Ruxolitinib is a Janus kinase 2 (JAK2) inhibitor with diverse indications covering conditions such as eczema, psoriasis, vitiligo and myelofibrosis.
Most recently, in the UK at least, it has been added to the treatment arsenal for the rare blood cancer polycythaemia vera (PV) after its recommendation in October 2023 by the National Institute for Health and Care Excellence (NICE).
Professor Claire Harrison, consultant haematologist, professor of myeloproliferative neoplasms at Guy’s and St. Thomas’ NHS Foundation Trust in London, UK, has dedicated much of the last decade to researching ruxolitinib for use in PV and was instrumental in securing NICE’s endorsement.
‘It’s [a good] example of following a scientific story from discovery of the mutation, development of the drug, testing it in a more severe but related condition (myelofibrosis) then putting it into second line for PV,’ she says.
Despite the approval, there’s still work to be done to achieve the next ambition of ruxolitinib being approved for first-line use in PV. And Professor Harrison is on hand to get the ball rolling.
Diagnosing and managing polycythaemia vera
Today, diagnosing PV is much easier than when Professor Harrison first started as a consultant in 2001.
Previously, the diagnosis was arrived at following a series of tests to exclude all other possible causes of a patient’s symptoms and abnormal blood count. But after the description of a JAK2 mutation which is present in 97–98% of patients with PV, the diagnosis can be arrived at much more quickly.
‘This particular mutation for which it’s very easy to test for. It’s a cheap test and, for the most part, if it’s present, the patient has either got PV or one of the family of conditions, or it has very low levels of mutations but is likely to change into that,’ Professor Harrison says.
In general, the lay perception of a cancer diagnosis is that it represents a death sentence, and it becomes difficult to assuage patients of this fear.
While PV is incurable and lowers life-expectancy, it is not usually life-threatening, although Professor Harrison says some patients do present with life-threatening blood clots.
‘It’s a cancer but some low-risk patients we just treat with aspirin and phlebotomy, so removing blood,’ she says. ‘So that’s quite tricky saying “you’ve got cancer, but all we’re going to give you is an aspirin and take a pint of blood off you”, and other patients we do give treatments to, but we have limited options.’
Moreover, while these treatments do provide a clinical benefit in some patients, they frequently fail to alleviate symptoms.
This has become abundantly clear from the findings of the ongoing prospective REVEAL study. This showed that patients with PV experience symptoms that affect their quality of life and lead to work productivity impairments with an overall negative impact on their lives.
‘So, 80% of patients will complain of fatigue,’ Professor Harrison says. ‘It’s PV, it’s not a nothing condition: 20% of patients have to give up work or reduce their working time, others do die of the condition and the average life-expectancy is probably 15 to 20 years.’
Professor Harrison also highlights poor awareness of PV. ‘What patients would say, probably, is that people don’t understand the condition, GPs don’t understand the condition and their employers don’t understand the condition. It takes up a lot of their time and it has a big burden on their quality of life.’
She hopes that greater awareness of the condition will make it easier for people to support and make adaptations for this patient group.
Addressing unmet needs in PV
There haven’t been any new treatments for PV in around 20 years, with hydroxyurea and interferon alpha having long been the two options.
But that all changed with the description of the mutation. Professor Harrison says that after first helping with diagnosis, these learnings aided the development of drugs that could target the downstream effects of that mutation, principally JAK inhibitors.
‘These were first tested and used in more aggressive conditions in the family such as myelofibrosis. But with the advent of these drugs and their use in PV, we have been able to show that we can address some of the other unmet needs for patients,’ she says.
‘I could comment on how disappointing it is that the UK is five years behind the rest of Europe in the approval of ruxolitinib for PV, but I would prefer to celebrate that it’s a really important milestone for patients that they have an alternative therapy.’
This is particularly important as resistance or intolerance to treatments can develop in some patients, and there are other side effects and contraindications that mean traditional treatments may not be suitable.
‘An important side effect of hydroxyurea, which is also a side effect of ruxolitinib, is skin cancer,’ says Professor Harrison. ‘That’s something that we need to manage very carefully. If a patient has a skin cancer on hydroxyurea, we will sometimes change the therapy.
‘Interferon does cause quite serious mood disturbance – sometimes suicidal ideation – so it can’t really be used in patients who’ve got a significant history of anxiety or depression.
‘Similarly, [hydroxyurea] can’t be used for the 20% of patients below the age of 40 who might want to conceive a child. But we have the option to alternate between the first-line therapies.’
Emerging benefits of ruxolitinib
One of the key studies that led to the approval of ruxolitinib for PV in the UK was MAJIC-PV. This phase II trial, for which Professor Harrison was the lead author, randomised patients to either ruxolitinib or best available care in those intolerant or resistant to hydroxyurea, which is the current standard care therapy.
What was clear from MAJIC-PV was the superiority of ruxolitinib, with 43% of patients achieving a complete response based on several haematological criteria compared with only 26% of those receiving current best practice care.
While ruxolitinib does not cure PV, the MAJIC-PV trial provided reassurance that over five years no new longer-term safety issues emerged, Professor Harrison notes.
The trial also uncovered several additional biological actions of the drug. During the study, researchers measured the amount of abnormal JAK2 present in patients. This enabled clinicians to determine whether treatments had any effect on the aberrant mutations that were present.
Surprisingly, in those assigned ruxolitinib, there was a reduction in the level of this mutation.
As such, the MAJIC-PV study hinted at a mutation-specific effect of the drug which hadn’t previously been observed. Furthermore, this reduction in the level of abnormal JAK was associated with an increased life expectancy and a reduction in PV-related complications for patients.
‘Interestingly, when we were using the drug to treat patients with myelofibrosis, colleagues in Italy were reporting that their patients who had myelofibrosis but had the autoimmune condition alopecia, the hair was coming back,’ Professor Harrison adds. This hints at the wider benefits of ruxolitinib as an anti-inflammatory drug which is being harnessed in for example the treatment of eczema.
Delving deeper, Professor Harrison also describes how in research by colleague Adam Mead ruxolitinib appeared to modify PV at the stem cell level using research tools enaling the analysis of mutations at a single cell level.
Ruxolitinib as a first-line option?
Despite MAJIC-PV showing that ruxolitinib reduced levels of the abnormal JAK mutations, the current NICE approval recommends that the drug is used second-line for patients who either become resistant to or intolerant of hydroxyurea.
Notwithstanding this restriction, Professor Harrison still feels that it is important for patients to have access to ruxolitinib as another treatment option, either because of contra-indications or adverse effects from the currently available drugs.
Another consideration is the issue of drug resistance. ‘All of the available drugs are generally effective for the majority of patients, but over time, around 20–25% of patients will become resistant to that drug,’ she explains.
As a result, relying on a single drug isn’t the most effective way of controlling a patient’s blood count over time.
Encouraged by the findings from MAJIC-PV, a further phase III open-label trial, MITHRIDATE, for which Professor Harrison is the chief investigator, is starting to enrol patients.
It is designed to compare ruxolitinib with either hydroxyurea or interferon alpha as first-line therapy for high-risk PV patients.
Ruxolitinib also has a powerful effect on disease related symptoms for example patients with PV experience pruritus (itching) which can be extremely disabling, and the drug has a big impact on this troublesome symptom.
Although it is too early to draw any conclusions, Professor Harrison is hopeful that the MITHRIDATE trial will demonstrate the advantages of using ruxolitinib as a first-line treatment option and perhaps offer further insight into the drug’s disease-modifying properties.
Future treatment developments
While the introduction of JAK inhibitors such as ruxolitinib are a welcome addition to a clinician’s arsenal in the treatment of PV, Professor Harrison believes that future treatments need to focus on the off-target effects of these drugs such as immune suppression.
Although the development of JAK mutation-specific therapies in PV would be an advantage, Professor Harrison is of the opinion that it is just as important to improve understanding of how and when to use ruxolitinib in patients with PV.
Alongside the potential development of mutation-specific drugs, there is increasing interest in immune-mediated therapy.
‘I think we’ve had this massive step forward with description of molecular markers and therapies targeting JAK. We’ll probably go to treating PV earlier, and treating with a disease-modifying therapy,’ she concludes.
But focusing on the latest developments, Professor Harrison believes the introduction of innovations such as ruxolitinib would not have been possible without the support of various charities such as MPN Voice and Blood Cancer UK, as well as various academic centres and companies such as Novartis.
Working collaboratively, it has been possible to clearly demonstrate that ruxolitinib can go a long way towards helping to relieve the symptom burden of patients living with polycythaemia vera and improve quality of life for this under-represented patient population.