Topic: Advancing Treatment-Free Remission (TFR) in CML Worldwide
Date: December 6, 2024 | Location: San Diego (USA)

Meeting chair: Dr Katia Pagnano, HEMOCENTRO / UNICAMP – Brazil)

The 2024 iCMLf Forum focused on advancing Treatment-Free Remission (TFR) for CML globally. Expert speakers shared progress in research, diagnostics, and strategies for enhancing TFR access, particularly in low- and middle-income countries (LMICs).

Session 1: The iCMLf – Planning for the future

Speaker: Nicola Evans, Chief Executive, iCMLf

Nicola Evans provided an overview of iCMLf’s mission, vision and future direction, emphasising the continued support for equal access to treatment, diagnostics, and care for all CML patients.

The iCMLf leadership is finalising the strategies and projects for the next 10 years.
This will focus on:

• Expanding CML education globally with a dedicated focus on LMICs
• Increasing access to diagnostics
• Providing overarching global patient support and information
• Continuing to research optimal treatment pathways

More details to follow in early 2025…

Session 2: Understanding the Optimal Pathway to Successful TFR

Presentation: Biological Barriers to Cure

Speaker: Professor Brian J. Druker, OHSU Knight Cancer Institute, USA

Professor Druker discussed intrinsic and extrinsic barriers preventing TFR and proposed research strategies to overcome them.

Key Points:

• Barriers to achieving TFR:
  • Cell-intrinsic factors: Kinase-independent survival pathways, epigenetic reprogramming, and metabolic adaptations allow residual leukemia cells to persist.
  • Cell-extrinsic factors: Immune system interactions, inflammatory responses, and the bone marrow niche play critical roles in maintaining minimal residual disease (MRD).
• Long-term patient management:
  • Achieving deep molecular response remains a priority, with current therapies enabling TFR in only 10-20% of patients.
  • Shared decision-making is vital for managing treatment cessation, balancing benefits (e.g., reduced toxicity) with potential relapse.
• Strategic goals for future therapies:
  • Targeting residual leukemic stem cells through safe, precise therapies.
  • Utilising global sample repositories to identify novel therapeutic targets and biomarkers for TFR success

Presentation: Innovative Biomarkers for TFR

Speaker: Professor Ong Sin Tiong, Duke-NUS Medical School, Singapore

Professor Ong presented data on biomarkers predicting TFR success and relapse, using single-cell technologies to identify stem cell differences.

Key Points:

• Role of leukemic stem cells (LSCs):
  • Pre-treatment biology at the LSC level determines TFR outcomes, with specific biomarkers predicting relapse or sustained remission.
  • Patients with high LSC burden or certain genetic signatures exhibit higher risk of relapse post-TKI cessation.
• Predictive biomarkers:
  • Rapid BCR::ABL1 decline at three months is linked to long-term TFR success, suggesting favourable pre-existing stem cell biology.
  • Identification of cell surface protein biomarkers (e.g., in CD34+ cells) at diagnosis may enable patient stratification for TFR attempts.
• Single-cell technologies:
  • Leveraging single-cell RNA sequencing to map stem cell states, highlighting proliferative pathways (e.g., IL-2/STAT5 signalling) in relapsed patients.
  • Epigenetic gene sets in relapsed LSCs provide potential therapeutic targets for future interventions.

Session 3: Successful TFR Globally

Presentation: TFR in Low-and-Middle-Income Countries

Professor Akhil Ranjon Biswas, Dhaka Medical College, Bangladesh (presented by Dr Shanmuganathan)

Insights on TFR in LMICs, including how this can be achieved, patient perceptions and the challenges of limited access to TKIs, testing, and monitoring infrastructure.

Key Points:

• Access barriers in LMICs:
  • Limited availability of TKIs due to lack of insurance and reliance on out-of-pocket expenses.
  • Variable access to molecular testing with concerns over sensitivity, reliability, and high costs.
• Practical monitoring solutions:
  • Use of FISH cytogenetics and qualitative PCR as cost-effective alternatives to quantitative BCR-ABL testing.
  • Reducing test frequency while maintaining safety, e.g., bimonthly testing in the first six months.
• Improving patient compliance:
  • Health literacy programs to educate patients on the importance of adherence and timely molecular monitoring.
  • Strengthening government support for free TKIs and subsidised diagnostics.

Presentation: Optimal TFR Monitoring

Speaker: Dr Naranie Shanmuganathan, Royal Adelaide Hospital, Australia

Dr Shanmunagathan presented optimised TFR monitoring strategies and practical approaches to improve global accessibility.

Key Points:

• Optimised monitoring protocols:
  • Modelling reduced testing regimes (e.g., monthly for six months, then bi-monthly) showed significant cost reductions while maintaining safety.
  • Real-world implementation of updated NCCN and ELN guidelines would reduce testing burden.
• Global disparities:
  • Successful TFR programs rely on reliable, timely, and affordable BCR::ABL1 testing infrastructure.
  • Regional and national efforts must address gaps in testing capabilities for widespread adoption of TFR strategies.

Presentation: Expanding Diagnostics for CML

Speaker: Professor Jerry Radich, Fred Hutchinson Cancer Center, USA

Professor Radich highlighted novel diagnostic solutions, including portable PCR devices, lateral flow assays, and nanopore sequencing for LMICs.

Key Points:

• InnovativeV diagnostic tools:
  • Development of electricity-free PCR and lateral flow assays as affordable, portable options for LMICs.
  • Digital PCR offers superior sensitivity compared to conventional RT-PCR for detecting MRD and predicting relapse.
• Advances in sequencing technologies:
  • Portable nanopore sequencing provides real-time results, enabling genetic analysis without reliance on centralised facilities.
  • Integration of sequencing data into mobile applications allows for rapid diagnostics and results sharing in remote areas.
• Future directions:
  • Use of dried blood spot technology for multiplexed testing, including resistance mutations and whole-genome panels.
  • Expanding programs like “Spot on CML” to support large-scale diagnostics globally.

Panel Discussion

Moderator: Giora Sharf, CML Advocates Network
Panellists shared insights on the challenges and future of TFR, emphasising practical, affordable solutations for LMICs. 

Key Topics:

• Balancing monitoring rigor and accessibility:
  • Flexible protocols (e.g., reduced testing frequency) are necessary for resource-limited settings without compromising safety.
• Long-term monitoring beyond five years:
  • Shared decision-making with patients is critical, with proposals for six-monthly or annual testing based on individual risk.
• Practical TFR implementation in LMICs:
  • Strategies to increase government-funded TKIs and diagnostics, alongside education programs to improve compliance and patient outcomes.

Conclusion

The 2024 iCMLf Forum delivered actionable insights to advance TFR worldwide. Experts emphasised collaboration, innovation, and equity in addressing barriers to care, particularly in LMICs, with a shared vision of achieving a cure for CML. 

As part of our monthly news service we would like to make you aware of the CML publications of the month. From the many papers published every month Professor Timothy Hughes has selected topical, interesting papers for your perusal that also include an interesting pediatric papers and publications from the LMICs.

Read Professor Hughes' CML publications of the month: September 2024

Clinical CML papers

• Perspectives on drug development for the treatment of chronic myeloid leukemia in pregnant patients and patients who are breastfeeding – Reviev
  Cortes JE et al. Clin Cancer Res, Sept 2024
  
• Outcomes of chronic myeloid leukemia patients after therapeutic failure to conventional tyrosine kinase inhibitors and asciminib
  Pérez-Lamas L et al. Ann Hematol, Sept 2024 (epub ahead of print) – open access publication
  
• Overcoming clinical BCR-ABL1 compound mutant resistance with combined ponatinib and asciminib therapy
  Eide CA et al. Cancer Cell, Sept 2024
  
• Choice of frontline tyrosine-kinase inhibitor and early events in very elderly patients with chronic myeloid leukemia in chronic-phase: A “Campus CML” Study
  Bucelli C et al. Eur J Haematol, Sept 2024 (epub ahead of print) – open access publication
  
• Real-world evaluation of treatment patterns and clinical outcomes among patients with chronic myeloid leukemia in chronic-phase treated with asciminib in clinical practice in the US: Real-world asciminib treatment outcomes in CML-CP
  Atallah E et al. Clin Lymphoma Myeloma Leuk, Sept 2024 (epub ahead of print)
  
• Outcome after short exposure to tyrosine kinase inhibitors in pregnant female patients with chronic myeloid leukemia
  Zu Y et al. J Hematol Oncol, Sept 2024 – open access publication
  
• Treatment-free remission as a new goal in the management of chronic myeloid leukemia: Clinical and biological aspects – Review
  Cattaneo D et al. Hematol Oncol, Sept 2024
• Deep molecular response rate in chronic phase chronic myeloid leukemia: Eligibility to discontinuation related to time to response and different frontline TKI in the experience of the Gimema Labnet CML National Network
  Breccia M et al. Clin Lymphoma Myeloma Leuk, Sept 2024 (epub ahead of print)
• Dose justification for asciminib in patients with Philadelphia chromosome positive chronic myeloid leukemia with and without the T315I mutation
  Combes PF et al. Clin Pharmacokinet, Sept 2024 – open access publication
• CML 25 years later – Poised for another breakthrough?
  Abruzzese E. N Engl J Med, Sept 2024
• Imatinib remains the best frontline therapy in patients with chronic myeloid leukemia: Critical analysis of the ASC4First trial
  Srinivasan N et al. Am J Hematol, Sept 2024 (epub ahead of print) – open access publication
• The initial molecular response predicts the deep molecular response but not treatment-free remission maintenance in a real-world chronic myeloid leukemia cohort
  Saugues S et al. Haematologica, Sept 2024 – open access publication
• Triplet therapy for advanced BCR::ABL1 positive myeloid leukemia
  Copland M. Lancet Haematol, Sept 2024 (epub ahead of print)

Scientific CML papers

• The e13a3 (b2a3) and e14a3 (b3a3) BCR::ABL isoforms are resistant to asciminib
  Leske IB and Hantschel O. Leukemia, Sept 2024 – open access publication
• Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy
  Innes AJ et al. Leukemia, Sept 2024 (epub ahead of print) – open access publication
• Absence of ABL1 exon 2-decoded SH3 residues in BCR::ABL1 destabilizes the autoinhibited kinase conformation and confers resistance to asciminib
  Leyte-Vidal A et al. Leukemia, Sept 2024 – open access publication

Pediatric papers

• A high proportion of germline variants in pediatric chronic myeloid leukemia in pediatric chronic myeloid leukemia
  Krumbhold M et al. Mol Cancer, Sept 2024 – open access publication
• CAR-T cells for the treatment of pediatric chronic myeloid leukemia in repeatedly relapsed lymphoid blast crisis
  Kramp LJ et al. Ann Hematol, Sept 2024 (epub ahead of print) – open access publication

LMIC Papers

• Impact of a guaranteed access program to imatinib on the survival of patients with chronic myeloid leukemia
  Barranco G et al. Cancer Causes Control, Sept 2024 (epub ahead of print)
• Late presentation of chronic myeloid leukemia patients in a low-income country: The prognostic implications and impact on treatment outcome
  Nelson EA et al. BMC Res Notes, Sept 2024 – open access publication
  
  

CML paper summary - October 2024

Point-of-care BCR::ABL1 transcript monitoring using capillary dried blood in CML patients

Sala-Torra O et al. Leukemia, June 2024
Leukemia (2024) 38:1822–1824  https://doi.org/10.1038/s41375-024-02285-9

Introduction:

This study explores a novel method for monitoring BCR::ABL1 transcripts in CML patients using a point-of-care dried capillary blood (DCB) collection system. With CML requiring lifelong treatment and frequent monitoring, the method aims to address the challenges faced by patients in remote locations or with limited access to healthcare facilities.

Study design:

• The researchers developed and evaluated a capillary dried blood collection method using the Tasso-M20 device.
• Twenty patients enrolled at Fred Hutchinson Cancer Center were monitored using DCB samples, which were compared with standard venous blood monitoring via quantitative reverse-transcription polymerase chain reaction (RT-PCR).
• The samples were tested for BCR::ABL1 transcripts using the Xpert® BCR-ABL Ultra assay (Cepheid).

Study endpoints:

• The primary goal was to assess the correlation between BCR::ABL1 transcript levels in DCB and standard venous blood samples.
• Key outcomes included major molecular response (MMR) rates and overall sensitivity of the DCB method compared to venous blood.

Study results:

• DCB collection using the Tasso-M20 device was well-tolerated, with patients reporting minimal pain (mean pain score <1.5).
• Strong correlations (r=0.96) between BCR::ABL1 levels in DCB and venous samples were observed.
• Fifteen patients achieved MMR by DCB measurements, of which 12 were concordant with venous blood results.
• Patients with BCR::ABL1 transcripts <0.09% in venous blood were not reliably detected by the DCB method.

Discussion:

The study demonstrates the feasibility of patient-directed DCB collection for CML monitoring, providing a low-cost, stable, and convenient alternative to traditional venous blood testing. While the method is effective for detecting MMR and loss of response, its sensitivity for deeper molecular responses may be limited due to the smaller blood volume.
Future improvements, including larger sample collections, could enhance detection sensitivity.

Conclusion:

Capillary dried blood sampling offers a promising point-of-care tool for CML monitoring, especially in resource-limited settings. However, further developments are required to expand its use in treatment-free remission assessments.

CML paper summary - July 2024

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia

Hochhaus A et al. NEJM, May 2024
ClinicalTrials.gov no. NCT04971226

Introduction

The study investigated the efficacy and safety of asciminib, a novel BCR::ABL1 inhibitor targeting the ABL myristoyl pocket, in patients newly diagnosed with chronic myeloid leukemia (CML). The objective was to determine if asciminib offered superior efficacy and safety compared to current first-line ATP-competitive tyrosine kinase inhibitors (TKIs), including imatinib and second-generation TKIs.

Trial Design

The trial enrolled a total of 405 patients, who were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or the investigator-selected TKI - one of the approved frontline TKIs, which included imatinib, nilotinib, dasatinib, or bosutinib.

Patients were stratified by European Treatment and Outcome Study long-term survival risk categories (low, intermediate, or high) and the TKI selected prior to randomization (imatinib or a second generation TKI).

Study endpoints

The primary endpoints were the major molecular response (MMR) at week 48, both for asciminib versus all TKIs collectively and specifically against imatinib.

Results
Patient Demographics and Follow-up:

• 201 patients received asciminib, and 204 received a TKI.
• Median follow-up was 16.3 months for asciminib and 15.7 months for TKIs.

Efficacy:

• At week 48, 67.7% of patients in the asciminib group achieved MMR, compared to 49.0% in the Investigator-selected TKI group (difference: 18.9 percentage points; 95% CI, 9.6 to 28.2; P<0.001).
• In the imatinib stratum (comparing only the patients where the investigator selected imatinib prior to randomization), 69.3% of asciminib-treated patients achieved MMR versus 40.2% in the imatinib group (difference: 29.6 percentage points; 95% CI, 16.9 to 42.2; P<0.001).
• In the second-generation TKI stratum, MMR was 66.0% with asciminib and 57.8% with second-generation TKIs (difference: 8.2 percentage points; 95% CI, −5.1 to 21.5).

Safety:

• Asciminib had a markedly favorable safety and tolerability profile, with fewer grade ≥3 AEs and AEs leading to treatment discontinuation vs all IS-TKIs

Discussion

The study demonstrated that asciminib significantly improved MMR rates compared to the investigator-selected TKI and to imatinib, in newly diagnosed CML patients. The safety profile of asciminib was also favourable, with a low rate of discontinuations due to side effects.

These results suggest that asciminib could become a preferred frontline therapy for CML,

Long-term follow-up is necessary to confirm the durability of these responses and the potential for treatment-free remission.