October 2025 - We're bringing you highlights from the recent ESH-iCMLf 27th Annual John Goldman Conference on CML: Biology and Therapy with a summary of selected scientific sessions.

🌟 Scientific Session: Stem Cells 🌟

Chair: Mary Scott (Glasgow)

This session explored new insights into leukemic stem cell biology, persistence, and the bone marrow microenvironment in CML. The speakers presented novel models and molecular mechanisms driving stem cell survival and relapse, highlighting inflammatory, metabolic, and stromal interactions shaping disease behaviour and treatment-free remission (TFR) potential.

Our key takeaways from the presentations:

Keynote presentation
Inflammation and CML stem cells: the devil is in the details 
Speaker: David Vetrie

“TR1 cells may be particularly vulnerable to cytokine modulation – and thus a real opportunity to improve treatment-free remission.”- David Vetrie

Key points:

• Dual molecular trajectories:Two distinct leukemic stem cell (LSC) programs – TR1 (inflammatory) and TR2 (quiescent) – were identified, differing in signalling and metabolic states.
• Inflammatory signatures:High NF-κB and TNF signalling linked to both optimal responders and blast crisis, suggesting inflammation shapes opposite disease states.
• Cytokine impact:Exposure to specific cytokines (TNFα, IL-6, IL-3) induced TR1-like trajectories and enhanced TKI sensitivity in experimental models.
• Interferon modulation:Interferon-α/γ altered balance between TR1 and TR2 lineages, reducing erythroid differentiation and stem cell inflammation.
• Recurrence modelling:Inflammatory LSCs and megakaryocyte progenitors re-emerged after TKI withdrawal, linking inflammation to relapse biology.
• Therapeutic perspective:Targeting TR1-like inflammatory LSCs could potentially enhance TFR success in CML.

Presentation 1:
Identification of leukemic stem cells of chronic myeloid leukemia in a new mouse model
Speaker: Yasmine Pobiedonoscew (Bordeaux)

“The disease we see in these mice truly originates from the stem cell compartment –  long-term HSCs can reinitiate leukemia.” – Yasmine Pobiedonoscew

Key points:

• New transgenic model: A refined CML mouse model allows distinction of normal versus leukemic cells and prolonged chronic-phase disease study.
• Stem cell origin confirmed: Long-term hematopoietic stem cells (HSCs) and LSK populations reinitiated leukemia after transplantation.
• TKI response: Dasatinib treatment cleared leukemic progenitors but spared quiescent long-term HSCs, mirroring clinical persistence.
• Relapse after discontinuation: Leukemic cells reappeared after TKI withdrawal in most mice, confirming the survival of dormant HSCs.
• Inflammatory gene expression: Residual HSCs post-TKI treatment displayed inflammatory and megakaryocytic signatures.
• Preclinical value: This model enables mechanistic studies of stem cell persistence and evaluation of novel eradication strategies.

Presentation 2:
Exploring the role of megakaryocytes in leukemic stem cell persistence

Presenter: Margherita Vieri (Aachen)
“Megakaryocytes are not only platelet factories – they actively shape the stem cell niche.” – Margherita Vieri 

Key points:

• Megakaryocyte expansion: Increased megakaryocyte numbers and progenitors observed in CML and during TKI therapy.
• Pro-stem cell niche: CML megakaryocytes expressed high TGFβ and low GATA1, consistent with stem cell–supportive signalling.
• Fibrotic potential: Megakaryocytes localised near fibrotic areas and may induce endothelial-mesenchymal transition in the spleen.
• CD38 pathway: High CD39 expression suggested metabolic cross-talk between megakaryocytes, adipocytes, and stem cells.
• Therapeutic target: Blocking CD36 reduced splenomegaly and leukemic burden in vivo, highlighting a potential treatment approach.
• Conceptual model: Megakaryocytes may maintain leukemic stem cell quiescence and disease persistence through metabolic and cytokine signalling.

Presentation 3:
A potential role for IGFBP2 in regulating the CML stem cell niche

Presenter: Henrike Jacobi (Aachen) 

“These findings suggest that microenvironmental IGFBP2 supports leukemic stem cell persistence in a context-dependent manner.”– Henrike Jacobi

Key points:

• IGFBP2 elevation: Mesenchymal stromal cells and serum from CML patients showed increased IGFBP2 expression, persisting even after long-term TKI therapy.
• TGF-β activation: IGFBP2 treatment induced TGF-β/SMAD signalling in both hematopoietic and stromal cells, affecting stem cell maintenance.
• Microenvironment remodelling: Knockout of IGFBP2 reduced extracellular matrix genes e.g., collagens, MMP9) and niche-support factors like CXCL12.
• Stem cell retention: Co-culture assays revealed that IGFBP2 promoted colony formation and possibly enhanced LSC retention.
• Context dependency: The functional role of IGFBP2 appears context-specific, potentially both protective and supportive in CML.
• Clinical link: Sustained IGFBP2 levels may serve as a marker of residual disease activity or altered microenvironment after therapy. 

🌟 Scientific Session: Cell Biology 🌟

Chair: Oliver Hantschel (Marburg)

This session explored how chromatin remodelling, stress response pathways, and metabolic adaptation contribute to disease progression and therapy resistance in CML. Using single-cell, multi-omics, and functional studies, the speakers revealed how epigenetic and metabolic reprogramming shape leukemic cell behaviour – and pointed to novel targets for preventing blast crisis and overcoming TKI resistance.

Key highlights from the session:

Keynote presentation
A single-cell chromatin accessibility atlas reveals transcription factor-driven epigenetic programmes underlying drug resistance and blast crisis progression in CML 
Speaker: Sin Tiong Ong (Singapore)

“Targeting shared transcriptional programs like JAK–STAT5 may prevent blast crisis across lineages.” – Sin Tiong Ong

Key points:

• Common epigenetic code: A shared “blast crisis epigenome” was identified across patients, independent of individual mutations.
• Cell lineage specificity: In lymphoid blast crisis, key changes occurred in pre-B and lymphoid progenitors; in myeloid cases, in HSCs and myeloid progenitors.
• Regulatory mechanisms: Only 5% of accessible chromatin regions defined the CML stem cell epigenome, driven by NF-κB, STAT5, and AP-1 signalling.
• Epigenetic evolution: Chronic-phase cells already harboured pre-blast crisis chromatin patterns months before clinical transformation.
• Therapeutic target: JAK–STAT5 inhibition reduced colony formation in both lymphoid and myeloid blast crisis models.
• Biological implication: The epigenome acts as a fertile “soil” for accumulating mutations and transformation.

Presentation 1:
A coordinated stress-adaptive response underlies the tumour suppressor role of G0S2 in CML
Speaker: Briandy Fernandez-Marrero (El Paso)

“Our findings position G0S2 as a potential tumour suppressor in non-resistant CML.” – Briandy Fernandez-Marrero

Key points:

• UPR regulation: G0S2 integrates the unfolded protein response (UPR), autophagy, and mitochondrial stress pathways to maintain cellular homeostasis. 
• Autophagy control: Overexpression of G0S2 suppressed autophagy in progenitor cells, while loss of G0S2 led to respiratory dysfunction and accumulation of misfolded proteins. 
• XBP1 signalling: The UPR was transcriptionally activated through the spliced XBP1 transcription factor, which directly bound to the G0S2 promoter. 
• Ferroptosis: G0S2 expression sensitized CML cells to ferroptosis, connecting stress signalling to programmed cell death. (Ferroptosis)
• Disease resistance: Reduced G0S2 expression was associated with disease progression and resistance in non-TKI-dependent CML models.
• Tumour suppression: G0S2 functions as a tumour suppressor by coordinating stress signalling and metabolic balance within leukemic cells. 

Presentation 2:
Integrating genomic and transcriptomic features for predicting responses and outcomes in chronic myeloid leukemia on third-generation TKI therapy

Presenter: Xiaoshuai Zhang (Beijing)

“Multi-omics integration brings us closer to truly predictive treatment models in CML.” – Xiaoshuai Zhang

Key points:

• High mutational burden: Over 80% of resistant patients harboured additional mutations beyond BCR::ABL1, including ASXL1, KMT2D, and SETBP1.
• High-risk variants: ASXL1 G646Wfs and SETBP1 mutations were strongly linked to poor survival under third-generation TKIs.
• Dynamic evolution: Longitudinal sequencing revealed mutation emergence or expansion correlating with resistance patterns.
• Transcriptomic clusters: Three molecular subtypes were identified — immune-activated, ECM-remodelling, and stemness-like – with distinct prognoses.
• Immune signature: The immune-activated cluster had higher T-cell and NK-cell infiltration and better therapy response.
• Clinical application: Integrated omics profiling may predict outcomes and personalise third-generation TKI use.

Presentation 3:
Complex metabolic reprogramming underlies TKI resistance in CML stem progenitor cells

Presenter: Ilaria Stefania Pagani (Adelaide) 

“TKI-resistant stem cells survive by remodelling their metabolism — they “breathe” differently.” – Ilaria Pagani

Key points:

• Metabolic shift: TKI-resistant CML stem and progenitor cells displayed increased mitochondrial respiration, oxidative stress, and lipid metabolism. 
• mtDNA mutations: Patients with multiple mitochondrial DNA mutations paradoxically showed better molecular responses to imatinib. 
• Mitochondrial dynamics: Resistant cells exhibited enhanced mitochondrial biogenesis but defective mitophagy, leading to metabolic inflexibility. 
• Metabolic rewiring: Single-cell transcriptomics revealed rewiring of glycolytic and phospholipid pathways in resistant clones. 
• Survival adaptation: Mitochondrial mutations and metabolic remodelling conferred survival advantages under TKI pressure. 
• Therapeutic targeting: Targeting mitochondrial integrity or energy metabolism could selectively eradicate resistant CML stem cells.

 
🌟 Scientific Session: Biomarkers, resistance and new targets 🌟

Chair: Simona Soverini (Bologna)

This session focused on new molecular and genomic insights into CML pathogenesis, drug resistance, and response prediction. Presentations covered advanced sequencing technologies revealing Philadelphia chromosome complexity, novel fusion mechanisms, STAT5-targeting strategies, epigenetic biomarkers, resistance mutations to allosteric inhibitors, and IPSC models to study primary TKI resistance. Together, the talks highlighted the expanding toolkit of biomarkers that can inform precision medicine and therapeutic innovation in CML.

Our key takeaways from the presentations:

Keynote presentation
Whole genome sequencing reveals that the Philadelphia chromosome (Ph) can evolve and gain complex sequence rearrangements associated with tyrosine kinase inhibitor (TKI) resistance
Speaker: Susan Branford (Adelaide)

“These complex rearrangements may underlie resistance and transformation in ways we are only beginning to understand.” – Susan Branford

Key points:

• Genomic complexity: Whole-genome sequencing revealed complex structural rearrangements involving multiple chromosomes in some CML patients. 
• Chromoplexy: These events include chromoplexy-like genomic rearrangements – deletions, inversions, and duplications – indicating early genomic instability signalling TKI sensitivity.
• Philadelphia variants: Philadelphia-associated rearrangements were identified both at diagnosis and during disease progression. 
• Genomic evolution: Amplified and inverted fragments of other chromosomes were sometimes incorporated into the Philadelphia chromosome, supporting ongoing genomic evolution.
• Gene disruption: These rearrangements could disrupt tumour suppressor genes such as LZTR1, potentially driving resistance and transformation. 
• Resistance mechanism: Findings suggest Philadelphia chromoplexy may represent a new mechanism of acquired TKI resistance and disease progression. 

Presentation 1:
Partner Matters: The role of the 5’ ABL fusion gene in asciminib efficacy
Speaker: Elias Lagonik (Adelaide)

“The 5′ partner gene can redefine kinase conformation and therapeutic vulnerability.” – Elias Lagonik

Key points:

• Fusion diversity: Alternative 5′ fusion partners of BCR can alter downstream signalling and TKI sensitivity in both CML and Ph+ ALL.
• Structural mechanism: Structural and biochemical analysis identified key interactions within the SH3–SH2–kinase region that define fusion-specific signalling. 
• Resistance modelling: Deletion mutants verified variable sensitivity to asciminib and other TKIs, revealing distinct fusion biology. 
• Cross-resistance: Cross-resistance patterns emerged across ATP-competitive and allosteric TKIs, depending on the fusion architecture.
• Fusion biology: Findings highlight that 5′ BCR fusions represent unique signalling entities, requiring tailored therapeutic strategies.
• Targeted therapy: The study provides a framework for designing fusion-specific inhibitors targeting resistant CML and Ph+ ALL 

Presentation 2:
STAT5-targeting monobodies as therapeutic (add-on) option in chronic myeloid leukemia

Presenter: Inga B. Leske (Marburg)
“This work opens the door to a completely new class of targeted therapies in leukemia.” – Inga B. Leske

Key points:

• STAT5 signalling: TAT5 is a central transcription factor downstream of BCR::ABL1, driving CML maintenance and TKI resistance.
• Monobody inhibitors: Novel monobody inhibitors were developed to selectively bind STAT5 and disrupt its oncogenic signalling.
• Clone characterisation: Three high-affinity monobody clones were identified with complementary mechanisms of action targeting SH2 and DNA-binding domains.
• Functional inhibition: Monobody expression reduced STAT5 activity, cell viability, and proliferation in CML cell lines.
• Therapeutic innovation: These agents represent first-in-class intracellular biologics targeting STAT5 for resistant CML.
• Combination potential: Co-treatment with imatinib and STAT5 monobodies further enhanced anti-leukemic efficacy, suggesting therapeutic synergy. 

Presentation 3:
DNA methylation instability as a biomarker for response to tyrosine kinase inhibitor therapy in chronic myeloid leukemia

Presenter: Dennis Kim (Toronto) 

 “Our data suggest that epigenetic profiling can complement genetic testing in predicting resistance.” – Dennis Kim

Key points:

• Epigenetic biomarker: Epigenetic instability reflects hematopoietic clonality and may serve as a measurable biomarker in CML.
• Clonal heterogeneity: Elevated DNA methylation instability (DMI) at diagnosis was linked to increased clonal diversity and treatment resistance.
• Therapeutic response: DMI levels decreased following TKI therapy, reflecting reduced genomic instability in responders.
• CpG mapping: Identified over 6,000 CpG sites contributing to a CML-specific methylation signature.
• Integrated profiling: Complementarity between ASXL1 mutation profiling and DMI supports integration of genetic and epigenetic markers.
• Prognostic utility: DMI may function as a predictive and prognostic biomarker for disease progression and resistance.

Presentation 4:
The majority of BCR::ABL1 mutations associated with clinical resistance to ascminib retain asciminib binding affinity, alter kinase structure, activate kinase activity and conver cross-resistance to TGRX-678

Presenter: Ariel Leyte-Vidal (San Francisco) 
“Most asciminib-resistant mutations lie outside the kinase domain – in regions controlling allosteric regulation.” – Ariel Leyte-Vidal

Key points:

• Resistance mutations: Identified ABL1 mutations in SH2 and linker regions associated with asciminib resistance, many located outside the kinase domain. 
• Structural alteration: These mutations retained drug-binding affinity but altered kinase stability and conformation. 
• Allosteric disruption: Disrupted autoinhibitory interactions led to enhanced kinase activation and downstream signalling.
• Cross-resistance: Cross-resistance to asciminib and investigational iPAL analogues was confirmed across multiple resistant variants.
• Kinase activation: Structural and biochemical data demonstrated kinase activation despite preserved binding affinity, revealing a novel resistance mechanism.
• Mechanistic insight: Findings highlight the need for expanded sequencing beyond the kinase domain to detect emerging resistance mechanisms.

Presentation 5:
Establishing an iPSC-based platform to elucidate and overcome primary imatinib resistance in chronic myeloid leukemia stem cells

Presenter: John Joson Ng (Singapore) 

“iPSC models allow us to recapitulate primary resistance in a patient-specific, renewable system.” – John Joson Ng

Key points:

• Disease modelling: Established patient-specific induced pluripotent stem cells (iPSCs) that retain genetic and molecular features of CML. 
• Stem cell biology: Generated iPSC-derived CD34⁺ progenitors that reproduce primary TKI resistance phenotypes seen in patients. 
• Lineage resistance: Observed myeloid-specific TKI resistance in progenitors from poor responders, consistent with clinical behaviour. 
• Transcriptional signature: Single-cell transcriptomic profiling identified RDX1 as a key transcriptional regulator in optimal responder networks. 
• Drug discovery: CBP/p300 inhibitor 399Tb was identified as a candidate to modulate these transcriptional programs and re-sensitize resistant cells.
• Therapeutic strategy: Combination treatment with imatinib and 399Tb restored sensitivity in resistant iPSC-derived hematopoietic cells. 

 
🌟 Scientific Session: New drugs and clinical trials 🌟

Chair: Fausto Castagnetti (Bologna)

This session highlighted recent advances in the development of next-generation TKIs and novel therapeutic strategies for chronic myeloid leukemia. The presentations covered BCR::ABL1 degraders, updated results from second-line asciminib trials, emerging data on olverembatinib and vamotinib, long-term results from the ASC4OPT asciminib study, and innovative patient-guided dosing strategies. Together, these studies showcased an evolving treatment landscape focused on improving efficacy, safety, and patient-centred care in CML.

Our key takeaways from the presentations:

Keynote presentation
Targeting chronic myeloid leukemia with potent and specific BCR::ABL1 degraders
Speaker: Michael Deininger (Ann Arbor)

“Degradation, rather than inhibition, offers a path to completely dismantle oncogenic signalling.” – Michael Deininger

Key points:

• Protein degradation: Novel BCR::ABL1 degraders (LPA1 and LPA2303) that eliminate both kinase-dependent and kinase-independent functions.
• Mechanism of action: Degraders use E3 ligase recruitment (CRBN-based PROTAC design) to induce targeted protein degradation via ubiquitination. 
• Structural biology: Lysine 202 in the SH2 domain identified as the main ubiquitination site responsible for degradation specificity. 
• Signalling inhibition: Phosphoproteomic profiling confirmed that degradation suppressed downstream signalling (RAS/MAPK and STAT pathways).
• Resistance bypass: Degraders remained effective in compound-mutant and asciminib-resistant CML models, overcoming kinase-domain resistance.
• Therapeutic advantage: Preclinical data showed superior potency to TKIs and specificity for BCR::ABL1-expressing cells with minimal off-target effects. 

Presentation 1:
Efficacy and safety of asciminib in patients with chronic-phase chronic myeloid leukemia (CML-CP) after 1 tyrosine kinase inhibitor (TKI): Interim analysis (IA) of the phase 2 ASC2ESCALATE trial
Speaker: Jorge Cortes (Augusta)

“These results confirm asciminib’s strong efficacy in the second-line setting with remarkable tolerability.” – Jorge Cortes

Key points:

• Trial design: Evaluated asciminib 80 mg daily with optional dose escalation to 200 mg in second-line chronic-phase CML. 
• Patient population: Included patients with intolerance or resistance to prior first-line TKI therapy (excluding T315I mutation).
• Efficacy results: At 48 weeks, 77.8% achieved cytogenetic response and 55% achieved MMR, showing similar efficacy in resistance and intolerance cohorts. 
• Dose optimisation: Dose escalation to 200 mg was performed in 16 patients, several of whom achieved further molecular improvement.
• Safety results: Safety profile remained favourable, with few discontinuations due to adverse events and no new safety signals.
• Therapeutic value: Findings support asciminib as an effective and well-tolerated second-line therapy for chronic-phase CML.

Presentation 2:
Olverembatinib (HQP1351) as second-line therapy in patients with chronic-phase chronic myeloid leukemia (CP-CML)

Presenter: Weiming Li (Wuhan)

“These preliminary data support olverembatinib as a viable second-line treatment.” – Weiming Li

Key points:

• Trial design: Conducted a phase II single-arm trial of olverembatinib 40 mg every other day in CML-CP patients without T315I mutation. 
• Efficacy results: Among 43 enrolled patients, 74% achieved complete cytogenetic response (CCyR) and 41% achieved MMR after a median follow-up of 16 months.
• Subgroup efficacy: Response rates were higher in patients previously treated with second-generation TKIs (CCyR 79%, MMR 44%). 
• Safety results: No new safety signals were observed; main adverse events were anaemia, leukopenia, and skin hyperpigmentation.
• Skin hyperpigmentation: Skin hyperpigmentation was common but reversible upon drug discontinuation.
• Therapeutic potential: Findings suggest olverembatinib as a promising second-line option with durable efficacy and manageable safety. 

Presentation 3:
First preliminary results of a multicentre randomised phase III study of vamotinib (PF-114) versus imatinib in Ph-positive chronic phase chronic myeloid leukemia patients

Presenter: Ekaterina Chelysheva (Moscow) 

“Vamotinib demonstrated superior molecular response and progression-free survival compared to high-dose imatinib.” – Ekaterina Chelysheva

Key points:

• Trial design: The phase III trial compared vamotinib 300 mg daily versus high-dose imatinib (600–800 mg) in resistant CML.
• Efficacy results: At 12 months, MMR rates were higher with vamotinib, confirming superior molecular efficacy. 
• Mutation subgroup: Patients with clinically relevant ABL1 mutations showed greater benefit from vamotinib treatment.
• Progression-free survival: Progression-free survival favoured vamotinib, with fewer progressions or deaths. 
• Safety results: Skin toxicity was the most common side effect but generally mild and manageable at the selected dose.

Presentation 4:
Asciminib once or twice daily demonstrates high efficacy and favourable safety in pretreated patients with chronic myeloid leukemia and suboptimal response, resistance or intolerance: 96-week results from the ASC4OPT study

Presenter: Carla Maria Boquimpani (Rio de Janeiro) 

“Even patients who lost response could regain MMR after dose escalation.” – Carla Maria Boquimpani

Key points:

• Trial design: Compared asciminib 40 mg twice daily vs. 80 mg once daily in resistant or intolerant CML-CP patients. 
• Efficacy results: At 96 weeks, more than 40% achieved MMR, with comparable outcomes between dosing schedules. 
• Dose escalation: 17% regained MMR after dose escalation to 200 mg once daily, confirming benefit of higher exposure. 
• Safety results: Safety remained consistent with previous data, showing low discontinuation rates and no new adverse events. 
• Adherence: Once-daily dosing improved convenience and adherence without compromising efficacy. 
• Clinical application: Female patients reported greater satisfaction and adherence, reinforcing the importance of patient preference. 

Presentation 5:
Interim analysis of a multicentre study of patient-guided does reduction of tyrosine kinase inhibitors in chronic myeloid leukemia (RODEO Study)

Presenter: Nienke Lokhorst (Nijmegen) 

“This study proves that individualised dosing can be both safe and empowering.” – Nienke Lokhorst

Key points:

• Study design: Prospective multicentre study tested patient-guided TKI dose reduction in 146 CML patients with stable deep molecular response. 
• Treatment adaptation: At 6 months, only 2.8% required dose re-escalation, confirming the safety and feasibility of guided reduction. 
• Quality of life: Patients reported improved quality of life, particularly in fatigue, diarrhea, and pain. 
• Shared decision-making: Shared decision-making was successfully implemented in 86% of cases, ensuring collaborative care. 
• Patient subgroups: Female patients experienced the largest quality-of-life gains, highlighting subgroup benefits. 
• Global application: The Dutch shared-decision model is now being adopted internationally, supporting broader clinical implementation. 

🌟 Scientific Session: CML special scenarios 🌟

Chair: Deborah White (Adelaide)

This session explored evolving treatment approaches for complex or special situations in CML, including the updated ELN 2025 recommendations, pediatric CML management, stepwise TKI discontinuation, long-term treatment-free remission (TFR) outcomes in children, and pregnancy management. The speakers presented new evidence guiding personalised therapy, dose optimisation, and TFR strategies across age groups and life circumstances, emphasising the importance of balancing efficacy, safety, and quality of life.

Our key takeaways from the presentations:

Keynote presentation
The new ELN recommendations: what is in, what is out, what is different, what is not
Speaker: Dragana Milojkovic (London)

“We have refined the milestones to better reflect real-world diversity — not all patients fit the same risk model.” – Dragana Milojkovic

Key points:

• Terminology: The ELN recommendations in 2025 replace optimal / warning / failure with favourable / warning / unfavourable, emphasising context over rigid molecular cut-offs. 
• Risk assessment: The ELTS risk score remains the preferred prognostic tool for outcome prediction and treatment planning. 
• Molecular markers: Somatic mutations (especially ASXL1) are linked to inferior responses but are not yet recommended for routine testing. 
• Individualisation: Personalised treatment should consider age, comorbidities, toxicity, and therapy goals such as TFR. 
• Dose management: Dose optimisation/dose reduction highlighted, particularly with the 2^ndGen TKIs, as durable responses can be maintained with lower toxicity.
• Monitoring principles: Monitoring frequency and confirmation of abnormal results before changing therapy are emphasised.

Presentation 1:
Dynamics and outcomes of second-line therapy in pediatric chronic myeloid leukemia: insights from the longitudinal German CML-paed II cohort
Speaker: Stephanie Sembill (Erlangen)

“Pediatric CML needs its own evidence base — not just an adaptation of adult data.” – Stephanie Sembill

Key points:

• Cohort data: The German Pediatric CML Registry analysed 189 cases; 37% required second-line therapy, primarily with dasatinib.
• Treatment rationale: Most switches (≈80%) occurred for response-related reasons, not intolerance – reflecting fewer comorbidities in children. 
• Therapeutic benefit: Patients with unfavourable responses showed significant improvement in molecular slope after switching TKIs. 
• Response variability: In contrast, warning-response patients did not benefit uniformly, suggesting biological heterogeneity in pediatric CML. 
• Timing effect: Median time to switch was 16 months, with earlier switching associated with faster achievement of MR3 and MR4 milestones. 
• Biological distinction: Pediatric CML displays distinct biology and immune features, underlining the need for age-specific strategies and trials. 

Presentation 2:
Chronic myeloid leukemia (CML) treatment discontinuation after two-step dose reduction: 
First results of the Phase 2 HALF study
Presenter: Daniela Žáčková (Brno)

“Patients feel more comfortable with de-escalation than abrupt cessation. The HALF trial shows that structured tapering might be part of future CML care.” – Daniela Žáčková

Key points: 

• Trial design: The HALF study tested a two-step discontinuation strategy: halving the TKI dose for 6 months, then giving the same dose every other day before complete cessation. 
• Efficacy results: Among 207 patients, 69% maintained molecular remission at 24 months after treatment stop. 
• Predictive factors: Male sex was the only predictive factor associated with higher TFR success.
• Safety results: Adverse events decreased during de-escalation; TKI withdrawal syndrome was milder and required minimal intervention. 
• Metabolic effects: Laboratory monitoring revealed favourable metabolic trends, including improved cholesterol profiles and reduced insulin resistance markers.
• Patient experience: The stepwise approach improved patient comfort and willingness to attempt discontinuation compared to abrupt stopping. 

Presentation 3:
Treatment-free remissions (TFR) in children with chronic myeloid leukemia (CML) – Longer-term results from the Tata Memorial Hospital (TMH) pediatric CML (pCML) cohort

Presenter: Nirmalya Roy Moulik (Mumbai) 

“TFR should now be considered a standard therapeutic goal in pediatric CML.” – Nirmalya Roy Moulik

Key points:

• Efficacy results: In a prospective study of 61 pediatric patients, TFR at 24 months was 64%, among the highest reported globally. 
• Relapse dynamics: Most molecular relapses occurred within the first six months, while re-treatment restored MMR in 75% within one year.
• Quality of life: TFR success was linked to improved bone mineral density and perceived psychological well-being.
• Safety results: About 30% experienced mild withdrawal symptoms, mostly musculoskeletal, manageable without hospitalization. 
• Second TFR attempt: A second TFR attempt is being explored in patients who regained stable DMR after relapse.
• Therapeutic milestone: The study supports TFR as a viable goal in pediatric CML, aligning with new international pediatric CML guidelines.

Presentation 4:
Molecular response in pregnant chronic myeloid leukemia patients during interruptions of tyrosine kinase inhibitors therapy and impact of interferon on response preservation

Presenter: Ekaterina Chelysheva (Moscow) 

“Women with stable DMR for more than three years can safely interrupt therapy for pregnancy. With modern monitoring, pregnancy in CML is both feasible and safe” – Ekaterina Chelysheva

Key points:

• Study cohort: Evaluated 79 pregnancies in CML patients who interrupted TKI therapy; median interruption period was 7.5 months. 
• Response stability: Patients with baseline deep molecular response (DMR ≥ MR4) maintained remission more often than those with MR2 or less. 
• Predictive factor: Duration of DMR (>3 years) before pregnancy was the main factor associated with sustained remission during interruption. 
• Risk of relapse: All patients with MR1–MR2 at baseline lost MMR, confirming the need for stable deep response before conception. 
• Therapeutic impact: Interferon therapy during pregnancy did not significantly prevent molecular relapse or improve post-delivery outcomes. 
• Response restoration: After restarting TKIs postpartum, all women regained MMR or deeper responses, typically within six month