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.

🌟 Scientific Session: Top scoring abstracts 🌟

This Scientific Session presented six top-scoring abstracts selected by the meeting organisers. These presentations highlighted key advancements in understanding the mechanisms of disease progression, the clinical implications of mutations, and factors driving relapse after CML cessation.

During this session, the best biological abstract was awarded to Daniele Sarnello for his work on BNIP3 as a potential therapeutic target in hypoxic CML cells, while the best clinical abstract went to Kendra Sweet, who presented results of the SWOG trial on the addition of ruxolitinib to BCR::ABL1 TKIs.

Our key takeaways from the presentations:

Presentation 1:
Investigation of Resistance Mechanisms of the Allosteric BCR::ABL1 Inhibitor Asciminib
Speaker: Inga B. Leske (Marburg)
“Mutations not only occur in the myristate pocket but are spread across the kinase domain, leading to distinct resistance mechanisms.” – Inga B. Leske
Key points:

• Asciminib mechanism of action: Asciminib is the first allosteric BCR::ABL1 inhibitor, working by locking the BCR::ABL fusion protein in an inactive state through interactions with the kinase domain.
• Mutation clusters linked to resistance: Resistance mechanisms are tied to various mutations across the kinase domain, with four identified clusters near the myristate pocket, ATP-binding pocket, SH2-SH3 domain, and kinase N-lobe.
• Binding affinity and resistance: Mutations in the myristate pocket significantly reduce asciminib’s binding affinity, while others exhibit resistance without altering the binding affinity.
• Therapy adjustment for resistance: Different resistance mechanisms require varied treatment adjustments, such as dose escalation or switching to ATP-competitive TKIs depending on the mutation.

Presentation 2:
Clinical Impact of ASXL1 Mutations in CML Patients Treated with Asciminib in Combination with ATP-Competing Tyrosine Kinase Inhibitors
Speaker: Thomas Ernst (Jena)
“The combination of asciminib with ATP-competing drugs might be able to overcome the negative impact of ASXL1 mutations regarding molecular response.” – Thomas Ernst
Key points:

• Frequent ASXL1 mutations in CML patients: ASXL1 mutations are common in CML patients, often occurring alongside BCR-ABL mutations, either as primary or secondary events.
• Negative impact on nilotinib response: In the TIGER study, patients with ASXL1 mutations had significantly inferior molecular responses to nilotinib treatment compared to those without mutations.
• Positive response with asciminib combinations: In the FASCINATION study, combining asciminib with ATP-competitive TKIs (e.g., nilotinib, dasatinib, imatinib) improved molecular responses for patients with ASXL1 mutations, showing a promising alternative therapy.
• High rate of MR4 in asciminib-treated patients: 75% of patients with ASXL1 mutations achieved MR4 at 12 months in the FASCINATION study, contrasting with the poorer results from the TIGER study with nilotinib alone.
• Further trials required: Although the results are promising, further clinical trials are needed to determine the best treatment strategy for CML patients with ASXL1 mutations.

Presentation 3: – Best biological abstract
BNIP3 is Required for Hypoxia-Induced Reductive Glutamine Carboxylation in Leukemic Cells
Presenter: Daniele Sarnello (Glasgow) 
"Removing BNIP3 not only impairs mitophagy but also disrupts the glutamine metabolic switch, leading to dysfunctional mitochondria, reduced cell growth, and enhanced cell death in hypoxic conditions." – Daniele Sarnello
Key points:

• Metabolic switch: Leukemic stem cells (LSCs) adapt to the hypoxic bone marrow niche by switching from glucose oxidation to glutamine metabolism to fuel the TCA cycle.
• Reductive carboxylation: Hypoxia induces reductive glutamine carboxylation, promoting the accumulation of fumarate, which stabilizes hypoxic signalling and supports cell survival.
• BNIP3 function: BNIP3, a mitochondrial receptor, plays a key role in maintaining mitochondrial health by driving mitophagy under hypoxic conditions.
• BNIP3 knockout: BNIP3 knockout leads to impaired mitochondrial turnover, dysfunctional mitochondria, and reduced glutamine flux, compromising cell survival in hypoxia.
• Therapeutic target: In a xenograft model, BNIP3 knockout cells showed reduced tumour growth and longer survival, suggesting BNIP3 as a potential therapeutic target in hypoxic CML cells.

Presentation 4:
The Negative Impact of Variants in Blood-Cancer Related Genes for Frontline Imatinib Treated Patients is Not Overcome by Frontline Treatment with More Potent BCR::ABL1 Inhibitors
Presenter: Susan Brandford (Adelaide)
"Mutated ASXL1 at diagnosis not only affects response to frontline treatment but also impacts outcomes with more potent BCR::ABL1 inhibitors." – Susan Branford
Key Points:

• Variants: A study identified cancer gene variants in 33% of patients, with 19.7% having variants related to cancer genes and 18.1% having Philadelphia-associated rearrangements.
• Impact on treatment: More potent BCR::ABL1 inhibitors (dasatinib, nilotinib, and asiminib) did not overcome the adverse effects of cancer gene variants on failure-free survival and molecular responses.
• ASXL1 mutations: ASXL1 was the most frequently mutated gene, associated with poor outcomes and resistance to BCR::ABL1 inhibitors.
• Clonal relationships: Inferred clonal relationships revealed complex interactions between BCR::ABL1 mutations and additional genetic variants, highlighting the evolving dynamics of leukemic cells during treatment.
• Clinical implications: Findings suggest the need for broader genomic profiling in diagnosis, including both myeloid and lymphoid genes, to better understand and predict treatment responses.

Presentation 5: – Best clinical abstract
A Randomized Trial of Ruxolitinib Addition to TKIs for Chronic Myeloid Leukemia (SWOG S1712)
Presenter: Kendra Sweet (Tampa, Florida) 
"The ultimate goal is to achieve more patients eligible for TKI cessation, thereby improving long-term patient outcomes." – Kendra Sweet
Key points:

• Study design: This phase 2 trial evaluated the combination of ruxolitinib and TKIs versus TKIs alone in chronic phase CML patients with detectable molecular disease after at least 12 months of TKI treatment.
• Primary outcome: The study met its primary endpoint, showing that 14% of patients receiving ruxolitinib achieved MR 4.5 at 12 months compared to 3% in the TKI-only group, with ruxolitinib also improving MR 4.0 rates (46% vs. 26%).
• TFR eligibility: After two years, 29% of patients in the ruxolitinib group were eligible for TKI discontinuation according to NCCN criteria, compared to 11% in the TKI-only group.
• Adverse events: Ruxolitinib was associated with higher rates of non-hematologic adverse events (e.g., fatigue, nausea) but was generally well-tolerated, with most events being low-grade.
• Conclusion: The addition of ruxolitinib to TKIs significantly enhances deep molecular response rates and eligibility for TKI cessation, suggesting potential benefits for long-term outcomes in CML patients.

Presentation 6: Deciphering the Biology of Leukemic Stem Cells Driving CML Relapse After TKI Cessation
Presenter: Vaidehi Krishnan (Singapore)
“We started asking, can we have a leukemic stem cell signature at the time of diagnosis that correlates with relapse? And the answer is yes, because it looks like there are three distinct stem cell states.” – Vaidehi Krishnan
Key points:

• Study objective: Her research investigates the gene expression signatures of leukemic stem cells (LSCs) at diagnosis to predict treatment-free remission (TFR) outcomes after TKI cessation, utilizing single-cell analysis of bone marrow samples.
• Findings on stem cell heterogeneity: The study identifies three distinct stem cell states in CML patients, with relapse patients showing heightened activation of pathways associated with relapse, such as IL-2-STAT5 signalling.
• Methodology: A single-cell RNA sequencing analysis of bone marrow samples from 26 CML patients revealed 84,000 CD34-positive cells, categorized into three stem cell types based on expression levels and lineage markers.
• Biomarker discovery: A membrane-associated protease was identified as a potential biomarker for relapse, displaying BCR-ABL dependence and elevated expression in relapsed samples.
• Future directions: The researchers plan to conduct follow-up studies with post-TKI samples to explore changes in stem cell states and validate their findings through collaboration with other research groups.
  
  

🌟 Scientific Session: New Drugs and Combinations 🌟

Chair: Tim Brümmendorf (Aachen)

This session explored the development of novel drugs and their potential integration into current treatment algorithms for CML. The discussions centered around the latest data on third-generation TKIs, allosteric inhibitors, and combinations of therapies to overcome resistance mechanisms and improve patient outcomes. The five presentations highlighted advances in new drug formulations, promising treatment combinations, and long-term data on molecular responses.

Key highlights from the session:

Presentation 1:
Incorporating New Drugs in Current Treatment Algorithms
Speaker: Michael Mauro (New York)
“We’ve come a long way, but there are still exciting new drugs under development to address current treatment gaps.”

Key points:

• New drug formulations: New forms of dasatinib and imatinib are being developed to address issues like gut toxicity and variable absorption rates, potentially improving patient tolerance and drug efficacy.
• Alternate inhibitors: Ongoing development of ATP-competitive and allosteric inhibitors is showing promise, with several new candidates currently in clinical trials.
• Resistance mechanisms: As CML treatment evolves, the importance of understanding and managing resistance mechanisms is critical, especially as new drugs come into play.

Presentation 2:
Olverembatinib (HQP1351) overcomes ponatinib and/or asciminib resistance in patients with heavily pretreated/refractory chronic myeloid leukemia (CML)
Speaker: Vivian G. Oehler (Seattle)
“Olverembatinib shows potent activity even in patients pre-treated with multiple TKIs, providing a valuable option for resistant CML cases.”

Key points:

• T315I mutation: Olverembatinib demonstrated significant activity in patients with the T315I mutation, achieving complete cytogenetic response in 61% and major molecular response in 46% of chronic-phase patients.
• Safety profile: The drug was generally well tolerated, though some hematologic and non-hematologic adverse events were noted, including elevated lipase levels and neutropenia.
  
  

Presentation 3:
Preliminary safety and efficacy of ELVN-001, a selective active site inhibitor of BCR::ABL1 in CML
Speaker: Fabian Lang (Frankfurt)
“We are seeing encouraging results with novel allosteric inhibitors, especially in cases resistant to ATP-competitive TKIs.”

Key points:

• Allosteric inhibitors: New agents like ELVN-001, a highly selective allosteric inhibitor, are advancing in clinical trials, showing potential for patients with resistant CML.
• Combination therapies: The use of allosteric inhibitors alongside ATP-competitive inhibitors is being investigated to enhance treatment efficacy and overcome resistance.
  
  

Presentation 4:
Asciminib provides long-term, durable molecular responses and a consistent safety profile in patients with T315I-mutated CML-CP with up to approximately 6 years’ exposure: final analysis from a phase 1 trial
Speaker: Jorge Cortes (Augusta)
“Asciminib’s durable efficacy and consistent safety profile make it a promising option for patients with T315I mutations, particularly those who have exhausted other treatment options.”

Key points:

• Durable molecular response: Asciminib has shown durable major molecular responses in approximately 50% of patients with the T315I mutation, with a high likelihood of maintaining response over time.
• Long-term safety: The safety profile remains consistent over six years, with manageable adverse events such as mild hematologic toxicities and lipase elevation, supporting asciminib’s long-term use.
  
  

Presentation 5:
Ponatinib and 5-Azacytidine for the treatment of chronic myelogenous leukemia in myeloid blast crisis. Results of the PONAZA trial (NCT03895671)
Speaker: Philippe Rousselot (Versailles)
“Combining Ponatinib with Azacitidine has shown high response rates in blast crisis CML, offering a well-tolerated treatment option.”

Key points:

• High response rates: 80% of patients achieved a complete hematologic response, with a two-year overall survival rate of 65%.
• Transplantation: Patients who achieved remission were able to proceed to transplantation, demonstrating the combination’s potential as a bridge to curative treatment.
  
  

Conclusion
The session highlighted significant progress in CML treatment, showcasing new drugs and combinations that address resistance mechanisms and improve outcomes, especially in patients with advanced disease or those harboring difficult mutations like T315I. As these novel therapies continue to evolve, ongoing trials will provide more insights into their roles within current treatment paradigms, offering hope for more durable responses and manageable safety profiles.

🌟 Scientific Session: Real World and Pediatric CML 🌟

This session focused on the differences between clinical trial outcomes and real-world data in CML treatment, as well as the unique challenges faced by pediatric patients undergoing TKI therapy. Key findings from registries were discussed, highlighting how treatment outcomes in real-world settings often differ from controlled clinical environments, the impact of TKI therapy on pediatric growth, sex-related differences in treatment outcomes, and a comparative analysis of asciminib and ponatinib in later-line treatments for CML patients.

Presentation 1:
Real-World Data in CML : does it match what we know from clinical trials?
Speaker: Valentín García-Gutiérrez (Madrid)
“While clinical trials offer controlled data, real-world outcomes reflect the actual complexities clinicians face in diverse settings.”

Key points:

• Variations in patient outcomes: Real-world registries show slightly lower overall survival rates compared to clinical trials, often due to older and more diverse patient populations.
• Treatment disparities: Access to different TKIs varies significantly between regions, influencing survival rates.
• Real-world efficacy: Despite some differences, real-world data largely aligns with clinical trial outcomes in terms of response rates, but with more variability in event-free and progression-free survival.
  
  

Presentation 2:
Pimpaired longitudinal growth under tyrosine kinase inhibitor therapy - Investigating influencing factors in the German CML-PAED II cohort and the in-vitro effects of asciminib on bone metabolism
Speaker: Stephanie Sembill (Erlangen)
“Our study showed that while imatinib is effective, it can cause significant growth impairment in pediatric patients, particularly those treated for longer periods.”

Key points:

• Growth impairment: Pediatric patients on long-term imatinib therapy experience reduced growth, especially during puberty. Pre-pubertal children are more likely to experience delayed growth, which worsens over time.
• Risk factors: Higher imatinib blood levels and early molecular response are linked to better therapeutic outcomes but also to more pronounced growth impairment.
• Potential alternatives: The use of more selective TKIs, such as asciminib, may offer less disruption to growth in pediatric patients, though further studies are needed.
  
  

Presentation 3:
Sex related differences in CML outcomes in a real-world prospective registry (GQR LMC NMP)
Speaker: Lambert Busque (Montreal)
“There are significant sex-related differences in CML treatment outcomes, with women showing more intolerance but achieving faster molecular responses compared to men, most notable for imatinib in first-line setting”

Key points:

• Sex-based differences: Women experience higher rates of treatment intolerance, leading to more frequent switching of TKIs, while men are more likely to exhibit resistance.
• Faster response in women: Women tend to reach major molecular response (MMR) faster than men, though both sexes achieve similar long-term outcomes.
• Personalised treatment: Understanding these differences can help guide more personalised treatment strategies, especially regarding dose adjustments and treatment-free-remission   (TFR) attempts in women.
  
  

Presentation 4:
Propensity-Score Matching Analysis Comparing Treatment Outcomes of Asciminib with Ponatinib in Later Line Treatment for Chronic Myeloid Leukemia Patients
Speaker: Dennis Kim (Toronto)
“Our analysis showed that asciminib offers at least equal, if not superior, efficacy compared to ponatinib in later-line treatment, particularly for patients with cardiovascular comorbidities or those without the T315I mutation.”

Key Points:

• Efficacy comparison: This analysis compared the efficacy of asciminib and ponatinib in later-line treatments for CML patients. While both drugs showed significant molecular response rates, asciminib had a more favorable safety profile.
• Safety profile: Asciminib demonstrated fewer adverse cardiovascular events compared to ponatinib, making it a potentially safer alternative for patients at higher risk for cardiovascular issues.
• Event-free survival: Asciminib showed superior event-free survival rates compared to ponatinib, particularly in patients without T315I mutations, suggesting asciminib may be the preferred option for certain patient populations.
  
  

Conclusion
This session highlighted important considerations for both pediatric and adult CML patients in real-world settings, demonstrating that while clinical trial data is invaluable, real-world outcomes provide crucial insights into patient care across diverse populations. The inclusion of pediatric growth concerns, sex-related treatment differences, and comparative efficacy of later-line treatments underscores the need for personalised approaches to therapy. Ongoing registry studies will continue to play a pivotal role in refining treatment strategies.