An important research article has just been published in Cancer Discovery titled ‘Genomic evolution and natural history of myeloproliferative neoplasms on therapy’.
In a small, but intensive study of 30 MPN patients in the UK, researchers (including 2 Australian researchers), used long-term whole-genome sequencing to track how MPNs evolve over time.
There were several findings of interest.
1. Progression in MPNs is “genomically encoded years before clinical transformation, with distinct evolutionary routes to leukaemia and myelofibrosis”. This process can happen silently while blood counts are stable and patients appear clinically unchanged. So whilst current patient care focuses on blood counts, thrombosis, bleeding and cardiovascular risks, the genomic risk of progression is also a factor.
Researchers note that “In patients who progressed to MF (myelofibrosis) and AML (acute myeloid leukaemia), genetically defined subclones harbouring additional driver mutations were detectable before changes in blood counts or other clinical features. In contrast, prolonged clonal equilibrium without acquisition of new drivers was strongly associated with clinical stability, even over decades of follow-up.”
The MPN AA notes however, that in Australia, and internationally, prohibitive costs limit routine whole-genome sequencing for MPN patients. But in future, it is hoped that genomics-guided monitoring and treatment may be more accessible.
2. Some patients with triple-negative essential thrombocythemia (ET) may not in fact have an MPN. In this study, some cases of triple-negative ET showed normal, age-related blood cell diversity. The authors point out that “this has important implications not only for diagnostic labelling of patients, but also therapeutic decision-making, particularly regarding exposure to long-term cytoreduction”
A very recent British Society of Haematology guideline addresses this issue. ‘Investigation and management of thrombocytosis without JAK2, CALR or MPL mutations: A British Society for Haematology Guideline‘
3. Hydroxycarbamide (and azacitidine) were found to cause specific DNA mutations in blood cells. Specifically, the researchers “observed that HC (hydroxycarbamide) exposure correlated with the presence of HC-induced mutations, cumulative HC dosage, as well as years of exposure.” Despite this, it was not found that these mutations drive any transformation to leukaemia.
Reassuringly, the researchers clarified that “large population-based and cohort studies consistently show no increased risk of AML or secondary solid organ malignancy with hydroxyurea, and leukemic transformation appears primarily driven by the underlying MPN biology rather than cytoreductive therapy.”
4. The MPN AA notes that skin cancer discussions and findings in this UK study are also of interest, especially for Australian patients. Researchers noted previously published studies that found “Non-melanocytic skin cancer, such as cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) are an increasingly emergent challenge during MPN therapy, and associated with both HC and ruxolitinib therapy.”
However the skin cancers that patients involved in this study developed (e.g. cutaneous squamous cell carcinoma) were found to be mainly caused by UV damage, not by any mutations from hydroxyurea (and interestingly there was no mutagenesis from hydroxyurea seen in skin.)
Researchers noted “These findings suggest that while HC leaves a detectable mutational footprint in haematopoietic cells, its contribution to cutaneous epithelial mutagenesis, if present, is not readily apparent in the context of dominant UV-induced damage, at least in this one individual.”
Press release and article
A news release including quotes from the researchers is available and condenses the key elements from the article.
The full article ‘Genomic evolution and natural history of myeloproliferative neoplasms on therapy’ is also free to access. (Please note that once on that webpage, the full article is available by clicking on the PDF link).
