Highlights from the SWG

SWG Session at EHA2023

ELN-EHA SWG for CML: CML: modelling the future

Chair

Jane Apperley (United Kingdom)

Topics and presenters

Identifying new targets for BCR::ABL1 inhibition: Oliver Hantschel (Germany).
Dissecting phylogenetic trees in CML: Aleksandra Kamizela (United Kingdom).
Drug profiling for CML blast crisis: Satu Mustjoki (Finland).

CML in the EHA Research Roadmap

Tyrosine kinase inhibitors (TKIs) have substantially improved the survival of chromic myeloid leukemia (CML) patients, and there is now a reasonable expectation that a significant proportion of patients will be cured.

The main objective of the EHA SWG is to integrate the leading European national trial groups in CML. In particular, it aims to form a cooperative network for advancements in CML-related research and healthcare.

Within the group of European Investigators on CML (EICML), a clinical trials platform has been created to promote the performance of clinical trials with new drugs and/or treatment strategies. Standardization of diagnostic and therapeutic procedures allows outcome comparison across Europe.

We aim to improve:

Tolerability of the treatment
The rate of deep molecular responses
The proportion of patients in durable remission after stopping TKI

Enhanced inhibition of BCR-ABL1 with more specific inhibitors or drug combinations are possible strategies to improve treatment-free remission (TFR) by increasing the rates of deep molecular response. Clinical approaches utilizing immune surveillance to eradicate residual leukemic cells are potential future research directions to improve TFR rates.

Despite major improvements in the standard of care for CML, further research is needed into the:

Complexity of CML blast crisis pathophysiology
Failure of TKIs to eradicate CML at the stem cell level
Observation of molecularly defined BCR-ABL1 negative clones

A better understanding of the events governing leukemic stem cell behavior might lead to the biological cure of CML and effective treatment of blast crisis.

Biostatisticians and patient advocacy groups cooperate with the study groups with a European clinical trials platform which will support coordination of the studies.

CML and HARMONY Plus

HARMONY was initiated in January 2017 for a period of five years and is funded through the European Union's (EU's) Innovative Medicines Initiative (IMI).

In June 2021, we launched a new project in HARMONY Plus focused on CML.

There is a need for a global platform to systematically evaluate the mutational landscape of CML:

At diagnosis
During treatment, should resistance occur
In advanced disease

This will provide evidence for informed expert international clinical practice guidelines for genomic-based monitoring in CML.

As the HARMONY BigData platform will be the largest CML register in Europe, this analysis:

Would greatly bridge the gap in knowledge
Could significantly contribute to improved outcome for patients with CML

Under the leadership of Thomas Ernst and Susan Branford, we will harness the wealth of genomic information that is generated in local CML research projects. We will do this by building a platform to facilitate data assimilation and analysis, in order to evaluate the clinical relevance of these variants.

We aim to discover biomarkers that could predict treatment response and progression, and guide drug use and development. Participating laboratories will contribute data to answer key clinical questions related to:

BCR-ABL1 independent mutations at diagnosis
The evolution of BCR-ABL1-independent clones during TKI therapy
Molecular aberrations during advanced phase disease
Mutations detected in single cells and specific cell populations, which might point towards strategies to increase the number of patients who achieve treatment-free remission

In 2022, a research proposal for the iCMLf TFR Alliance and global TFR registry was officially accepted by HARMONY PLUS. The resulting research project is known as ‘CML-2: Using Big Data to Map and Identify Optimal Treatment Pathways to Treatment-Free Remission in CML.’ The key objective of this project is to evaluate a multitude of factors that likely predict and influence successful TKI discontinuation for patients with CML.

This evaluation will be conducted utilizing updated and novel epidemiological approaches. The aim here is to accumulate and analyze ‘big data’ in a wide, collaborative international effort from multiple contributors within the iCMLf TFR Alliance.

At present, 24 sites from 16 countries are participating in the global TFR registry and beginning the process of signing data sharing agreements with HARMONY.

To read more, visit the CML-2 project page on the HARMONY website.