Clinical trials critical to finding curative therapies for MPN
Associate Professor David Ross is a clinical and laboratory haematologist who has always had an interest in MPN. His clinical PhD scholarship in CML, monitoring residual disease, was funded by the Leukaemia Foundation. He is Head of the Clinical Trials Unit at the Royal Adelaide Hospital and Director of the South Australian Cancer Research Bio Bank. In this comprehensive interview he discusses everything from research, current therapies, clinical trials, diagnosis, prognosis, incidence, and more, and says, “it’s a very exciting time in MPN”.
After “almost nothing” by way of new treatments for 20 or 30 years, “there’s just been this massive explosion of clinical trial activity in MPN, said Associate Professor David Ross.
“We’ve gone from a situation where there were basically no new treatments, to one where a dozen drugs have been in clinical trials over the past few years.”
But one of the big issues in MPN remains.
“In CML, we have drugs like imatinib that essentially turn the disease off and, for most patients, ensure that it will never transform to a more aggressive phase, and the patient will never die from leukaemia,” explained Dr Ross.
“Therapies have improved some of the clinical manifestations in MPN, but the drug treatments available don’t change the long-term outcome of the disease.”
Does he see this changing?
“Look, I think it will. There’s been a huge amount of research on MPN in the last 10 or 20 years.”
Dr Ross said his holy grail is “to have a treatment for MPN that is curative, to be able to give someone a course of treatment that completely gets rid of the disease, gets rid of future risk, gets rid of any current symptoms or problems”.
JAK2 mutation – the key discovery
“That key discovery, first published in 2005, has given scientific insights into these diseases that has spurred a lot of research and development,” said Dr Ross.
“Then there’s the calreticulin (CALR) mutation, found in about a third of patients with ET and MF. This second most common mutation was only discovered in 2013.
“That extra scientific information is a clue for academic researchers and drug companies to start understanding the disease and looking for drugs that can target those particular pathways.
“That’s where the JAK inhibitors came from, like ruxolitinib (Jakavi®), but as people better understand what CALR does, and what JAK2 does, and what MPL [another MPN mutation] does, they may find other targets that might be more effective.”
Next generation sequencing
Another important development was ‘next generation’ sequencing (NGS). Traditional sequencing looks at one small section of a single gene. NGS looks at many different sequences, often in many different genes, all at the same time.
“NGS panels are available for various blood diseases with lots of different mutations. These may test five or six genes, sometimes 30 or 40 genes, so a single test will give you a large amount of information,” said Dr Ross.
“There’s an increased use of sequencing panels to look for not only JAK2, MPL, and CALR, but also other mutations that may be associated with higher risk disease and that currently are most relevant for MF. They are IDH1, IDH2, ASXL1, EZH2, U2AF1, and SRSF2.
“The presence of a mutation in one of those genes increases the risk of MF, and for a small group of patients that’s really essential information, used in guiding transplant decisions.
Sequencing panels may also be useful to clarify the diagnosis.
Dr Ross went on to explain that if someone is intermediate risk, but doesn’t have any bad mutations, that might downgrade that person to being low-risk. Whereas, if someone is intermediate risk and has one or two of those mutations, that might push that person up into a high-risk group where the life expectancy might be only two or three years, and convert them from a watch and wait approach to going straight to a bone marrow transplant.
Dr Ross said this panel test was not currently funded by the Federal government.
“As is usually the case, the Medicare rebate for the test lags years behind research and clinical practice, so individual hospitals are paying for it, or sometimes individual patients pay to have it done privately.”
He said the cost varied from $400 for a small panel looking at the most common mutations in a particular gene, up to $1500 for a more extensive panel that sequenced 30-40 genes.
“But when you think that a bone marrow transplant might cost quarter of a million or half a million dollars, this is a trivial amount of money.”
Each state has different rules about getting tests done.
“In South Australia, everyone with MF who’s been discussed for transplantation would get this done; that’s a small number of patients out of the total MPN population, because MF is the rarest of the MPNs and only 25% or less of MF patients will be transplant-eligible.”
Clinical trials in MPN
Most recent studies have been for myelofibrosis, reflecting it being the MPN with the highest need.
Ruxolitinib was the original JAK inhibitor. Several studies have explored other JAK inhibitors (fedratinib, pacritinib, and momelotinib) on their own, or comparing them to ruxolitinib.
“Different companies are looking to see if one of the newer JAK inhibitors works after ruxolitinib has failed, or offers advantages over ruxolitinib in certain patients,” said Dr Ross.
“For instance, there is some hope that pacritinib might be better in people with a low platelet count, and momelotinib might be better in people with a low haemoglobin.
“Neither has been proven, but these are the questions that are being looked at in clinical trials.
“We currently have a momelotinib study [called Momentum] that is recruiting patients with myelofibrosis who are anaemic.
“The ‘mel’ in the name is because it was originally developed in Melbourne,” he explained.
“It’s already been used in hundreds of patients, so we know that it works.
“Most people on ruxolitinib have a modest drop in haemoglobin; they become more anaemic. It’s been observed that with momelotinib, the drop in haemoglobin is less, and some patients have an improvement in anaemia.
“So, whether momelotinib will offer an advantage specifically in the subgroup of people with myelofibrosis who are anaemic is being explored,” said Dr Ross.
Momelotinib and ruxolitinib both inhibit JAK1 and JAK2. Another study testing fedratinib will try to answer the question of whether there is some advantage to a pure JAK2 inhibitor [it doesn’t inhibit JAK1]. This study will recruit MF patients who have a had a suboptimal response on ruxolitinib, but is currently on hold due to COVID-19.
The Kartos study opened recently. KRT-232 is an MDM2 inhibitor being tested in MF patients who have failed on ruxolitinib therapy. Dr Ross said MDM2 was involved in the P53 pathway, which is important in lots of different cancers. It’s a quality control pathway within the cell that senses DNA damage and causes the cell to undergo apoptosis [cell death] if there has been DNA damage.
“These are all international studies that include Australian sites,” said Dr Ross.
And there are other drugs in completely different classes that have different mechanisms of action that have been tried in early phase studies.
Australians were among the first patients enrolled on an ongoing study of bomedemstat that inhibits an epigenetic enzyme involved in controlling blood cell production.
“It’s a tablet and it’s shown some improvements in symptoms and spleen size and is generally quite well tolerated,” said Dr Ross.
An initial study of ruxolitinib combined with another class of drugs, called BET inhibitors, showed some encouraging responses. Now a larger study is in the planning stage and may open in Australia in the next six months.
Experimental data suggests navitoclax, which is related to venetoclax, and inhibits another member of the BCL-2 family, may be useful in MF, and luspatercept is being explored to see if it improves anaemia in MF.
The ADORE study is open at several sites for Australian MF patients who are on ruxolitinib and are anaemic. It is a Phase I platform study looking at a series of experimental drugs being added to ruxolitinib. A small number of patients will try each combination and then the results will be reviewed to decide which combination is the most promising, to take it to a bigger study.
“So, it’s a ‘pick a winner’ study,” said Dr Ross.
Studies in PV and ET
Dr Ross said that the first clinical trial in Adelaide for PV closed recently. It was using another MDM2 inhibitor called idasanutlin, “and it definitely works in some people who failed standard treatment”. The study closed due to toxicity concerns.
“The main issue was nausea. You can imagine that if you’ve got PV and you’re going to live with the disease for 10 or 20 years, having a drug that causes nausea for a week every month is not very good for quality of life.”
He also is “quite excited” about an upcoming ET study, also using bomedemstat. The opening of this study has also been delayed by COVID-19 but is expected in late-2020.
“It will be our first ever ET study in Adelaide.”
“Because we’ve already had experience with that drug, we know that its safety profile is pretty good, so I’m optimistic about that.
“It will be for people who have been resistant to, or intolerant of hydroxyurea, which is the standard treatment for most people with ET.”
Ask about studies for you
“There are many studies for myelofibrosis at the moment – we’ve currently got four in South Australia – and a lot of the time they’re competing for the same rare patient population,” said Dr Ross.
“For companies to test their drugs, they need more patients.
“If we can’t enrol patients in clinical trials, it slows down the development of a drug and means that our patients won’t get normal access to the drugs because it takes longer to do the study properly.
“This is the problem of a rare disease.”
Dr Ross urged patients with MF to be proactive in asking their clinicians about clinical trial options in their city.
“A lot of these studies are open in only one hospital or maybe two hospitals in a bigger city. We need people to be referred to sites where a study is open, so we can put people on them,” he said.
“And they can look on the ClinTrial Refer app or website to see whether there’s anything that meets their particular circumstances.
“A lot of these studies are looking for only a few patients in each hospital, who meet very specific criteria, but if there are five or six studies, there is room for a lot of patients,” said Dr Ross.
The prime target population in MF are those patients on ruxolitinib or who have been on ruxolitinib and have not had an optimal response, and the main focus of these studies is to improve on the benefits already seen with ruxolitinib.
MPN is different from other blood cancers
MPN is a blood cancer, said Dr Ross, “but the way it behaves is completely different from lymphoma or leukaemia, so many people with MPN can go undiagnosed”.
“What sets ET and PV apart from other diseases, is that many people have either no symptoms or vague symptoms, like tiredness, together with blood count abnormalities, which means they may go undiagnosed for some time,” he explained.
“They’re often overlooked for a long period of time. That’s one of the standout features of ET and PV, and the main risk is bleeding and clotting (venous or arterial thrombosis) that can come out of the blue in people who didn’t know that they had an MPN.
“That makes it quite different from most other cancers. You’re not treating a tumour or trying to clear out the leukaemic cells, you’re mostly trying to protect the patient from having a clotting or bleeding episode.
“And the longer you leave it, the more chance there is of having a clot.
“What we know is that some people turn up and they have a clot that could potentially have been prevented if the diagnosis had been made earlier. So, a significant fraction of people with MPN will first be diagnosed when they present with a blood clot or a stroke or a heart attack.
“Sometimes, in those cases, we see someone who comes in having had a high platelet count for three years, and nobody’s done anything about it. So possibly, if that person had received appropriate treatment, he or she might never have had that clot,” said Dr Ross.
He cited the findings of a colleague with a long-standing interest in MPN, Dr Cecily Forsyth. She went back through the records at her centre, at Gosford (NSW), looking at people with a diagnosis of MPN and tracked their haemoglobin, white blood cell, and platelet counts.
“One of the patients had a high platelet count for 20 years before a diagnosis was made,” said Dr Ross.
“The estimated risk of having a clot is about 2% per year for ET, and maybe about five or 10% for PV. Many people, just by chance, will go years without having any problems, but someone’s got to be the one who’s unlucky.
“If someone has blood tests for other reasons and a mildly elevated platelet count is noted, it would often be disregarded if the person is otherwise well.
“In most laboratories, a normal platelet count is 150-450. In fact, your platelet count might be 300 or 200, but the top of the normal range is commonly close to 450.”
What complicates things is that if you are unwell, for instance if you have a chest infection, or if you are iron deficient, your platelet count might go up.
“In young women, in particular, it’s quite common to be iron deficient due to periods or pregnancy, so a slightly high blood count may be disregarded.
“And in an older person who’s got arthritis or other chronic health problems, a slightly high platelet count might be put down to inflammation.
“It’s when there’s a sustained elevation, with no obvious cause, that someone needs to think, ‘well, actually, this has been present two or three times. It needs to be looked into’.”
Myelofibrosis and stem cell transplantation
Dr Ross said myelofibrosis (MF) is completely different from ET and PV.
“Most people with MF feel unwell. They often have severe tiredness, itching, sometimes night sweats, and discomfort from enlargement of the spleen,” he said.
“The main aim of treatment is to lessen the severity of those symptoms, improve quality of life, and make people feel better.
“And, because MF is a more serious disease with a shorter life expectancy, we do bone marrow transplantation for higher risk MF patients who are young and fit, in whom the risks of transplantation are warranted.
“The age limit for transplantation has been continually creeping up over the past decades. Now, for most sites around the country, it’s up to age 70.
“Unfortunately, the risks associated with the transplant rise steeply once you’re above 50 [years old], and the chances of dying from the transplant if you’re nearly 70 are pretty high. The average age at diagnosis of MF is also around 70, so we don’t do very many transplants for myelofibrosis, but it is a potentially curative treatment,” said A/Prof. Ross.
Transplantation is not used for ET or PV because the risk is rarely justified. The treatments for those diseases are about controlling the blood counts and reducing the risk of clotting, but they’re not eradicating the disease or reducing the risk of future progression.
Diagnosis of MPN and its importance
MPN diagnoses are currently based on blood counts, bone marrow appearance, and clinical features, such as itching, sweating and spleen enlargement, said Dr Ross.
“It’s an old-fashioned classification system.”
He said Professor Tony Green’s group in the UK published a “highly influential” paper in the New England Journal on the results a large group of 2000 patients whose MPN was classified based on the results of genomic sequencing.
“They looked at patterns of mutation and showed that the behaviour of the disease and long-term survival could be predicted with some accuracy just by looking at the genes without the traditional pathological classification,” said Dr Ross.
“This hasn’t yet changed the way that we diagnose MPN, but it has emphasised the fact that you can get a lot of useful clinical and biological information from extended sequencing that may add to our old-fashioned classification system.
“And, in some cases where the bone marrow appearance is difficult to interpret, and one pathologist might think it’s ET, and another thinks it’s early myelofibrosis, looking at the sequencing for these difficult-to-classify cases might tell you, well, actually this is more likely to be MF, or actually, this is more likely to be PV.
“The biggest distinction is to identify early myelofibrosis and that’s important because the life expectancy is much shorter, and transplantation might be an option.
“And drug access is determined by having a biopsy that says you have myelofibrosis. You can only get ruxolitinib on the Pharmaceutical Benefits Scheme (PBS) if you have myelofibrosis; you can’t get if you’ve got PV or ET.
“It has been proven that ruxolitinib is effective in hydroxyurea-resistant and -intolerant PV, but it hasn’t been funded [by the PBS] because of the cost.”
“At the moment ET and PV are treated similarly. They both usually get hydroxyurea or interferon plus aspirin.
“The difference is that in PV, we aim to keep the hematocrit, which is a measure of haemoglobin, below 45%, as well as the platelet count and white cell count in the normal range. Whereas in ET, we only look at the platelet and white cell counts.
“Lots of drugs are being investigated at the moment and if any of those make it to clinical practice, the implication of making an accurate diagnosis will become more important,” said Dr Ross.
Incidence and prevalence of MPN
A paper published last year in the American Journal of Hematology based on epidemiology work by Professor Peter Baade reported on the latest available statistics on incidence, prevalence, and survival of MPN in Australia.
“This showed there are 23 cases of MPN per million population per year, so it’s a pretty uncommon disease, but because many people with MPN will live for many years, the prevalence is relatively higher, considering the low frequency of diagnosis,” explained Dr Ross.
“For instance, somebody with ET might live for 20-30 years, whereas for many cancers the survival will be much shorter.
“According to that study, new diagnoses of PV and ET were roughly equal; at about nine per million per year, and primary myelofibrosis is the rarest at about five per million per year.”
Regarding age at diagnosis, Dr Ross said the average age of diagnosis for all MPNs was 68. The oldest cohort, with an average age of 72 years, were those with primary myelofibrosis, and the youngest was ET at 66 years, closely followed by PV at 67.
However, he said, “there’s a tail of younger patients”.
“We see people in their 20s with ET, whereas myelofibrosis is rare below the age of 40.”
“The cause of MPN in most cases is unknown. If you have a family member with MPN, your risk of getting an MPN is increased about five-fold compared to the general population.
“Although it’s not an inherited disease, there’s an inherited risk component. We do occasionally see brothers and sisters or parents and children that both have MPN.”
Dr Ross said there weren’t any known strong risk factors, although there is an increased risk with exposure to radiation and, rarely, to industrial chemicals.
“No-one has ever done a proper, large epidemiological study of MPN risk factors.”
Disease progression and risk
Dr Ross said ET and PV can both turn into MF.
“It’s generally estimated to be something like 20-30% lifetime risk, but that might depend on the age at diagnosis.
“If you’re diagnosed [with ET or PV] at 75, you may never get myelofibrosis. But if you are diagnosed at 30, your risk of getting myelofibrosis might be substantially higher because you’re potentially going to live for another 50 years.
“All three diseases can turn into acute myeloid leukaemia (AML).”
However, Dr Ross said the risk of AML for ET patients is very low, around 2%, and 5% for PV, so it is rare.
“Every now and again it happens, and it is a shock for those people.”
For MF, the risk of AML is 20-30%.
* Dr David Ross received a Leukaemia Foundation clinical PhD scholarship (January 2006-January 2009, $120,000) for his research project, Characterisation of persistent CML cells in patients treated with ABL kinase inhibitors.
For information about any of the studies mentioned, download the Clinical Refer app on your smartphone and search using the name of a drug or study.