5 Big Questions
I Have for MF
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Aaron Gerds, MD
Cytopenic MF manifests through the intricate workings of a negative feedback loop between the disease itself and its many clinical symptoms.
The hallmark characteristic of MF—the fibrous scar tissue that builds in the bone marrow— interrupts the production of blood cells, eventually causing the marrow to fail. As a result, cytopenias develop anemia and thrombocytopenia, which in turn prompt splenomegaly. An enlarged spleen can sequester platelets and red blood cells, which in turn creates more cytopenia.
Meanwhile, the fibrotic scar tissue in the marrow spurs on inflammation, which influences splenomegaly and, in true ouroboros fashion, leads to more fibrosis.
“All of these problems are intricately related,” says Dr. Gerds. “Before you can assess how each individual component weighs in, you need to understand the relationship between them.”
While prioritizing the most dramatic clinical symptom helps to improve quality of life, Dr. Gerds cautions against a narrow view.
“If you’re just focusing on one aspect of the disease and ignoring the rest, you can impede the potential progress an individual can make.”
For example, if a patient presents with a large spleen or heavy symptom burden, just addressing those facets of MF could lead to “trashing the blood counts,” says Dr. Gerds.
Or if a patient is put on blood transfusions for severe anemia but the physician ignores the fact that the patient’s spleen is huge, they are missing out on addressing the splenomegaly that might ultimately help improve the anemia.
Alternatively, if a patient has a JAK mutation, and that is the only treatment target, one risks worsening cytopenias with a JAK inhibitor known to cause myelosuppression.
“Really, I think the holistic approach,” says Dr. Gerds, “which addresses the most pressing issue at hand while looking at the whole picture in each domain, will help physicians come up with the most customized package for each individual.”
There is a puzzling paradox in MF—patients who share similar mutations, like the JAK2 mutation or calreticulin mutations, present with various types of symptoms and blood counts.
Take MF, polycythemia vera, and essential thrombocytopenia for instance. They all have the same genotype, but their phenotypes are vastly different, says Dr. Gerds. “So when second, third, and additional mutations were discovered, it made sense that they would be involved in MF.”
The challenge now is figuring out what we know and what we don’t know about mutations that affect the pathophysiology of MF, says Dr. Gerds. What we do know is that in all types of cancers, researchers agree on universal truths around mutations. One is—certain mutations are always problematic, like the P53 gene, which is the most frequently altered gene in all cancers. Another universal truth is— the more mutations, the more aggressive the disease.
But we can only detect the mutations we know about, explains Dr. Gerds.
Researchers are trying to address the complexity of MF and tease out the unanswered questions, like how many mutations are involved in the disease? What are their roles? How do accessory pathways impact JAK-STAT, TGF-β, and NF-κB? How does the bone marrow fail over time? How do those mutations ultimately lead to those outcomes? “We have our panels, but we’re probably still missing critical mutations for MF, and those don’t account for epigenetic changes—genes that are not necessarily mutated but are turned on or off in those cells.”
Good news is some answers are trickling in, says Dr. Gerds. Studies have shown that certain mutations are associated with early disease progression in MF. Among patients with smoldering diseases, newly developed somatic mutations can speed-up disease progression, and these mutations are different from those seen in patients with early disease progression.
“We’re starting to link different genotypes with the actual disease course of an individual. It is very exciting. But we have a long way to go.”
While patient-run social media pages bring the MF community together, Dr. Gerds says the technology helps him professionally as well.
For instance, over the years, many patients found Dr. Gerds thanks to recommendations from other patients on social media. For patients with rare diseases, who may not even know MPN specialists exist, this connection serves as a vital link to receiving the best care available.
“We can offer treatments to patients who may not have had access to them otherwise.”
Increasing clinical trial awareness and enrollment is another advantage of social media, says Dr. Gerds. “Thinking about conducting clinical trials and moving the field forward, we can say on social media, ‘Hey, we have this trial open. If you’re a patient with myelofibrosis, you may want to check it out.’ In that way, we can offer treatments to patients who may not have had access to them otherwise.”
Another perk? Patients who participate in social media come to Dr. Gerds’ clinic well-informed about MF, which enriches the conversation between himself and his patients. “Since patients already have the basic knowledge of the disease established, we can spend more time sorting out the finer details,” he says.
“Hey, we have this trial open. If you’re a patient with myelofibrosis, you may want to check it out.”
In a way, the knowledge patients glean from each other on social media has helped evolve the doctor-patient relationship, says Dr. Gerds. “As practice moves further away from the paternalistic and closer to a more common model of shared decision-making, we are better able to discuss different options and arrive at a group decision on the best course of action for that individual at that time,” he says.
Dr. Gerds thinks about platelet counts in ranges. There are patients with platelet counts >100,000, others in the 50,000 to 100,000 range, then <50,000, and <25,000. It is with these lower numbers, when thrombocytopenia becomes severe, that disease risk and bleeding risk increase, and the ability to use available therapy wanes because it is myelosuppressive, says Dr. Gerds.
His sweet spot for platelet count and treatment strategies hits around 50,000.
“When platelet counts are above, say, 50,000, I’m still pretty aggressive about treatment, but I will watch blood counts more closely and more frequently in those patients.” When patients’ platelet counts dive below 50,000, Dr. Gerds begins to worry about greater bleeding risk. “At that point, I start backing off therapy or adjust therapy, and begin to think about it in a different way.”
Prognosis and thrombocytopenia are interrelated, says Dr. Gerds. “If we think about models that predict outcome in myelofibrosis, such as the MIPSS70 score, thrombocytopenia—platelet counts above or below 100,000—plays a dominant role. And whether we’re talking about individual univariate analysis, or we add in variables to come up with the outcome, platelet counts and severity of thrombocytopenia often rise to the top of prognostic risk stratification.”
But one blood count doesn’t show the big picture.
Platelet counts are dynamic, and the overall trend is always more helpful than any individual number, says Dr. Gerds, especially when factors like infections and fevers can falsely elevate or lower counts. “I tend to ignore platelet counts that are measured in the hospital. Instead, I tell my patients, let’s wait until you’re back in the clinic to see if there truly has been a change.”
That said, if a patient’s platelet count begins to drop for no good reason, say they were at 100,000, then a couple of months later 80,000, then two more months later 50,000, “that is definitely a red flag that something is dramatically changing in their bone marrow, in the state of their disease,” says Dr. Gerds. “As platelet counts become more severe, the disease can definitely become more aggressive.”
“I would like to think that one day, during my career, we’re going to reminisce about 2021 and say, ‘Wow, remember when we used to do XYZ because we had nothing to offer these folks,’” says Dr. Gerds. For him, hindsight will reveal how the work we put in now to address the hard questions, like identifying signaling pathways beyond JAK-STAT and the role of cytokines, will eventually shape the trajectory of MF into tomorrow.
“The advent of JAK inhibitors changed the treatment paradigm, and new MF drugs are on the horizon,” says Dr. Gerds. “I think we’re going to keep chipping away at this disease, and eventually there will be a point when we look back and say, ‘We still have a long way to go, but look how far we’ve come.’”
“We still have a long way to go, but look how far we’ve come."