One patient called Janus kinase (JAK) inhibitors a “miracle,” and an expert noted that they work “overnight” for some. These sentiments illustrate just how impactful treatment with JAK inhibitors has been for patients with myeloprolif- erative neoplasms (MPNs).

, one of our feature articles examines the advances made with 

 and how they’ve benefited patients with MPNs. Although not a cure, JAK inhibitors may help reduce the often-heavy symptom burden — something else you will read about in this issue. Setbacks and limitations, however, remain with JAK inhibitors. While one patient shares how this therapy was life-changing for him, another patient explains why he had to stop it. In addition, experts discuss the previously unmet need that is filled and the future of JAK inhibitors for patients with MPNs.

Because MPNs can cause chronic disease that spans years or even decades, some patients need their significant other to become their caregiver. The adjustment can strain a relationship and impact quality of life for both patient and caregiver. Findings from a study demonstrate that patients and caregivers may benefit from seeking support based on individual needs. This is exactly what one married couple did. 

talked with Wim Smits, a patient with myelofibrosis, and his wife and caregiver, Harriet Randall, about how his diagnosis has affected their relationship and how counseling and social support have educated them and helped them feel not so alone.

 also spoke with an expert about how important it is for patients with MPNs to have a specialized care team. She advises patients with MPNs to “take a breath” and to understand that adjusting to life with a chronic disease will take time.

Because patients with MPNs often experience a heavy symptom burden — resulting from the disease and its treatments — it’s important to be proactive whenever possible. 

 spoke with a registered dietitian on how to 

. She shares tips on tailoring a diet to your specific needs and symptoms.

Also in this issue: How to build your own smoothie to help maintain or gain healthy weight during MPN treatment.

As always, we hope you and your families find this information helpful and inspiring. Thank you for reading.

Articles

Because MPNs can cause chronic disease that spans years or even decades, some patients need their significant other to become their caregiver. 

Strategies for Improving Life With a Chronic Disease

Because myeloprolifeartive neoplasms (MPN) can cause chronic disease, spanning years or even decades, some patients need their significant other or another loved one to become their caregiver. This change and the adjustment it requires can strain a relationship and impact quality of life.

 found that patients with MPNs and their caregivers have a hard time adjusting to “the lives the disease enforced upon them” and would benefit from “psychosocial support, patient education, peer support and rehabilitation interventions” based on individual needs.

Wim Smits and his wife, Harriet Randall, understand the challenges firsthand — Smits received a diagnosis of primary myelofibrosis in 2018 after routine bloodwork.

“We were at the appointment together ... and we (were) both shocked,” Randall recalled. “He wasn’t sick at all (and) felt well. It was a total shock. And (when we were) told the name of this disease, (it was) something that we’d never heard of. I remember asking (the doctor), ‘How do you spell that?’ and trying to write down the name. And it was shocking to discover that there was no real treatment or cure, per se, other than treating the symptoms. I just remember leaving there in complete shock.”

The study on patient and caregiver needs included 48 patients diagnosed with an MPN and seven caregivers. It found that the two main themes affecting patients were:

The loss of choice and identity due to the need to prioritize energy.

The schism of being a person but also a patient.

Patients in the study reported that due to the disease and its symptoms, they have to prioritize their energy, which results in losing the freedom to do what they want. This, in turn, changed their identity and negatively affected their quality of life. In addition, the study found that patients of working age seemed to “struggle the most in balancing the disease, family, social relationships and work.”

Smits noted that he isn’t experiencing too many symptoms, so he doesn’t feel as if he has lost his identity. His approach to life with a chronic disease is probably best explained as pragmatic.

“I just accept it now, and say, ‘It is what it is,’ ” Smits explained. “And you try to look on the bright side (and) do the best that you can. It’s life, and that’s the way things are.”

For caregivers in the study, one main theme was the influence of the disease. Caregivers reported how the disease limited their social lives, brought psychological strain and caused extra work.

Smits and Randall agree that their relationship has changed since Smits received his MPN diagnosis.

“It certainly has changed our focus as a couple,” Randall said. “Rather than trying to decide, ‘Where do we want to go this winter on vacation?’ it’s ‘Are you feeling well?’ ”

Caregivers in the study also reported that “communication between couples was impaired,” noting that they felt frustrated when talking about cancer and its effect on them.

“No, I don’t think (it had an impact on communication). In fact, it may have even improved the commu- nication. Both of us being retired and being home was probably a greater adjustment than this adjustment (to cancer),” she said.

The study concluded that when patients and caregivers participated in rehabilitation courses, they reported “better understanding between couples and more open conversations.” Although the rehabilitation needs identified in the study were mainly in relation to psychosocial support and patient education, needs varied depending on the individual.

Both patients and caregivers in the study reported that meeting other people who are going through the same thing was rewarding and helpful, as was receiving education about the disease — which Smits and Randall did.

The couple also benefited from counseling provided by their hospital when Smits first received his diagnosis.

“(The counselor’s) main point, and one we’ve kept in mind, is don’t catastrophize,” Randall said. “Don’t suddenly reach to the end point or (think) of the worst thing that can happen. Just stay right in the moment and enjoy everything. And that was more than three years ago and just something I think we both keep in mind.”

Smits will soon undergo a stem cell transplant, so Randall said it might be a good time to go speak with that counselor again. Smits added that Princess Margaret Cancer Centre in Toronto, where he’ll undergo the transplant, offers a support program for caregivers, which his wife may benefit from.

Like those in the study, Randall and Smits have found it helpful to interact with people on the same journey. Specifically, online groups and various Zoom meetings have helped educate them as well as connect them with people going through the same thing.

“It’s very useful to talk to somebody who’s been there and done that. It does give you a different perspective,” Smits explained.

Randall added that she’s also a member of different Facebook groups that provide information and support — but it’s even better to know that she and Smits aren’t alone.

“(When) I’m on Facebook and I check out those groups ... if it’s anything interesting, I’ll read it aloud. It’s been some good information and (helps) to know that we’re not alone in this,” she concluded. “Certainly, in the beginning, it felt like such a rare disease that no one else had. But that is one positive thing about Facebook — that you can find out there are a lot of other people who have gone through this experience.”

For more news on cancer updates, research and education, don’t forget to 

Patients and their caregivers may benefit from community support and education following an MPN diagnosis

Adjusting to Cancer Together

INFORMATION PROVIDED by ABRAMSON CANCER CENTER AT THE UNIVERSITY OF PENNSYLVANIA IN PHILADELPHIA

Choose one option from each category, and blend away! Please note: Nutrient information varies by brand, so it’s important to read the labels.

1 cup whole milk (160 calories, 8 grams of protein)

1 cup FairLife whole milk (150 calories, 13 grams of protein)
1 cup Ensure Plus or Boost Plus (350-360 calories, 13-14 grams of protein)

1⁄2 cup ice cream (160 calories, 3 grams of protein)

2⁄3 cup Greek yogurt (120 calories, 11 grams of protein)

1 tablespoon nut butter (190 calories, 7 grams of protein) 

1 tablespoon chocolate syrup (50 calories)

1⁄2 avocado (120 calories, 1.5 grams of protein)

1⁄2 cup fortified dry milk powder (80 calories, 8 grams of protein)

1 tablespoon chia seeds (70 calories, 2 grams of protein)

Blend FairLife whole milk, banana, peanut butter and fortified dry milk powder. Add ice if desired. This shake contains 510 calories and 28 grams of protein.

 Blend whole milk, ice cream, peaches and honey. This shake contains 415 calories and 11 grams of protein.

Drink this between meals to help gain or maintain a healthy weight during and after cancer treatment. 

4 Steps to a Delicious, Healthy Smoothie for Cancer Survivors

David Alexander was a passionate runner. He belonged to a running club, and regularly ran marathons. So when he found himself having trouble keeping up with his running buddies, he was concerned.

“I was marathon trained,” recalls Alexander, a lawyer for the Environmental Protection Agency in Washington, D.C., and a native of Queens, New York. “I was in good shape. I knew what I could do, but then I couldn’t do it.”

In addition to having trouble running, Alexander found himself experiencing “horrible brain fog.” He once caught himself looking for his keys as he got ready for work in the morning, searching all over the house before he realized they were in his hand. Other times he’d come home and find that he’d put the shredded wheat cereal in the refrigerator and the milk in the cupboard. Once, in trying to find his way through an unfamiliar area of New York, he realized he couldn’t read a map.

“In retrospect, I knew something was wrong with me,” says Alexander. So he went to see his doctor, who seemed unconcerned. Alexander recalls his physician asking: “What do you want me to diagnose you with? Not being able to run a marathon anymore?”

“He later apologized,” Alexander adds.

The answer came in 2005, when Alexander was participating in a medical trial run by the National Institutes of Health as a healthy volunteer. He was part of the study’s control group. Investigators left him a message asking him to call for the results of a blood test, but he put it off. When he got in touch, he learned that his hematocrit levels were “sky-high,” meaning that red blood cells constituted too large a proportion of his blood. He was told to get to a doctor soon. On his way out the door, a receptionist wished him good luck.

“I knew it was not the kind of ‘good luck’ I wanted to hear,” says Alexander. “But I was damn lucky.” 

Alexander followed up on the advice and was diagnosed with polycythemia vera (PV), a rare blood cancer characterized by an excess of red blood cells that belongs to a group of diseases called myeloproliferative neoplasms, or MPNs.

In patients with MPNs, the bone marrow produces inappropriate amounts of different types of blood cells. Other examples of MPNs include essential thrombocythemia (ET), in which the blood contains too many platelets, and primary myelofibrosis (MF), in which a person’s bone marrow develops scar tissue, causing low red blood cell and platelet counts. 

Symptoms of MPNs are varied and can include anemia, splenomegaly (an enlargement of the spleen that may cause abdominal pain, weight loss and loss of appetite), fever, night sweats, fatigue, cognitive difficulties and itchy skin. Patients with MPNs often experience a decline in their quality of life, and as many as half of myelofibrosis patients can become dependent on blood transfusions within a year of diagnosis. Worse than that is the possibility that an MPN can progress to life-threatening acute leukemia.

Twenty years ago, few registered treatment options existed for patients with MPNs. There were medications to help with symptoms, but nothing to address the diseases themselves. In recent years, however, a fairly new class of drugs called Janus kinase (JAK) inhibitors has offered relief, though not a cure, to the hundreds of thousands of people estimated to be living with MPNs, according to the MPN Research Foundation.

Although the famous hematologist William Dameshek posited the idea that MF, ET and PV were all related in 1951, it wasn’t until 2005 that several groups of researchers independently identified a mutation in the JAK2 gene as one genetic driver of these diseases. In the several years that followed, researchers also identified the roles of the MPL and CALR genes.

The first JAK inhibitor, Jakafi (ruxolitinib), was approved by the Food and Drug Administration (FDA) for treating MF in 2011.

“It really has not been around that long, when you consider other drugs that we’ve had forever,” adds Dr. Aaron Gerds, an assistant professor of medicine and deputy director for clinical research at Cleveland Clinic Taussig Cancer Institute in Ohio, who has worked as a principal investigator on several JAK inhibitor clinical trials. For example, compared with certain chemotherapy options, JAK inhibitors are practically brand new.

“The unmet need that JAK inhibitors fill is the ability to have an agent that significantly improves quality of life for the majority of patients, particularly in regard to constitutional symptoms and bothersome spleen-related symptoms,”
says Dr. Olatoyosi Odenike, a professor of medicine and the director of the leukemia program at University of Chicago Medicine who has also worked on studies of JAK inhibitors. “There is also a modest survival benefit,” she adds.

Like all cancers, MPNs are rooted in a problem with the mechanisms that control cell growth.

“The JAK2 protein is central to a number of processes in the body, but particularly blood cell production,” says Odenike. She adds that not all diseases that can be described as MPNs are suitable for treatment with JAK inhibitors. This class of drugs works specifically on what are called the “classical” MPNs: PV, MF and ET.

JAK inhibitors are oral drugs that block the JAK-STAT pathway, a signaling system in the body’s cells that regulates how the bone marrow produces blood cells.

“Patients with myeloproliferative neoplasms all have one unified theme of hyperactivity of the JAK-STAT signaling pathway that seems to be occurring in their bone marrow cells, and this is irrespective of the driver mutation present in these cells,” explains Dr. John Mascarenhas, a professor of medicine at Icahn School of Medicine at Mount Sinai in New York who has also worked on multiple JAK inhibitor trials. “We realized that this common theme of hyperactivity of the JAK-STAT signaling pathway could be interrupted by these small-molecule inhibitors, whereas previously, the treatments we gave were really nonspecific chemotherapies like hydroxyurea. This was a targeted therapy that depresses the activity of the signaling pathway, and in doing so, it quiets down the proliferation of cells that leads to problems in the disease.”

These corrections in cellular activity reduce many of the signs and symptoms associated with MPNs, such as an enlarged spleen and its related problems, making JAK inhibitors an ideal example of targeted cancer therapy, notes Mascarenhas. JAK inhibitors are also used in other hematological, rheumatologic and dermatological diseases, as well as in graft-versus-host disease, which occurs as a complication following transplants.

One of the most striking effects of JAK inhibitors is how quickly they can reduce a patient’s symptom burden.

“Folks who practiced before 2011 will often talk about patients with huge spleens, (who were) emaciated with loss of weight, fevers and night sweats, and incredibly short lifespans,” says Gerds. “And you would put them on these JAK inhibitors, and overnight, almost, it seemed like these people would have miraculous turnarounds.”

Not only were patients living better lives with major reductions in symptoms, but they were also living longer.

Alexander, who is president of the MPN Education Foundation, managed his PV without medication for 12 years. To lower his hematocrit counts, he underwent regular phlebotomy, or blood drawing. He began taking Jakafi after he developed pruritus, a severe, painful itching of the skin and a common symptom in MPNs.

“They call it itching,” he says. “I’m here to tell you, when it gets bad, it ain’t itching. It was life-stopping.”

The pain, he continues, was comparable to the worst sunburn imaginable topped off with being bitten by horseflies.

After Alexander began Jakafi treatment, his symptoms reduced in a matter of days. It particularly helped with the pruritus, but he says it did not help with episodes of transient global amnesia, a sudden, passing memory loss.

“Within a day or two, and I am not exaggerating, of taking the first pills, I just felt 20 years younger,“ he says. “My legs didn’t ache when I bounded up the steps at work. Within two days, according to my stopwatch, I could get up the steps faster.”

In 2014, three years after approving Jakafi for the treatment of patients with MF, the FDA approved the drug for the treatment of PV, making it the first drug specifically approved for that disease. The agency based its initial approval of Jakafi on two phase 3 clinical trials in which Jakafi outperformed both placebo and the best previously available therapy in reducing patients’ spleen sizes and overall symptom burdens. The 2014 expansion to use the drug for PV came on the heels of a study demonstrating that Jakafi reduced the need for phlebotomy among patients with PV and significantly reduced splenomegaly.

In 2019, a second JAK inhibitor, Inrebic (fedratinib), received FDA approval, also for MF related to MPNs, after study results showed that it significantly reduced spleen volume. Further, the clinical trial that served as the basis for Inrebic’s approval found that the drug reduced symptom burdens by more than half in about 40% of patients. Inrebic, Mascarenhas notes, can even be useful for patients whose treatment with Jakafi fails.

More recently, the FDA has approved Vonjo (pacritinib) for treating patients with myelofibrosis. And another JAK inhibitor, momelotinib, also shows promise for patients with MPNs and is the subject of a phase 3 trial.

One of Mascarenhas’ patients, Joseph Cusati, of Long Island, New York, received a diagnosis of MF in October 2019 and opted to participate in a trial of Vonjo rather than undergo a bone marrow transplant.

When he first began treatment, Cusati was told his red blood cell count was less than half of what it should be.

“I’d had nothing — absolutely nothing,” Cusati says when asked about his symptoms at the time of diagnosis. “I got a call from my primary physician who told me I had an issue with my blood. I went, and then they told me to go to the hospital. And I’ve been on this program ever since.”

He had heard of JAK inhibitors in passing as part of his job at HealthCare Partners. And when he looked up his diagnosis on the internet, he learned there was no cure.

“That was in the back of my mind, that I needed to make a decision one way or the other,” he says.

Although Cusati briefly considered a bone marrow transplant, he turned it down, in part because he wanted to avoid graft-versus-host disease.

“When you get a transplant, it’s not you that’s the problem,” he says. “It’s the bone marrow. Does it accept your body?”

Cusati received regular transfusions, usually about every week or two, early on in his treatment. But as the months on the study drug went by, he found he no longer needed transfusions.

“Whatever started to work is working,” he says. “It’s like a miracle. My energy level is astronomical. So, something is working.”

Although Cusati needed a wheelchair to move around the hospital during his early visits to see Mascarenhas at Mount Sinai, at his most recent visit, Cusati was able to walk everywhere he went. He can now spend two hours on an exercise bike at the gym.

Gerds notes that whereas many cancer drugs are approved based upon their effects on tumor size, the approval of JAK inhibitors for MPNs is based on reductions in symptoms and improvements in patients’ quality of life. He expects further innovations in the field of MPN treatment to include combining the drugs with other medicines.

JAK inhibitors also have their downsides. One major drawback is that because the drugs lower counts of certain blood cells, they can cause these counts to drop too low.

“If we are blocking JAK1 and JAK2 too much, we can cause worsening of anemia and thrombocytopenia: low red blood cells and low platelets,” says Gerds. “In someone with PV, that’s a wanted side effect. We’d want to control the red blood cell count. Same with ET: We’d want to control that platelet count. But for someone who’s already starting out with anemia and thrombocytopenia, it can certainly make that worse.”

For this reason, experts and patient advocates say that among the current options available, no JAK inhibitor is necessarily superior to another. Jakafi or Inrebic may not be safe for use in patients who have low platelet counts because they could reduce those low counts even further, so pacritinib will offer another option for those with thrombocytopenia. Momelotinib, says Mascarenhas, may be particularly useful for patients with transfusion-dependent anemia.

“It all depends,” says Alexander. “What is an undesired effect in one context (lowering counts) can be treatment in another context (PV)."

In Alexander’s case, Jakafi’s effect on his immune system meant he had to stop using the drug after two years and four months. He developed a dry cough and found himself struggling to bicycle up a small hill that was part of his usual morning commute. Eventually, doctors identified spots on his lungs and determined that he had an infection from Cryptococcus neoformans, a common fungus that occurs virtually everywhere in the world, which can be fatal in people who are immunocompromised.

To beat the infection and avoid similar ones in the future, Alexander had to stop taking Jakafi, which he describes as “very sad.” Treatment with the drug had been a positive experience, largely controlling his symptoms and shrinking his spleen.

“Would I take (Jakafi) again if I could? Sure enough,” says Alexander. “Would I suggest a fellow patient take it, based on my experience? Of course I would, with qualifications.”

Those qualifications, he adds, include being on the lookout for the risk of severe infections.

Beyond side effects, doctors say, one of the biggest caveats is that JAK inhibitors do not cause remission from MPNs.

“For all the good they do, they don’t, unfortunately, cure patients,” says Mascarenhas. “So the disease can continue and progress, despite (the patient) even enjoying some benefits of the drug.”

Odenike points out that the classical MPNs tend to progress to acute myeloid leukemia, which is much more aggressive. “(Researchers) shared the enthusiasm that (JAK inhibitors) would be tantamount to attacking these diseases at their root cause, which would lead to transformational effects,” she adds.

She and other researchers hoped that the medications could stop fibrosis, or scarring of the bone marrow, and perhaps even make the JAK2 mutation undetectable, possibly halting the progression to leukemia. None of this, she continues, has turned out to be true so far.

“It seems now, after 10 years of experience with JAK inhibi- tors, that this is not a realistic goal with this class of drugs in their current form,” Odenike explains.

In addition, although JAK inhibitors demonstrate some improvement in survival for patients who take them, Odenike has been somewhat disappointed by the results.

Alexander encourages anyone with PV or another MPN to consult with an expert because “your hometown internist isn’t likely” to have much experience with these diseases.

“For most people, you’re going to be managing a chronic disease and its symptoms, which can be annoying or more than annoying for a long time,” he says.

Alexander also emphasizes that although receiving a diagnosis of PV is an initiation into a club nobody wants to join, it is possible to live a long and fulfilling life with the disease.

“You’re going to have years and years in front of you,” says Alexander, who remains an active runner and cyclist. “We’ve all gone through the adjustment of having a disease (that) is indeed likely to be life-shortening. The way I think of it, I don’t think (about) my prognosis. According to what I read in the literature, at 17 years, I think I’m at my median prognostic lifespan. Which is ridiculous. I’m not done. I’m not close to done.“

Alexander adds, “Be glad you’re diagnosed in this modern era. Better things are here, and better things are coming for you.”

Gerds agrees. “The combinations that are forthcoming are really exciting,” he says.

A nonprofit group, the MPN Research Foundation, is dedicated to ongoing efforts to treat, and perhaps someday cure, these diseases.

In the MANIFEST trial, pairing Jakafi with another drug appears to significantly improve response rates and the durability of benefit. Another combination is showing responses even with relapsed or refractory disease, and still more combinations attack disease from multiple pathways at once.

“We’re expecting readouts from at least four or five randomized trials in the next year and a half,” Gerds says. “It’s an exciting time.”

Treatments with JAK inhibitors are continuing to make their way into the MPN space, providing symptom relief, but not yet a cure.

One Step Closer to an MPN Cure

Many patients with myeloproliferative neoplasms (MPNs) experience a heavy symptom burden due to the disease and its treatments, including weight fluctuation, inflammation and nausea. A nutritious diet, however, may help ease these symptoms, according to Doris Piccinin, a registered dietitian in the Department of Patient and Family Services at Abramson Cancer Center of the University of Pennsylvania in Philadelphia.

Piccinin emphasized that the diet needs to be individualized to the patient based on their needs and the symptoms they’re experiencing.

“I think we have to look at each and every patient, and no one diet fits all,” Piccinin said in an interview with 

®. “What we might think of as a healthy, clean diet, we might have to put on the back burner, depending on what’s going on with the patient.”

Tips for Patients With Weight Loss, Abdominal Pain 

Piccinin noted that 30% of patients with MPNs going through active treatment experience weight loss. It is important that these patients do not lose a significant amount of weight because that can lead to loss of muscle mass. And strong muscles, she explained, can help maintain an effective immune system as well as help patients tolerate treatment and remain physically active.

Abdominal pain is another factor that sometimes contributes to weight loss. Piccinin explained that patients with MPNs often have a feeling of fullness because their spleen may be enlarged and pressing against part of their digestive tract or because of abdominal blood clots.

She asks patients to weigh themselves three times a week, and if they’re losing weight she recommends that they begin recording everything they eat to ensure they’re meeting their daily calorie and protein goals. Specifically, she advises that they incorporate a protein as the center of their meals and build on the calories with healthy fats.

If they cannot eat a full meal, peanut butter and crackers, full-fat yogurt or a high-calorie, high-protein shake several times per day can be used to replace meals. She suggests aiming for six to eight mini meals per day if they’re feeling bloated or having difficulty meeting their nutritional needs.

“If (a patient) has lost a significant amount of weight, this may lead to dose reductions of treatment medi- cations or cause a delay in treatment, emphasizing the importance of weight maintenance throughout treatment,” she said.

For those looking to add healthy calories to their diet, Piccinin recommends:

For some patients, a healthy diet might include foods that are high in fiber; however, for those experiencing mouth sores due to treatment, high-fiber foods can cause discomfort. For these patients, Piccinin recommends:

Hot cereals like oatmeal, cream of wheat or cream of rice; you may need to cool them down before eating.

Flaked white fish with butter and small white beans, mashed.

Canned turkey, chicken or tuna fish with mayonnaise or avocado to moisten.

Softer foods such as mashed potatoes and meatloaf with gravy.

Pastina pasta cooked with eggs and ricotta cheese.

For patients experiencing diarrhea during treatment, she recommends restricting lactose or using soluble fiber such as:

It is important to drink plenty of fluids if diarrhea is severe, and electrolyte replacement beverages may be needed for some patients.

Piccinin also mentioned that ginger can be incredibly helpful to patients experiencing nausea. Adding ginger to a smoothie or tea can increase gastric emptying, limiting nausea and bloating. In addition, foods prepared at room temperature may be better tolerated because odors can worsen nausea. She noted that eating dry toast or crackers as the first food of the day may help prevent nausea and that waiting one hour after eating to drink fluids may help prevent stomach upset. She also suggests avoiding fried foods and spicy, acidic foods as well as limiting the amount of added fat to better control nausea.

Piccinin concluded that patients should talk to their doctor for a referral to a registered dietitian to find a diet that works best for them. She said the Academy of Nutrition and Dietetics can help patients find a registered dietitian in their area and, the Leukemia & Lymphoma Society offers nutrition resources on their website as well.

Patients with MPNs should consult with their treating physician to individualize a healthy, nutritious diet to help ease symptoms.

Diet May Impact Symptom Burden in Myeloproliferative Neoplasms

In 1999, Meg Lowry learned that her platelet count ran high after having routine bloodwork done during an annual physical exam. Her primary care physician told her not to worry. 

Eight years later, after her annual physical, she received a life-changing phone call from her doctor’s office. 

“The nurse said, ‘We need to see you at 8 a.m. tomorrow.’ When I went in, I was told that my platelet count was 890,000 and that I needed to start taking Hydrea (hydroxyurea),” Lowry recalls. 

Normally, platelet counts range from 150,000 to 400,000 platelets per microliter. Although Lowry was hesitant at first, she followed the instruction to take the chemotherapy medication. At the same time, she developed painful lesions on her skin. 

“They almost looked like mosquito bites. They were raised and itchy, then would scab over and stay on my skin for weeks,” she says.

Lowry saw a dermatologist who biopsied the lesions and was told she had Sweet syndrome, a rare skin condition characterized by infiltration of neutrophils (a type of white blood cell) that can be triggered by an infection, an illness such as cancer, medication and sometimes even pregnancy. She was given cortisone and told she would need to see an oncologist. Trying to wrap her head around those words, Lowry called her friend who works at The University of Texas MD Anderson Cancer Center in Houston to share what she was told. Within five days, Lowry had an appointment with the head of the leukemia department. In January 2008, Lowry, who was 56 years old at the time, received a diagnosis of essential thrombocythemia (ET), which is a rare blood cancer and one of three main types of myeloproliferative neoplasms (MPNs). She was told to continue the Hydrea and see an oncologist every six months.

The three main types of MPNs are ET, polycythemia vera (PV) and myelofibrosis (MF). ET is caused by the bone marrow producing too many platelets, the part of the blood needed for clotting; PV occurs when the bone marrow produces too many red blood cells; and MF is characterized by the buildup of scar tissue in the bone marrow. It is often found during routine bloodwork, usually in its early phases. Symptoms of the group of incurable diseases include anemia, fatigue, pain or fullness in the belly from an enlarged spleen, prolonged bleeding from minor cuts, shortness of breath and weakness. It can also less commonly cause blood clots. It wasn’t until 2014, however, that Lowry felt her condition was more dire. She began to run a low-grade fever daily, had brain fog, fatigue, joint and muscle aches, nausea and night sweats. 

“I got to the point where I carried a thermometer in my purse. I was always pushing through,” she says. In May 2015, Lowry left her home in Austin, Texas, and headed for MD Anderson Cancer Center yet again, where her labs showed that her platelets were 3.1 million and that her hemoglobin level had dropped.

“The doctor told me, ‘I think you have leukemia or myelofibrosis,’” Lowry recalls. Ten days later, she learned that her ET diagnosis had progressed to accelerated MPN and that she was positive for an IDH1 mutation. MPN in the accelerated phase is not as common as the chronic phase and is defined by 10% to 19% myeloid blasts (a type of immature white blood cell) in the peripheral blood or bone marrow, according to Dr. Aaron Gerds, an assistant professor of medicine and deputy director for clinical research at Cleveland Clinic Taussig Cancer Institute in Ohio. Accelerated-phase MPN is often a precursor to blast-phase MPN, also referred to as acute myeloid leukemia (AML). Blast-phase MPN is associated with 20% or more myeloid blasts. 

“Depending on the analysis, the lifetime risk for ET to turn into blast-phase disease is less than 5%,” Gerds says. “(For) MF, (it) is much higher — 10% to 20%.”

Progression can only be confirmed through blood or bone marrow biopsy analysis. Typically, patients will have significant blood changes — decreased hemoglobin, a rapid platelet drop and a rapid rise in white blood cells, explains Dr. Abdulraheem Yacoub, an associate professor of medicine in the Division of Hematologic Malignancies and Cellular Therapeutics and clinical director of the Ambulatory Hematology Clinics at University of Kansas Medical Center in Kansas City. Patient symptoms may also worsen, or new symptoms will develop, such as drenching night sweats, weight loss and an enlarged spleen. 

“Usually transformation is gradual, not sudden,” Yacoub says. “Patients considered high risk will be watched closely with labs every one to three months. So even at this rate, you can still catch it early as it happens.”

Although there is no specific predictor of which patients with MPNs might progress over time, certain patients are at higher risk based on specific disease features, i.e., having a primary diagnosis of MF and testing positive for genetic mutations such as IDH1/IDH2, RAS and TP53. 

“You can test for mutations at any time,” Gerds says. “Generally, it’s advised to test, if you can, a large panel of genes not only for driver mutations, but also others that can be important in prognosis.”

The only way to potentially cure MPNs in accelerated phase or blast phase is through an allogeneic stem cell transplant, which uses healthy blood stem cells from a donor to replace diseased or damaged bone marrow. Without a transplant, other therapies are short-lived — effective for just a few months — according to Dr. Naseema Gangat, an associate professor of medicine at Mayo Clinic in Rochester, Minnesota. However, based on age, functioning and comorbidities, not every patient is a good candidate for stem cell transplant.

“The majority of patients are about 65 years of age and not in the position to tolerate aggressive treatment,” Gangat says. “If they are fit and (younger than) 70 years old, I would go with intensive AML chemotherapy, followed by transplant.” 

Even with transplant, two-year overall survival rates (the time from treatment that a patient with cancer is still alive) range from 29% to 75% for advanced MPNs. With limited treatment options, researchers have begun to borrow therapies from other blood cancers, particularly molecularly targeted therapies, to see how well they work for these patients. Clinical trials, although small because of the available patient population, are being conducted for efficacy and safety. In one study, Venclexta (venetoclax), an inhibitor of the BCL2 protein, was combined with a hypomethylating agent (which can trigger the reprogramming of tumor cells), such as Vidaza (azacitidine) or decitabine, in patients with blastphase MPNs. 

The study included 32 patients with a median age of 69, and two-thirds of them had a mutation or three or more chromosomal aberrations. Twenty patients had not received prior therapy. A complete response (defined as a disappearance of all signs of cancer) was achieved by 14 patients and was more likely in those who did not have preleukemic PV/post-PV myelofibrosis. Six of these patients were able to go on to receive an allogeneic stem cell transplant.

“Even though these new approaches are available, they are being used more as a bridge to allogeneic stem cell transplant. And if you’re an unfit patient, they improve your quality of life,” says Gangat, who was an author on the study. Another study, presented at the 2021 annual meeting of the American Society of Hematology, included 39 patients with blast-phase MPNs and found that they responded best to the combination of Venclexta and a hypomethylating agent compared with intensive chemotherapy or a hypomethylating agent alone. Patients were divided into four groups to receive one of the following: Venclexta/hypomethylating agent; fludarabine, high-dose cytarabine and granulocyte-colony stimulating factor; a hypomethylating agent only; or daunorubicin and cytarabine. 

“What’s more important is understanding accelerated- and blast-phase disease and targeting it in innovative ways,” Gerds says. “There are patients who can have ET for decades, and then all of a sudden, it turns into blast-phase disease. The pattern of mutations is very different. Mutations in genes like TP53 and NRAS seem to be key with late disease progression, whereas mutations in EZH2 and RUNX1 are key players in those who progressed more (quickly) after diagnosis.” 

Unfortunately, there are no specific medications to target many of these mutations, explains Yacoub. Yet other mutations seen in MPNs can be targeted. For example, researchers are exploring the use of Rydapt (midostaurin), which targets the FLT3 mutation. This mutation appears in approximately 3% of patients with MPNs in accelerated phase or blast phase. Rydapt is already approved by the Food and Drug Administration (FDA) for the frontline treatment of patients with AML.

IDH1 and IDH2 are also potential targets because up to 20% to 25% of patients with accelerated- or blast-phase MPNs have one of these mutations. Tibsovo (ivosidenib), an IDH1 inhibitor, and Idhifa (enasidenib), an IDH2 inhibitor, are being examined in combination with chemotherapy or a hypomethylating agent. Lowry was lucky enough to arrive back at MD Anderson Cancer Center when she did because she was one of the first patients to join a clinical trial in June 2015 that investigated Tibsovo and which ultimately led to the FDA approval of this agent. 

“Before this, I was constantly nauseated,” Lowry says. “This was the best I’ve felt.” Within a year of starting the trial drug, her platelets were in normal range and all her symptoms disappeared. Lowry calls her response miraculous. “It gave me my life back, my energy back,” she says. “I try to live in gratitude.”

In addition to these approaches, research is being conducted using Janus kinase (JAK) inhibitors in combination with other medications because MPNs are caused in a large part by mutations that drive the JAK-STAT growth signaling pathway. For instance, clinical trials have examined Jakafi (ruxolitinib) plus decitabine. But patient responses have been modest, Gangat explains. The immunotherapy medication Keytruda (pembrolizumab) is also under investigation in an early clinical trial for patients with advanced MPNs, including accelerated phase and blast phase, who did not respond to therapy with a hypomethylating agent. Because so much research is evolving, Yacoub notes that it’s crucial for patients to be their own best advocates. 

“Sometimes you might have to travel for a clinical trial that would be best suited for your diagnosis,” he says. “I strongly recommend that patients seek care under the care of experts in a center that can deliver a transplant.” 

The ultimate goal, says Gerds, is to help patients with accelerated-phase and blast-phase MPNs live better and longer lives. “I think the key is finding treatments that can improve remissions but don’t cause a lot of toxicities,” he says. “We need to focus on treatments that can lead to response but not at the risk of a patient’s quality of life.” 

Currently, Lowry’s platelets are in the low 400,000s, and she continues to receive Hydrea and Tibsovo. The married mother of two is back to enjoying time with her five grandchildren, traveling with high school girlfriends and doing yoga three days a week. 

“If you know you have a blood disease, you need to see a hematologist,” Lowry says. “You need to be in a supportive community because if I had been going to someone who was more knowledgeable about blood, I wouldn’t have suffered so long.”

Researchers may have uncovered new ways to help patients with accelerated-phase and blast-phase MPNs live longer by borrowing therapies from other blood cancers.

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