New CML compounds in development 

Source: www.clinicaltrials.gov
Last update: April 24, 2025

On this page, you'll find a regularly updated list of recruiting clinical trials focused on novel therapies — including study details, sponsors, estimated enrolment, locations and the number of study centres.

A downloadable searchable Excel file spreadsheet (28 KB) to filter by sponsor, compound, or trial phase
(Updated regularly; the current file is from April 2025)

For an overview of clinical trials in CML not yet recruiting, click here.

Disclaimer
The information presented in this overview has been sourced from www.clinicaltrials.gov and reflects data available as of April 24, 2025. While the iCMLf strives to ensure accuracy, it is not responsible for any errors, updates, or changes that may have occurred since that date. This list is provided solely for informational purposes and is organized alphabetically by investigational compound. The iCMLf does not endorse or recommend any specific clinical trial, investigational drug, or sponsor mentioned. For the most current and comprehensive details - including eligibility criteria, study locations, and contact information - please consult the official listing on clinicaltrials.gov.

CML paper summary - January 2025

The e13a3 (b2a3) and e14a3 (b3a3) BCR::ABL1 isoforms are resistant to asciminib

Leske IB and Hantschel O. Leukemia, September 2024

Leukemia 2024 Sep;38(9):2041-2045: https://www.nature.com/articles/s41375-024-02314-7

Introduction:

Asciminib, a first-in-class allosteric BCR::ABL1 inhibitor, has shown significant efficacy in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who have been previously treated with other tyrosine kinase inhibitors (TKIs). This study by Leske and Hantschel investigates the potential resistance of specific BCR::ABL1 isoforms to asciminib, particularly focusing on the e13a3 (b2a3) and e14a3 (b3a3) isoforms. These isoforms, which lack exon 2 of ABL1 and are present in less than 1% of CML patients, hypothesised to be resistant to asciminib due to the absence of a functional SH3 domain crucial for the drug's mechanism of action.

Fig 1: Overview of BCR::ABL1 exon organisation of the common e13a2, e14a2 transcript variants, as well as e13a3 and e14a3 that lack ABL1 exon 2.

Study design:

• Objective: To evaluate the resistance of BCR::ABL1 e13a3 and e14a3 isoforms to asciminib treatment.
• Methodology: The study involved generating cDNAs for the e13a3 and e14a3 isoforms and testing their response to asciminib in BaF3 cells. The effect of asciminib on BCR::ABL1-dependent cell proliferation and survival was measured using a range of asciminib concentrations.
• Comparison: The results for e13a3 and e14a3 were compared to the more common e14a2 isoform, which is known to be sensitive to asciminib.

Study results:

• Asciminib sensitivity:
  • The e13a3 and e14a3 isoforms demonstrated significant resistance (~10,000-fold) to asciminib, with no inhibition observed at concentrations below 50 µM. In contrast, the e14a2 isoform showed a half-maximal growth inhibition (GC50) of approximately 1 nM.
  • Both e13a3 and e14a3 isoforms were highly sensitive to dasatinib, an ATP-competitive inhibitor.
• Mechanism of resistance:
  • The resistance observed for the e13a3 and e14a3 isoforms was attributed to the absence of a functional SH3 domain, which is required for asciminib's allosteric inhibition of BCR::ABL1. Structural modelling and binding studies confirmed that the lack of exon 2 disrupts the SH3 domain, preventing the necessary conformational changes for asciminib-mediated inhibition.
  • Immunoblotting revealed that STAT5A/B phosphorylation, critical for leukemogenesis, remained unaffected by asciminib in e13a3 and e14a3 cells.

Fig 2: BCR::ABL1 e14a2 and e14a3 are asciminib resistant, but sensitive to dasatinib. Normalised viability of Ba/F3 cells expressing BCR::ABL1 e14a2, e14a3 and e13a3 fusion transcripts was measured in the presence of the indicated concentrations of asciminib (a)
or dasatinib (b) after 48 h.

Conclusion
This study provides evidence of a primary resistance mechanism to asciminib in CML patients with the e13a3 and e14a3 BCR::ABL1 isoforms. These findings are crucial for personalising treatment strategies in CML and suggest that ATP-competitive BCR::ABL1 inhibitors, such as dasatinib, should be preferred for patients with these isoforms. Genetic screening for BCR::ABL1 isoforms is crucial before initiating therapy to ensure optimal treatment selection for CML patients.

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.