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Comprehensive molecular characterization of treatment-free remission and molecular relapse in chronic myeloid
S Rinaldetti1,2, M Chepeleva3,4, A Hedblom5
1Department of Hematology and Oncology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg.
Abstract:
The European Stop Kinase Inhibitors (EURO-SKI) trial was launched to investigate the discontinuation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML). The molecular mechanisms underlying sustained treatment-free remission (TFR) and loss of TFR, are still poorly understood. To address this, we performed whole transcriptome gene expression analyses coupled with NanoString nCounter-based absolute gene quantification. Gene expression was assessed in peripheral blood leukocytes from 240 CML patients on the final day of TKI intake (training sample: n = 122, validation sample: n = 118) as well as from 10 healthy controls. To identify TKI-specific mechanisms, transcriptomic data from an external dataset of 96 TKI-naïve CML patients was incorporated into our analyses. TFR patients showed an activation of GATA1, KLF1 and MYBL1 regulons characteristic for erythroid progenitor cells. TFR patients maintain persistent communication between innate (natural killer and dendritic cells) and adaptive immunity (e.g., CD8+, CD4+, and γδ T lymphocytes), mirroring patterns observed in healthy controls. This intercellular communication is disrupted in patients with loss of TFR. Furthermore, we identified an FLT3 threshold that distinguished two patient groups with significantly different probabilities of TFR loss. Leveraging mechanisms that reestablish or reinforce the communication between innate and adaptive immunity could be pivotal in achieving durable TFR.
Insights
Discontinuing tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients is possible for some. Sustained treatment-free remission (TFR) depends on immune cell communication, which is disrupted upon TFR loss.
Area of Science:
- Hematology
- Immunology
- Genomics
Background:
- Chronic myeloid leukemia (CML) treatment often involves tyrosine kinase inhibitors (TKIs).
- Discontinuation of TKIs to achieve treatment-free remission (TFR) is a goal, but relapse mechanisms are unclear.
- Understanding molecular drivers of TFR maintenance and loss is crucial for CML management.
Purpose of the Study:
- To investigate the molecular mechanisms of sustained treatment-free remission (TFR) in chronic myeloid leukemia (CML).
- To identify gene expression patterns associated with TFR maintenance versus loss after tyrosine kinase inhibitor (TKI) discontinuation.
- To explore the role of immune cell communication in TFR.
Main Methods:
- Whole transcriptome gene expression analysis and NanoString nCounter quantification in CML patients undergoing TKI discontinuation (EURO-SKI trial).
- Analysis of peripheral blood leukocytes from 240 CML patients and 10 healthy controls.
- Integration of external transcriptomic data from 96 TKI-naïve CML patients to identify TKI-specific mechanisms.
Main Results:
- TFR patients exhibited activated erythroid progenitor cell regulons (GATA1, KLF1, MYBL1).
- Sustained TFR patients maintained immune cell communication (innate and adaptive) similar to healthy controls.
- Loss of TFR correlated with disrupted intercellular communication and identified an FLT3 expression threshold impacting TFR durability.
Conclusions:
- Sustained TFR in CML is associated with specific gene expression profiles and robust immune cell communication.
- Disruption of innate and adaptive immune cell crosstalk is linked to TFR loss.
- Targeting mechanisms to restore immune communication may improve durable TFR in CML patients.
