A decision to rename myeloproliferative neoplasms led to a plethora of developments in a space where there was once little interest.
Name recognition. The term is often associated with Fortune 500 companies like Coca-Cola, famous celebrities and politicians running for office. But what about medicine and the subsequent treatment of diseases? What if a name — or rather, name change — could influence how the world views a particular disease and ultimately revolutionize the space?
To a greater extent, how would the evolution of the term myeloproliferative disorders (MPDs) — a group of diseases including polycythemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythemia (ET) — to myeloproliferative neoplasms (MPNs) affect the lives of thousands upon thousands of people living with a rare disease?
As it turns out, that decision would transform the trajectory of a cancer space where there was once very little interest.
In 2008, the World Health Organization (WHO) in collaboration with the United States-based Society for Hematopathology and the European Association for Haematopathology published a revised classification of the diseases that made up MPDs and officially classified them as neoplasms.
“They were considered a ‘disorder’ and then a ‘neoplasm,’” says David Ricci, a long-time member of the MPN Research Foundation Board of Directors. “The diseases had not changed. There was nothing about these diseases that was different before the change versus after the change.”
Instead, the change of name was made largely to be more accurate, Ricci
explains. The term MPDs dates back to a former president of the American Society of Hematology, Dr. Louis Wasserman, who coined the phrase to describe a range of diseases that had elevated blood counts, including chronic myeloid leukemia (CML), notes Dr. Ruben Mesa, executive director of Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center.
In PV, patients experience an increase in all blood cells, particularly red blood cells, which supply oxygen. Patients with ET have bone marrow that produces too many platelets, which can cause abnormal bleeding or blood clots. And in PMF, patients build up scar tissue in the bone marrow that produces blood cells, impairing the body’s ability to make normal blood cells.
“Over time we learned that all of these were neoplasms,” Mesa says. “All of the abnormal cells are related to one another, and that is a defining charac-teristic of a neoplasm.”
This characteristic is called clonality. Neoplasms are an abnormal growth of cells that can be either benign or malignant. MPNs start out as benign but may progress to being malignant.
“As science progressed and we learned this was a clonally driven disease, that sounded more like cancer,” says Dr. Michael R. Savona, head of hematology, cellular therapy and stem cell transplantation at Vanderbilt University Medical Center in Nashville, Tennessee.
“It would have been technically inaccu-rate to consider it otherwise.”
The impetus for the name change came in part after the 2005 discovery of the JAK2 mutation. A team of researchers in France announced the discovery of a single mutation in the JAK2 gene that appeared in 97% of patients with PV and about half of patients with ET (57%) and myelofibrosis (50%). These findings were confirmed by two additional research teams later the same month.
“In the end, there were four similar studies published in top-notch journals confirming the results, and this took the field by storm,” Dr. Attilio Orazi, a professor and chair of the Department of Pathology at Texas Tech University Health Sciences Center El Paso, says.
“Researchers started working and thinking about how we could use this information not only to create a drug to treat these patients, but how to integrate this information into a diagnostic algorithm.”
Shortly after the discovery of the JAK2 mutation, researchers discovered that mutations in another gene – MPL — are sometimes present in patients with ET (approximately 3% to 5%) and PMF (about 5% to 10%) who do not have JAK2 mutations.
Armed with this new knowledge, the International Working Group- Myeloproliferative Neoplasms Research and Treatment, a group of MPN experts, met to discuss how best to integrate these new molecular discoveries into the classification of these diseases.
According to Orazi, the group knew that the WHO was considering an update of its classification of myeloid neoplasms, and they wanted to provide expert consensus on how to properly diagnose these conditions.
“The ability to integrate molecular knowledge into the diagnosis of these diseases went hand in hand with the change of name,” Orazi recalls. “At that point, it made no sense to call it ‘syndrome’ or ‘disorder’ when we knew it was a tumor.”
The discovery of these mutations led to the name change and also increased attention from scientists and pharmaceutical companies, Orazi exclaims.
In the late 1990s/early 2000s, a blockbuster drug had been developed and approved by the Food and Drug Administration (FDA) to target BCR-ABL, an abnormal tyrosine kinase protein that causes cells to grow and reproduce out of control in patients with CML.
Of note, many patients with CML in remission after two years of treatment with Gleevec (imatinib) have similar life expectancies as a person without cancer, although this is not the case for every patient.
“There was hope that we would get the same kind of results for a drug targeting JAK2 in MPNs,” Orazi says.
“It kind of became a bonanza,” Ricci explains. “The reclassification to a neoplasm played a part in attracting new interest on the academic side, clinical side and pharmaceutical side.”
Ricci says that until about 15 to 20 years ago, the incidence of MPNs had not even been well studied. According to the National Cancer Institute, an estimated 20,000 new people in the United States are diagnosed with an MPN each year and about 295,000 are living with the disease.
“These studies identified that it was bigger than most people thought and deserving of attention not only from the biotech industry, but also from the research and academic community,” Ricci recalls.
To put it in perspective, David Boule, treasurer of the board of directors for MPN Research
Foundation, explains that before the discovery of the mutations and the subsequent name change, one of the biggest challenges for the MPN Research Foundation was finding researchers to give money to.
“Not a lot of people were concerned about MPNs. If anything, the research was focused more on reducing myelofibrosis symptoms and how to keep it
from progressing,” Boule says. “Now pharmaceutical companies understand that (for) PV or ET, which someone can have for 25 to 30 years, it makes good economic sense to develop drugs to treat these diseases.”
In fact, Savona describes drug development for MPNs as a “ghost town” prior to the discovery of the driver mutations.
Mesa agreed that the reclassification has had a significant effect.
“There has been impact in terms of being a research focus for philanthropic organizations, and it has helped to augment scientific focus on MPNs that would not have occurred if they were not considered a blood cancer,” Mesa says. “It brings more people to the field (and) more investment from the pharmaceutical industry and increases support for research.”
Indeed, less than five years after the reclassification of MPDs to MPNs, the FDA approved the JAK inhibitor Jakafi (ruxolitinib) for myelofibrosis based on its ability to reduce spleen volume and ameliorate disease-related symptoms. Since then, Jakafi has also been approved for PV.
In 2019, the JAK2 inhibitor Inrebic (fedratinib) was also approved for myelofibrosis after studies showed it reduced overproduction of damaged blood cells and increased control of disease-related symptoms.
Then in November 2021, Besremi (ropeginterferon alfa-2b-njft) became the first interferon therapy approved for PV and the first PV therapy that patients can receive regardless of their treatment history. This interferon is long acting and should decrease the number of depressive episodes and flu-like symptoms seen with traditional interferon, Savona noted.
A shift from referring to something as a disorder to a cancer can be tough for some.
“It is not lost on me that the term cancer or leukemia creates a very negative connotation for patients. That is why, depending on the patient, discussing that these are cancers may not be the first thing I try to get across,” notes Mesa. “When people hear cancer, they sometimes jump three steps ahead and assume (they) are going to die tomorrow. I don’t want anyone led down a path of misunderstanding.”
When the name change was announced, the MPN Research Foundation led an effort to educate people about the disease.
“Hearing it is cancer provokes anxiety,” Ricci says. “We try to help people understand that many cancers can be managed or cured and that for the most part, many patients with MPNs live with the disease in a chronic format.”
Savona adds that he often sees patients whose referring physicians avoided using the word cancer or even said the condition was not cancer.
“The word ‘cancer’ creates a lot of anxiety, but I think it is important to address it head on,” Savona says. “I tell them, ‘Technically, yes, it is cancer, but it is something we can manage, and often, not something that leads to earlier death or decreased quality of life.’”
Mesa emphasizes that he explains to his patients the term “cancer” does not refer to the severity of a disease, but rather, simply describes biology.
In addition, because of the name change to “neoplasm,” Mesa notes that, “there are a whole range of supportive mechanisms that are available to patients that have cancer versus other medical problems.” This includes copay assistance and other aid.
All the scientific discoveries related to MPNs during the past two decades not only led to a change in name, but also brought about much greater diagnostic certainty, Mesa says.
“We have a much greater understanding of the natural history of the disease,” he explains. “This means we have a better ability to understand the biology and the prognostic implications.”
In 2013, additional research filled another knowledge gap related to MPNs: Mutations in CALR, the gene that encodes the protein calreticulin, were discovered in most patients with ET or PMF who did not have mutations in the JAK2 or MPL gene.
Although most patients with MPNs have a single mutation in one of the three “driver” genes (JAK2, CALR or MPL), a small number of individuals may have concomitant additional “non- driver gene mutations,” which can occur at the disease outset or during its progression and can affect its prognosis. These additional mutations provide clues as to the risk of disease progression, or rarely, transformation of the disease to acute leukemia.
“All of this knowledge helps us approach patients in a much more rational way using objective tools,” Orazi says.
Information on CALR mutations and other diagnostic updates were included when the WHO again updated its classifications in 2016.
The future continues to look bright for the development of new treatments for patients with MPNs, according to Savona.
In addition to the drugs already available, another drug that targets JAK2, Vonjo (pacritinib), received FDA approval in February for the treatment of patients with high-risk myelofibrosis with thrombocytopenia. The FDA is also expected to review the JAK1/JAK2/CRV1 inhibitor momelotinib for patients with myelofibrosis and anemia.
“All of this discovery in the laboratory builds upon itself and becomes, ultimately, translated to the clinic,” Savona concludes. “In the end, it is our patients who we hope will see the benefit.”
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