We're bringing you highlights from the conference with a summary of selected scientific sessions. Check back over the next couple of days for updates on more sessions.

 
Day 4 - Monday 9th December 2024

Oral Session: Chronic Myeloid Leukemia: Clinical and Epidemiological – Alternative Laboratory Predictors of Outcome

This session explored advanced laboratory predictors of outcomes in CML, shedding light on genetic, immunological, and cellular factors influencing treatment response, resistance, and remission.

Presentation 1:

Strong Association between Cancer Gene Variants at Diagnosis, Especially ASXL1, and Emergence of Kinase Domain Mutation-Driven Resistance in CML Patients Despite Frontline Treatment with More Potent BCR::ABL1 Inhibitors

Speaker: Dr. Naranie Shanmuganathan (Adelaide)

“ASXL1 variants were associated with inferior outcomes, despite treatment with potent TKIs.” – Naranie Shanmuganathan

Key points:

• Cancer variant prevalence: 20% of patients treated with potent TKIs had cancer variants at diagnosis, with ASXL1 being the most frequent (8%).
• Inferior molecular responses: Patients with ASXL1 mutations had significantly lower 12-month MMR rates and higher kinase domain mutation acquisition rates at two years.
• Resistance patterns: ASXL1-mutated patients faced a 29% risk of developing kinase domain mutations, often driving treatment resistance.
• Comparison of TKIs: ASXL1 mutations showed poorer outcomes across all TKI types, with failure-free survival significantly impacted.
• Future strategies: Results suggest the need for combination therapies to improve outcomes in high-risk patients with ASXL1 mutations.

Presentation 2:

Molecular Outcome of Chronic Myeloid Leukemia-Affected Patients Not in Deep Molecular Response: The “Others” from the GIMEMA Labnet Network

Speaker: Prof. Fabio Stagno (Italy)

“The GIMEMA LabNet-CML network harmonises molecular diagnostics across Italy, ensuring equitable access to testing.” – Fabio Stagno

Key points:

• Stability of response: 32% of patients maintained a stable MR3/MR2 response at 48 months, while 66% progressed to a deep molecular response.
• Early fluctuations: Molecular fluctuations in BCR::ABL1 transcripts were predictive of instability and relapse risk.
• Uniform diagnostic tools: The GIMEMA LabNet provided harmonized molecular diagnostic access for over 9,000 patients across Italy.
• Age-independent outcomes: No significant differences in molecular responses were observed between age groups.
• Clinical utility: Molecular response monitoring using the GIMEMA framework aids in identifying patients at risk of poor outcomes.

Presentation 3:

Increased Inflammatory Cytokines in Plasma Are Associated with Sustained Treatment-Free Remission in Chronic Myeloid Leukemia

Speaker: Dr. David Ross (Adelaide)

“Patients with a ‘hot’ cytokine profile had significantly better treatment-free remission outcomes.” – David Ross

Key points:

• Cytokine clustering: Patients were categorised into “hot” (high cytokine levels) and “cold” (low cytokine levels) groups, with 73% of hot patients achieving TFR.
• Biomarker development: A six-cytokine panel predicted TFR outcomes across Australian and U.S. cohorts with high consistency.
• Independence of clinical features: Cytokine profiles were independent predictors of TFR, unaffected by traditional factors like treatment duration or transcript type.
• Validation across cohorts: Both Australian and U.S. cohorts displayed similar cytokine clustering patterns and predictive outcomes.
• Simplified analysis potential: Findings suggest that streamlined cytokine testing could improve TFR prediction accuracy.

Presentation 4:

Common Lymphoid Progenitors and B Cell Subpopulations in the Bone Marrow Are Predictive of Treatment-Free Remission in Chronic Myeloid Leukemia

Speaker: Dr. Shaun Patterson (UK)

“Memory B-cell expansion and skewed progenitor differentiation may be critical for predicting relapse.” – Shaun Patterson

Key points:

• Progenitor differences: Reduced common lymphoid progenitors (CLPs) and altered differentiation patterns were observed in relapsing patients.
• B-cell subtypes: Increased activated switched memory B-cells were a hallmark of relapsing patients, reflecting immune perturbations.
• Metabolic insights: Downregulated mTORC1 signaling in relapsing patients indicated potential metabolic disruptions.
• Predictive modeling: A ratio of naïve to memory B-cells emerged as a strong predictive marker for TFR.
• Therapeutic implications: Findings highlight immune modulation as a potential strategy for improving TFR outcomes.

Presentation 5:

FATE and Role of Peripheral Blood CD26+ Leukemia Stem Cells at Diagnosis in Chronic Myeloid Leukemia Patients: FINAL Results of Prospective Flowers Study

Speaker: Prof. Monica Bocchia (Siena)

“The CD26+ leukemia stem cell burden at diagnosis is a prognostic indicator of treatment outcomes.” – Monica Bocchia

Key points:

• Stem cell presence: CD26+ leukemia stem cells were detectable in 100% of patients at diagnosis, with high variability in numbers.
• Decline with treatment: CD26+ stem cells rapidly decreased during TKI therapy but persisted at low levels over time.
• Prognostic value: High CD26+ cell counts at diagnosis correlated with poorer molecular responses and higher treatment failure rates.
• TFR persistence: Persistent CD26+ cells did not prevent successful TFR in some patients, suggesting immune system control mechanisms.
• Clinical application: CD26+ cell quantification offers a simple, rapid biomarker for predicting TKI response and outcomes.

Presentation 6:

Longitudinal Clonal Tracking Reveals That Early and Sensitive Detection of Blood Cancer-Related Gene Variants in Patients with Chronic Myeloid Leukemia Predicts Treatment Failure

Speaker: Prof. Susan Branford (Australia)

“Early detection of cancer variants may enable proactive intervention to prevent treatment failure.” – Susan Branford

Key points:

• Variant co-occurrence: 83% of patients with treatment failure had cancer variants, often preceding kinase domain mutations by nine months.
• Clonal complexity: Multiple cancer gene variants were detected, with ASXL1 being prevalent in chronic phase and other genes dominating in blast phase.
• Dynamic evolution: Clonal tracking revealed convergent evolution, clonal competition, and mutation emergence tied to treatment changes.
• Predictive insights: Early cancer variant detection offered a proactive avenue for mutation management and treatment adjustment.
• Targeted therapies: Findings highlight the potential for combined therapies targeting both BCR::ABL1 and associated cancer variants for improved outcomes.
  
  

Day 3 - Sunday 8th December 2024 

Oral Session: Chronic myeloid leukemia – Novel molecules in clinical practice 

This oral session provided an in-depth exploration of emerging therapeutic strategies and novel agents in CML. The presentations highlighted advancements in targeting resistant mutations, optimising sequencing strategies, and enhancing treatment-free remission potential while addressing safety and tolerability challenges.

Our key takeaways from the presentations:

Presentation 1:
Asciminib demonstrated favourable safety and tolerability compared with each investigator-selected tyrosine kinase inhibitor (IS TKI) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) in the Pivotal Phase 3 ASC4FIRST Study
Speaker: Professor Jorge Cortes (Augusta)
“All subsets of patients, regardless of risk classification, showed better outcomes with asciminib."
- Jorge Cortes

Key points:

• Superior efficacy: Asciminib showed significantly higher rates of major molecular response (MMR) and deeper molecular responses (MR4, MR4.5) compared to other TKIs in the 96-week data. The MMR rate exceeded 75% across all treatment arms.
• Sustained response: Response curves continued to diverge in favour of asciminib, with no sign of plateauing, showcasing long-term efficacy advantages.
• Lower discontinuation rates: Only 17.9% of patients discontinued asciminib due to adverse events, compared to 38.2% in the control arms, highlighting better tolerability.
• Safety profile: Fewer arterial occlusive events and grade 3 and 4 adverse events were reported with asciminib compared to imatinib and second-generation TKIs.
• Study conclusion: Asciminib’s favourable benefit-risk profile compared with all IS-TKI’s, imatinib and 2^nd generation TKIs in patients with newly diagnosed CML-CP, reinforces the use of asciminib as a standard of care for this patient population

Presentation 2:
Update of the Ascend-CML study of frontline asciminib: High rate of optimal response and resistance due to mutation is rare
Speaker: A/Professor David Yeung (Adelaide)
“Deep molecular responses continued to improve even after three years, showcasing the long-term potential of asciminib.”– David Yeung

Key points:

• High efficacy in newly diagnosed patients: The ASCEND trial reported an 87% cumulative incidence of MMR at 24 months and deep molecular responses (MR4 and MR4.5) of 73% and 55%, respectively, at three years.
• Adverse events concentrated in year 1: Grade 3 and 4 lipase and amylase elevations occurred predominantly in the first year, with minimal new toxicities in subsequent years.
• Mutation insights: Mutations in BCR::ABL1, particularly at residues 337 and 244, were the most common resistance mechanisms, but responses were salvageable with subsequent therapies like dasatinib.
• Escalation benefits: Dose escalation for patients failing to meet molecular milestones led to a median BCR::ABL1 log reduction of 0.4, improving outcomes in warning and failure categories.
• Study highlight: The trial's long-term follow-up demonstrates sustained safety and efficacy, with no new arterial occlusive events reported in three years.

Presentation 3:
Safety and efficacy of TGRX-678, a potent BCR::ABL1 allosteric inhibitor, in patients with tyrosine kinase inhibitor resistant and/or intolerant chronic myeloid leukemia: Updated results of phase 1 study TGRX-678-1001
Presenter: Professor Qian Jiang (Beijing)
"The absence of significant new mutations with TGRX-678 is a critical finding in resistant CML therapy."– Qian Jiang

 Key points:

• Promising efficacy across mutations: TGRX-678 achieved complete hematologic remission in 88% of chronic-phase patients and major cytogenetic responses in nearly 50%. MR4 and MR4.5 were observed in approximately 30% of patients over time.
• Accelerated phase responses: Among accelerated-phase patients, 90% achieved major hematologic responses, with 20% reaching MMR, demonstrating efficacy in advanced disease.
• Safety profile: Grade 3 and 4 thrombocytopenia and neutropenia were the most common adverse events, while non-hematologic toxicities like hyperlipidaemia were mild and manageable.
• Treatment durability: At the two-year follow-up, 95% of chronic-phase patients remained progression-free, with an overall survival rate of 80% in the accelerated-phase cohort.
• Implication: TGRX-678 offers a viable option for heavily pretreated patients, including those with T315I mutations, with limited new mutations detected during therapy.

Presentation 4:
18-months follow-up of the trial of imatinib after ponatinib induction (TIPI) in the front-line treatment of chronic phase CML setting
Presenter: Dr Delphine Réa (Paris)
" A strong induction phase followed by lighter maintenance could redefine frontline CML treatment." – Delphine Réa

Key points:

• Ponatinib-induction results: The trial reported MMR in 57% of patients at six months and 72% at 18 months. Deep molecular responses (MR4 and MR4.5) reached 45% and 21%, respectively, at 18 months.
• Transitioning to imatinib: After ponatinib induction, molecular responses were maintained or deepened during imatinib maintenance, with only 7% of patients losing MMR.
• Mutation control: BCR::ABL1 mutation analysis revealed three mutations, two of which emerged during imatinib maintenance. None were associated with T315I.
• Cardiovascular safety: Grade 3 and 4 cardiovascular events occurred in 4.5% of patients during ponatinib induction, but no significant events were reported during imatinib maintenance.
• Study implications: This strategy may provide a safer path to treatment-free remission, particularly for patients at risk of mutation-driven resistance.

Presentation 5:
Efficacy and safety of asciminib in chronic myeloid leukemia in chronic-phase: Interim results from the phase 2 ASC2ESCALATE trial in the cohort of patients after 1 prior tyrosine kinase inhibitor
Presenter: Professor Jorge Cortes (Augusta)
" The second-line efficacy of asciminib reinforces its potential across multiple treatment lines."
– Jorge Cortes

Key points:

• High efficacy after TKI failure: The study reported an MMR rate of 43% by 12 months, with deep molecular responses (MR4) in 25% of patients at six months.
• Low dose escalation requirement: Only two patients required dose escalation due to suboptimal response, highlighting the drug’s potency even at standard dosing.
• Robust responses across subgroups: Both TKI-intolerant and resistant patients demonstrated strong responses, with efficacy rates exceeding 40%, even among those with >10% transcripts at baseline.
• Safety and tolerability: Only one patient discontinued due to adverse events, with the most common side effects being mild gastrointestinal symptoms and hypertension.
• Potential second-line standard: These results solidify asciminib’s role in second-line therapy, with consistent efficacy and a favourable safety profile.

Presentation 6:
Olverembatinib as second-line therapy in patients with chronic-phase chronic myeloid leukemia
Presenter: Dr Li Weiming (Wuhan)
"The efficacy in TKI-resistant cases demonstrates its robust potential as a second-line agent." – Li Weiming

 Key points:

• Strong efficacy post-TKI failure: In 33 evaluable patients, complete cytogenetic response (CCyR) was achieved in 74%, and MMR in 41%. Among those resistant to second-generation TKIs, CCyR reached 80%, with 43% achieving MMR.
• Baseline mutation impacts: Patients with mutations other than T315I showed better outcomes, achieving CCyR in 85.7% and MMR in 55.6%.
• Durable responses: 95% progression-free survival (PFS) at two years in chronic-phase patients, with no new mutations detected during treatment.
• Safety profile: Grade 3 and 4 hematologic toxicities (e.g., thrombocytopenia) were manageable, and no arterial occlusive events were reported.
• Clinical potential: Olverembatinib emerges as a viable option for second-line therapy, particularly for patients with resistant mutations and limited options.
  
  

Day 1: Friday 6th December 2024

Satellite Symposium: What clinicians want to know: Addressing current questions and controversies in the management of CML

Supported by an educational grant from Novartis

This Satellite Symposium provided a comprehensive exploration of CML therapy, focusing on advancements in resistance mechanisms, strategies to optimise treatment-free remission, and addressing tolerability and practical challenges in therapy.

The content was developed based on a survey conducted among general medical oncologists prior to the meeting, with questions submitted during the live Q&A session guiding the discussions.

Our key takeaways from the presentations:

Module 1:
Up-front therapy for chronic myeloid leukemia (CML)
Speaker: Professor Andreas Hochhaus (Jena)
“Additional chromosomal aberrations and specific mutations can influence prognosis and treatment response, underscoring the need for personalised therapy strategies in CML management.”
- Andreas Hochhaus

• Evolution of treatment goals:
  • Initial treatment goals focused on achieving complete cytogenetic remission and progression-free survival.
  • Today, deep molecular response (DMR) is prioritised to enable treatment-free remission (TFR), improving both outcomes and patient quality of life.
  • Balancing efficacy with reduced long-term side effects has become central to defining therapy success.

• Therapeutic landscape:
  • Asciminib: A novel allosteric inhibitor targeting the myristoyl pocket of BCR-ABL, offers a distinct mode of action compared to ATP-competitive TKIs.
  • Clinical trial evidence: ASCEMBL study demonstrated asciminib’s superior efficacy in early molecular response and overall tolerability versus bosutinib.
  • ASCEND trial update: Confirmed asciminib’s effectiveness across various risk groups, as recently presented in Blood.
  • Combination therapies involving asciminib and ATP-competitive inhibitors (e.g., nilotinib, dasatinib) are under investigation to enhance efficacy in resistant mutations
    (e.g., FASCINATION study).
    
    
• Safety and tolerability:
  • Cardiovascular risks (e.g., nilotinib) and pleural effusions (e.g., dasatinib) are key considerations. The DASA-HIT trial showed reduced pleural effusions with a five-day dasatinib schedule while maintaining efficacy.
  • Asciminib’s selective inhibition limits off-target effects, contributing to its superior tolerability and lower discontinuation rates due to adverse events.
    
    
• Role of genetic factors:
  • Patients with high-risk chromosomal aberrations (e.g., ASXL1 mutations) exhibit inferior responses to some TKIs, necessitating genetic profiling for personalised therapy.
  • FASCINATION study: Demonstrated that combining asciminib with ATP-competitive TKIs significantly improves molecular responses for ASXL1-mutated patients compared to nilotinib monotherapy.
  • ASXL1 mutations, identified in the TIGER study, showed a negative impact on nilotinib response.
    
    
• Recommendations and monitoring:
  • NCCN guidelines endorse asciminib as a first-line therapy across all risk groups due to its robust efficacy and safety profile.
  • Monitoring every three months during the early treatment phase is recommended, transitioning to less frequent evaluations once DMR is sustained.
  • PCR monitoring has the potential to improve compliance by providing tangible response data to patients.
    
    
• Challenges and future directions:
  • Resistance mechanisms, including mutations outside the myristoyl pocket, are under active investigation. Adjustments like dose escalation or switching TKIs are being explored based on clinical trial findings (e.g., START trial).
  • Combination therapies are being refined in studies like FASCINATION and START, particularly to counteract resistant mutations.

Module 2:
Management of relapsed CML, including in patients with T315I mutation
Speaker: Professor Michael Mauro (New York)
“Mutational analysis is central—resistance isn’t a blanket issue; it’s about identifying which drugs will work for which mutations and tailoring treatment accordingly.”– Michael Mauro

• Assessing treatment failure:
  • Early identification of suboptimal response or resistance involves evaluating adherence, drug interactions, and mutation analysis.
  • Guidelines emphasise prompt mutation profiling and therapy adjustment for patients failing to achieve molecular response milestones (e.g., MMR by six months).
    
    
• Mutational analysis and resistance mechanisms:
  • Point mutations in the ATP-binding or myristoyl pockets can lead to drug resistance, necessitating tailored treatment strategies.
  • Asciminib shows efficacy in overcoming resistance linked to ATP-binding mutations but may face challenges with newer mutations.
    
    
• Advanced disease management:
  • Ponatinib: Effective for T315I mutations, as evidenced in the PACE trial, but requires vigilant cardiovascular monitoring due to arterial occlusive risks.
  • Asciminib: Superior to bosutinib in the ASCEMBL trial, with promising results even in heavily pretreated patients, but requires attention to mutation-specific efficacy and safety concerns.
  • Transplant remains a vital option for selected high-risk cases with advanced disease or refractory mutations.
    
    
• Emerging therapies and future directions:
  • New ATP-competitive agents like olverembatinib and allosteric inhibitors like TERN701 are showing promise in clinical trials for resistant mutations and later-line therapy.
  • Sequencing TKIs based on resistance mechanisms and individual patient profiles is becoming more nuanced, particularly for T315I-positive and multi-resistant cases.

Module 3:
Tolerability and other practical issues with commonly employed CML therapies

Presenter: Professor Douglas Smith (Baltimore)

"Each of these TKIs tends to have a slightly unique profile. While there are common side effects across all of them, such as fatigue or liver function abnormalities, tolerability issues can vary significantly. This highlights the importance of understanding these differences to personalise therapy effectively for each patient."– Douglas Smith

• Tolerability and side effects profiles
  • Early side effects include myelosuppression, liver function abnormalities, and fatigue, requiring frequent monitoring.
  • Long-term side effects such as cardiovascular risks, muscle cramping, and chronic fatigue can impact daily life and treatment adherence.
  • Trials like IRIS and ENEST highlight differences in toxicity profiles between imatinib and second-generation TKIs (dasatinib, nilotinib), with newer-generation options often offering specific tolerability advantages. Asciminib, studied in other trials, presents a distinct and favorable safety profile compared to earlier TKIs.
    
    
• Treatment adjustments
  • Side effects like pleural effusions and nephrotic syndrome with dasatinib are managed with dose reduction or structured treatment gaps.
  • Combination therapy with asciminib and ATP-competitive TKIs, as demonstrated in the FASCINATION study, improves molecular responses for patients with ASXL1 mutations, achieving a 75% MR4 rate at 12 months.
  • The SWOG S1712 trial shows ruxolitinib combined with TKIs enhances deep molecular response rates and TFR eligibility, with manageable low-grade non-hematologic adverse events.
    
    
• Personalised therapy
  • TKIs are chosen based on patient-specific factors, such as comorbidities and cardiovascular risks, and the side effect profiles of available drugs.
  • Asciminib's reduced risk of cardiovascular events and low-grade side effects compared to first- and second-generation TKIs, was highlighted as a potential new standard for first-line therapy, pending EMA approval in Europe.
  • Clinical data suggest that broader genomic profiling could better predict resistance and guide treatment selection, emphasising the integration of mutation analysis in clinical practice.
    
    
• Future directions
  • Mutations driving resistance to asciminib occur in clusters across the kinase domain, emphasising the need for mutation-specific therapeutic strategies.
  • Single-cell RNA sequencing identifies leukemic stem cell signatures correlating with relapse and TFR outcomes, offering potential predictive biomarkers.
  • Immunotherapies for CML, including targeting leukemic stem cells, are under investigation, focusing on resistant cases and high-risk patients.
  • Continued monitoring for late-stage complications and long-term safety data will inform the optimal use of new and existing therapies.