Highlights from the SWG
1. SWG Session at EHA2022
ELN-EHA SWG for CML: Understanding the pathogenesis of CML
Chair: Jane Apperley (UK)
Lessons from EUTOS 2018-2021
Katerina Machova Polakova (CZ)
Non-BCR-ABL1 molecular biomarkers of prognosis
Shady Awat (FL)
Mechanisms of stem cell persistence in CML
Mirle Schemionek (GE)
Mechanisms of disease progression in CML
Tiong Ong (Sin)
2. CML in the EHA Research Roadmap
TKIs have substantially improved the survival of 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 to form a cooperative network for advancements in CML-related research and health care. Within the group of European Investigators on CML (EICML), a clinical trials platform was 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, and 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 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, the complexity of CML blast crisis pathophysiology, together with the failure of TKIs to eradicate CML at the stem cell level, as well as the observation of molecularly defined BCR-ABL1 negative clones demand further research. 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.
3. 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 focussed 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, and 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 and 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 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 project: 'Use of big data to identify optimal treatment pathways leading to successful treatment-free remission in CML' has a key objective 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 to accumulate and analyze “big data” in a wide collaborative international effort from multiple contributors within the iCMLf TFR Alliance. There are currently 24 sites from 16 countries participating in the global TFR registry and beginning the process of signing data-sharing agreements with HARMONY.
4. Michele Baccarani 1942-2021
It is with deep regret that we announce the death of Michaele Baccarani in December 2021. Prof. Baccarani graduated from the University of Bologna School of Medicine in 1966, trained in internal medicine at the Sant’Orsola-Malpighi University Hospital of Bologna, and specialized in haematology at the University of Modena in 1969. In 1979 he was appointed Professor of Cancer Chemotherapy at the University of Chieti and in 1986, he moved to Trieste as a Professor of Haematology. In 1987, he took the chance to create a strong haematology group as Head of the Division of Hematology and the Department of Bone Marrow Transplantation at Udine University Hospital. When Prof. Tura retired in 2000, Baccarani succeeded him as Prof. of Hematology at the Alma Mater Studiorum, Università di Bologna, and Head of the Institute of Hematology and Medical Oncology and Department of Hematology and Oncology “L. and A. Seràgnoli” until his retirement in 2012. From 2001 to 2007, he served as Vice-Dean of the Faculty.
Throughout his career and despite increasing administrative and teaching responsibilities Prof. Baccarani never lost his enthusiasm for CML. He was instrumental in the development of the Sokal risk score through a collaboration with Prof. Joseph Sokal in 1983 at Duke University, USA. Prognostic scores for CML remained a passion when he later cooperated with Prof. Jörg Hasford in developing the Euro risk score and, again with Profs. Hasford and Markus Pfirrmann, in developing the more recent EUTOS and ELTS scores. He was one of the founders and one of the most active members of the Italian Study Group on CML that later became the GIMEMA CML Working Party, a multi-center cooperative including more than 80 centers. The group became internationally prominent in 1994 when they reported in a randomized controlled trial superiority of interferon-alpha over conventional chemotherapy. In 1993, Prof. Tura with Prof. Baccarani’s help invited the leading European clinicians interested in interferon and CML to a meeting in Venezia which started the annual workshops of the European investigators in CML (EI-CML) and which had a lasting impact on cooperative CML research across Europe and became the nucleus of the future European Leukemia Net (ELN). As a Member and Chairman of the ELN-WP 4 on Chronic Myeloid Leukaemia, he led the development of the widely cited 2006, 2009 and 2013 ELN CML therapy recommendations putting him at center stage of international CML. He served in multiple international committees and panels, most notably on the Boards of Directors of the ELN-Foundation and the International CML Foundation. The international CML-community remembers Michele Baccarani as a brilliant researcher of great intellectual honesty and an international leader in CML.