Results of an important observational study were published on 31 August 2026 in Hemasphere.
Titled, ‘Allele burden expansion in JAK2V617F and CALR-mutated myeloproliferative neoplasms predicts disease progression and is associated with anagrelide treatment,‘ it provides valuable real world insight into how MPN patients’ mutation levels and treatments may impact the course of their disease.
What was the study investigating?
The researchers, led by Australia’s Zi Ng, in collaboration with Australian and international haematologists, wanted to understand whether changes in the variant allele burden/frequency (amount of abnormal blood cells carrying an MPN mutation and often called the VAF), can tell us something about how our MPN is progressing.
They specifically looked at JAK2 V617F and CALR mutations.
In simple terms, the allele burden shows what proportion of the tested blood cells carry the particular mutation. The researchers wanted to know whether increasing or decreasing allele burden were associated with better or worse disease outcomes.
What did researchers do?
They studied 347 MPN patients from eight international centres:
157 had JAK2 mutations and 190 had CALR mutations.
15 of these patients had PV. Most had ET or myelofibrosis.
Patients were receiving different treatments:
- Pegylated interferon
- Ruxolitinib (Jakavi)
- Hydroxycarbamide (hydroxyurea)
- Anagrelide
Researchers compared mutation levels at two different time points and followed patients to assess disease progression.
What did they discover?
There were several valuable findings.
A. Increasing mutation levels were associated with disease progression
People whose JAK2 or CALR mutation burden increased by at least 10 percentage points were more likely to experience disease progression. Progression included:
- Transformation to myelofibrosis
- Development of more advanced or aggressive disease
- Development of MDS or CMML
For every 10 percentage-point increase in mutation burden, the risk of subsequent progression increased by approximately 58% in their statistical analysis. This is an association, not proof that increasing mutation levels directly cause progression.
B. Interferon performed well
Of the treatments studied, interferon produced the highest rate of substantial molecular responses. Patients achieving a deep molecular response:
- Pegylated interferon 14.5%
- Ruxolitinib 8.6%
- Hydroxycarbamide 2.3%
- Anagrelide 0%
This is encouraging evidence supporting interferon’s ability to reduce the underlying abnormal cell population, rather than simply controlling blood counts.
C. Anagrelide was associated with increasing mutation burden
More than half (55.2%) of patients receiving anagrelide experienced an increase in mutation burden of at least 10 percentage points, compared with an increased allele burden for patients on the following treatments:
- Hydrea 23.9%
- Interferon 19.7%
- Ruxolitinib 14.3%
The researchers suggest this may help explain previous observations linking anagrelide with an increased risk of fibrotic transformation. However, the study cannot establish that anagrelide itself caused disease progression.
This association between anagrelide and increased allele burden of more than or equal to 10%, was independent of driver mutation type and was retained when the analysis was restricted to ET patients.
Why is this study important?
Traditionally, MPN treatment has focused heavily on controlling blood counts and reducing the risk of blood clots.
This study adds to the growing evidence that what is happening at the molecular level is also of interest. A rising JAK2 or CALR allele burden may be an early warning sign of disease evolution, potentially appearing years before clinical progression becomes apparent. Mutation burden may provide an additional way of assessing how well treatment is working.
It may also help identify people who need closer monitoring or consideration of a change in treatment.
It raises questions about the suitability of anagrelide as a long-term treatment for some people with MPNs. However it does not establish a universal 10% threshold for changing treatment.
What are the study’s limitations?
There are some important qualifications:
This was an observational study, not a randomised clinical trial.
The majority of participants had ET or myelofibrosis, rather than PV.
The researchers could not prove that reducing mutation burden directly prevents disease progression.
Researchers did not establish that every patient needs regular mutation testing.
The study examined JAK2 and CALR driver mutations, not the behaviour of additional mutations over time.
Access to full letter
The letter and study are freely available to read in full due to publication in Hemasphere. ‘Allele burden expansion in JAK2V617F and CALR-mutated myeloproliferative neoplasms predicts disease progression and is associated with anagrelide treatment.‘
