The ideal new TKI should prevent progression, deliver rapid and durable deep molecular responses, overcome relevant resistance mechanisms, minimise toxicity, improve quality of life, increase durable TFR and support an individualised lifetime treatment strategy at sustainable cost.

Presentation 1

ENABLE: Efficacy and safety of ELVN-001, a novel, selective ATP-competitive inhibitor of BCR::ABL1, in patients with previously treated chronic-phase (CP) chronic myeloid leukemia (CML)
Speaker: Dragana Milojkovic (London)

“Very impressive molecular responses in patients who often have no other treatment options.” - Dragana Milojkovic 

Key points:

• Mechanism of action: ELVN-001 is a highly selective ATP-competitive BCR::ABL1 inhibitor with activity against T315I and mutations associated with resistance to allosteric inhibitors, offering the potential for improved tolerability.
• Patient population: The phase 1 ENABLE study included 161 heavily pretreated patients with CP-CML, many previously treated with multiple TKIs, including asciminib and ponatinib.
• Dose: Based on safety, efficacy and pharmacokinetic/pharmacodynamic modelling, 80 mg once daily was selected as the optimal biological dose.
• Efficacy: At the selected dose in phase 1b, 61% of patients had MMR overall, with 48% achieving MMR by week 24. Molecular responses remained stable or improved in all phase 1b patients, including those with extensive prior treatment.
• Safety: ELVN-001 demonstrated favourable safety and tolerability, with low discontinuation rates due to adverse events and no evidence of increased cardiovascular toxicity to date.
• Outlook: Encouraging molecular responses, including after asciminib and ponatinib failure, support further development, with the pivotal phase 3 ENABLE-2 trial expected to initiate towards the end of 2026.

Presentation 2

Asciminib once or twice daily demonstrates sustained efficacy and favourable safety in patients with chronic myeloid leukemia resistant or intolerant to prior TKIs: End of study results from ASC4OPT
Speaker: Massimo Breccia (Rome)

“Asciminib demonstrated durable efficacy, favorable safety profile, and stable patient reported outcome.”  - Massimo Breccia 

Key points: 

• Dosing: ASC4OPT evaluated asciminib 40 mg twice daily and 80 mg once daily in patients with CP-CML previously treated with at least two TKIs.
• Efficacy: Asciminib demonstrated durable efficacy with 49.7% of patients in the main cohort achieving MMR at week 48 and sustained deep molecular responses through 144 weeks.
• Dose escalation: Among 42 patients whose dose was escalated to 200 mg once daily, 26.2% achieved MMR, with a manageable safety profile.
• Maintenance: Patients in the exploratory intolerance cohort who were already in MMR maintained or deepened their molecular responses on asciminib, regardless of dosing schedule.
• Quality of life: Patient-reported symptoms and daily functioning remained stable, with no deterioration in MDASI-CML scores over time.
• Safety: Both dosing regimens showed similar favourable safety profiles, with no new or unexpected safety signals and infrequent discontinuation due to adverse events, supporting asciminib as an effective long-term treatment option.

Presentation 3

Patient-guided dose reduction of tyrosine kinase inhibitors in chronic myeloid leukemia: final outcomes of the RODEO study
Speaker: Nienke Lokhorst (Nijmegen)

“Patient-guided dose reduction can serve as sort of a middle path towards TFR.” - Nienke Lokhorst 

Key points:

• Participation: The multicentre RODEO study investigated patient-guided TKI dose reduction in patients with stable molecular remission, using decision aids and shared decision-making to individualise treatment.
• Effectiveness: Following a stepwise median dose reduction of 50%, 9% of patients met the primary endpoint of intervention failure at 12 months, well below the pre-specified threshold of 19%.
• Recovery: Patients who lost MMR regained molecular response following dose re-escalation, supporting the feasibility of carefully monitored dose reduction.
• Quality of life: Health-related quality of life and treatment-related side effects improved after 12 months, particularly among patients experiencing greater symptom burden before dose reduction.
• Patient experience: Treatment adherence remained high, with strong beliefs in the necessity of TKI treatment, fewer concerns about medication and generally low decisional regret.
• Cost and implementation: Patient-guided dose reduction resulted in estimated mean annual TKI cost savings of over €5,700 per patient, supporting its consideration in clinical practice alongside shared decision-making.

Presentation 4

Updated efficacy and safety of TGRX-678, a novel STAMP inhibitor, in heavily pretreated TKI-resistant/intolerant CML patients from phase 1 study
Speaker: Qian Jiang (Beijing)

“TGRX-678 achieved a strong efficacy in both the CML chronic phase or the accelerated phase who had failed TKIs and multiple TKIs.” - Qian Jiang 

Key points:

• Mechanism of action: TGRX-678 is a novel STAMP inhibitor targeting the ABL1 myristoyl pocket, investigated as an alternative for patients with resistance or intolerance to previous TKIs.
• Patient population: The phase 1 study included 180 heavily pretreated patients with chronic- or accelerated-phase CML, including patients with T315I mutations and resistance to multiple previous TKIs.
• Efficacy: In CP patients at three years, more than half achieved a CCyR and more than 40% achieved MMR, with most responses durable. In AP, 28% achieved a CCyR and while these were durable, most patients who achieved MMR subsequently lost it.
• Resistance: Activity was observed in patients with T315I mutations and following treatment with third-generation TKIs or STAMP inhibitors, suggesting potential utility in difficult-to-treat populations.
• Dose optimisation: Complete cytogenetic and major molecular responses were observed in lower-dose cohorts. No clear dose-response relationship was seen, supporting further exploration of lower doses in T315I-mutated patients.
• Biomarkers: Exploratory genomic profiling identified RUNX1 variants and selected pathway-level alterations as potential adverse biomarkers, warranting further investigation for molecular risk stratification. 

Presentation 5

Evaluation of cognitive functions in patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy
Speaker: Seymen Dobur (Istanbul)

“At this stage, we cannot identify clear effects specific to CML or TKI treatment.” - Seymen Dobur 

Key points:

• Rationale: With improving survival in CML, potential long-term cognitive difficulties have become an important aspect of patient wellbeing, particularly among patients receiving prolonged TKI therapy.
• Study design: The ongoing study compared cognitive performance in patients with TKI-treated CML, Philadelphia-negative myeloproliferative neoplasms and healthy controls.
• Findings: No statistically significant group differences remained after correction for multiple comparisons. CML and MPN patients performed similarly, although these findings do not establish equivalence or exclude potential cognitive effects.
• Language: MoCA language scores were numerically lower in CML patients than healthy controls (1.5 versus 2.3 out of 3), but the difference was not statistically significant after correction.
• Executive function: Trail Making Test Part B non-completion was numerically more frequent in CML patients (9/34) than healthy controls (1/15), highlighting the importance of considering test completion alongside completion time.
• Next steps: Continued recruitment, larger comparison groups, age- and education-adjusted normative scores and longitudinal follow-up are needed to clarify whether these exploratory patterns persist and whether cognitive function changes over time.