One Step Closer to an MPN Cure

Posted on June 14, 2023June 14, 2023 by mpn_admin

Published on: June 8, 2023

Andy Polhamus

CURE, MPN Special Issue 2023, Volume 22, Issue 03

“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.

Meeting an Unmet Need

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.”

The Current Landscape of JAK Inhibitors

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.

Drawbacks and Limitations

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.

“We wanted so much more,” she says.

‘Better Things Are Coming’

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.”

Novel Approaches Create a Bridge to Transplant in MPNs

Posted on June 14, 2023June 14, 2023 by mpn_admin

Published on: June 7, 2023

Katie Kosko

CURE, MPN Special Issue 2023, Volume 22, Issue 03

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.

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.

Road to Progression

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.”

Evolution of Treatment

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.”

Living With a Chronic Disease

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.”

Ruxolitinib Improves Spleen Volume, TSS in Myelofibrosis Irrespective of Anemia, Transfusion Status

Posted on June 14, 2023June 14, 2023 by mpn_admin

Jun 10, 2023

Gina Mauro

Conference|European Hematology Association Congress

Ruxolitinib was found to improve spleen volume and tumor symptom score in patients with myelofibrosis, irrespective of their anemia and transfusion status, according to data from a post-hoc analysis of the phase 3 COMFORT-I and -II trials.

Ruxolitinib (Jakafi) was found to improve spleen volume and tumor symptom score (TSS) in patients with myelofibrosis, irrespective of their anemia and transfusion status, according to data from a post-hoc analysis of the phase 3 COMFORT-I (NCT00952289) and -II (NCT00934544) trials that were published during the 2023 EHA Congress.¹

Results showed that the reduction in spleen volume of 35% or greater from baseline (SVR35) rates at week 24 in patients with new or worsening anemia up to week 12 were 48.8%, 33.3%, and 41.4%, respectively, for those who were nonanemic, anemic/nontransfusion dependent, and anemic/transfusion dependent at baseline. These rates were 43.2%, 23.1%, and 28.2%, respectively, in patients who did not have new or worsening anemia at week 24.

SVR35 at week 48 was achieved in 42.1%, 44.1%, and 34.6% of patients who had new or worsening anemia and were nonanemic, anemic/nontransfusion dependent, and anemic/transfusion dependent at baseline compared with 42.4%, 22.2%, and 27.3% in those who did not have new or worsening anemia.

A 50% or greater reduction in TSS at week 24 was achieved by 51.1%, 42.1%, and 46.7% of those with new or worsening anemia up to week 12 and who were nonanemic, anemic/nontransfusion dependent, or anemic/transfusion dependent at baseline. In patients who did not have new or worsening anemia up to week 12, these rates were 42.9%, 40.0%, and 54.2%, respectively.

Ruxolitinib, a JAK1/2 inhibitor, is indicated for patients with intermediate- or high-risk myelofibrosis. The FDA approval for ruxolitinib in this setting was based off findings from the COMFORT-I² and COMFORT-II³ trials. Findings showed that ruxolitinib demonstrated a reduction in spleen volume, improved myelofibrosis-related symptoms, and prolonged overall survival. This was in comparison with placebo in COMFORT-I and with best available therapy (BAT) in COMFORT-II.

Transient dose-dependent anemia is a treatment-related adverse effect (TRAE) that has been observed with ruxolitinib. In COMFORT-I, grade 3/4 anemia occurred in 45.2% of patients on ruxolitinib vs 19.2% with placebo. In COMFORT-II, the most frequently reported serious adverse effect in both arms was anemia (5% with ruxolitinib vs 4% with BAT).

Therefore, in the post-hoc analysis presented during the congress, investigators sought to determine how new or worsening anemia from ruxolitinib treatment impacts SVR and TSS in this patient population.¹

Patients were treated with ruxolitinib twice daily with an initial dose based on platelet count. For those with a platelet count of 100 to 200 x 109/L, the dose was 15 mg vs 20 mg for those whose platelet count was above 200 x 109/L. Stratification factors included anemia status at baseline (yes vs no) and transfusion status at baseline (transfusion dependent vs nontransfusion dependent).

Anemia was defined as hemoglobin less than 100 g/L and patients were considered transfusion dependent if they received 2 or more units of red blood cells over 8 to 12 weeks before their first dose of ruxolitinib. Investigators stratified outcomes via presence or absence of new or worsening anemia postbaseline, which was defined as a decrease in hemoglobin of at least 15 g/L or new transfusion requirement at weeks 4, 8, or 12.

Specifically, investigators assessed patients with a reduction in spleen volume of at least 35% from baseline from the pooled COMFORT-I/-II data at weeks 24 and 48, and with at least a 50% reduction in modified Myelofibrosis Symptom Assessment Form TSS at week 24, from the COMFORT-I data.

A total of 277 patients were included in the analysis. Regarding baseline characteristics, the median age ranged from 65.0 to 71.0 years, and between 47% and 56% were male. More than half of patients were baseline nonanemic (n = 154; 55.6%) 19.9% (n = 55) were anemic/nontransfusion dependent, and 24.5% (n = 68) were anemia/transfusion dependent.

References

Al-Ali HK, Mesa R, Hamer-Maansson JE, Braunstein E, Harrison, C. Effect of new or worsening anemia on clinical outcomes in patients with myelofibrosis (MF) treated with ruxolitinib (RUX): a post hoc analysis of the COMFORT-I and -II trials. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract PB2185.
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/NEJMoa1110557
Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK Inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-798. doi:10.1056/NEJMoa1110556.

JAK2 gene: Function, conditions, and research

Posted on June 14, 2023June 14, 2023 by mpn_admin

By Oladimeji Ewumi

June 9, 2023

The JAK2 gene is a protein-coding gene of the Janus kinase family. It plays a role in cellular signaling. Evidence notes connections between this gene and some medical conditions.

The JAK2 geneTrusted Source is present on chromosome 9. It produces a protein that sends signals in cells to help control how many blood cells the bone marrow produces.

Variations in this gene may cause the body to produce too many blood cells. Evidence suggests a link between alterations in the JAK2 gene and some types of blood conditions.

This article will provide an overview of the JAK2 gene, including its functions and related medical conditions.

According to a 2014 article, the JAK2 gene instructs cells to make the JAK2 protein. This protein helps control cell growth and division. Specifically, JAK2 proteins help control the activation and production of hematopoietic stem cells.

Hematopoietic stem cellsTrusted Source are immature cells present in bone marrow. They can differentiate into all blood cell types, including red blood cells, white blood cells, and blood platelets.

A 2017 reviewTrusted Source suggests that the JAK2 gene regulates the JAK-STAT signaling pathway — a chain of enzymatic interactions that controls cell division, immunity, cell death, and tumor formation.

Dysregulation of the JAK-STAT pathway can result in immune disorders. The National Library of MedicineTrusted Source notes that the JAK2 gene and the JAK-STAT signaling pathway are therapeutic targets for treating excessive inflammatory responses and viral infections.

JAK2 function

The following are the most common functions of the JAK2 gene:

regulating the production of blood cells
promoting cellular processes, including cell growth, development, differentiation, and modifications
mediating essential signaling events in immunity
acting as a diagnostic biomarker for most myeloproliferative neoplasms (MPNs), which are rare disorders of the bone marrow

JAK2 and blood conditions

Evidence notes an association between the expression of the JAK2 gene and some blood conditions. For example, MPNs are a group of hematopoietic stem cell conditions that arise due to an overproduction of mature blood cells.

JAK2 V617F is the most common alteration of the JAK2 gene present in blood conditions. According to a 2019 study, this alteration has a prevalence rate of 0.2% in the general population.

Primary myelofibrosis

In primary myelofibrosis (PMF), JAK2 gene variations replace typical bone marrow cells with scar tissue. This alteration affects 50%Trusted Source of people with PMF.

These JAK2 variations lead to the overproduction of atypical megakaryocytes that stimulate other cells to release collagen in the bone marrow. This causes scar tissue to form in a process called fibrosis. Due to this fibrosis, the bone marrow cannot produce enough typical blood cells, leading to symptoms of PMF.

Polycythemia vera

Polycythemia vera (PV) occurs when JAK2 overstimulates the production of red blood cells, causing an excess in the circulatory system. About 96%Trusted Source of people with PV have the V617F variation of the JAK2 gene.

Having extra cells in the bloodstream increases the risk of atypical blood clots. In addition, the thicker blood flows more slowly through the vessels, reducing the amount of oxygen in body tissues.

Essential thrombocythemia

In around 50% of people with essential thrombocythemia (ET), the JAK2 V617F alteration results in the body replacing the amino acid valine with phenylalanine. Switching these amino acids results in the continual activation and production of the JAK2 protein, leading to an overproduction of megakaryocytes.

Since platelets form from megakaryocytes, an increased number of platelets may result in more blood clots.

JAK2 and inflammatory bowel disease

Inflammatory bowel disease (IBD)Trusted Source is a term for two conditions: Crohn’s disease and ulcerative colitis. Both occur due to inflammation of the gastrointestinal tract.

According to a 2016 studyTrusted Source, increased expression of the JAK2 gene may impact inflammatory responses, causing severe gut inflammation in people with IBD.

JAK2 and other conditions

Research suggests that JAK2 may play a role in other blood disorders, including leukemia and Budd-Chiari syndrome (BCS).

A 2018 studyTrusted Source indicates that JAK2 variation is rare in de novo acute myeloid leukemia, an aggressive cancer of the bone marrow.

Additional research from 2015 that analyzed JAK2 alteration in those with BCS suggests that 20% had latent MPNs. BCS occurs when a blood clot blocks the hepatic veins. This blockage can cause blood to flow back to the liver.

JAK2 research

Many clinical trials are focusing on trying to manipulate the JAK2 gene and enzyme to find a better treatment for many related conditions the protein causes.

These suggest that therapeutic approaches targeting the JAK2 signaling pathways may prove Trusted Source effective in inhibiting pathogenic variations, providing new insights for developing pharmacological interventions.

For example, ruxolitinibTrusted Source is part of a Janus kinase inhibitor class of medication doctors prescribe to treat several conditions, including PMF and PV. Some other examples of Janus kinase inhibitors include Trusted Source:

abrocitinib
baricitinib
filgotinib
delgocitinib

Summary

The JAK2 gene is a protein-coding gene of the Janus kinase family. It initiates several cellular signaling processes, including cell division, immunity, and tumor formation.

Evidence notes that problems with this gene can result in the body producing too many blood cells. Medical experts have found links between the JAK2 gene and some blood conditions, including myelofibrosis, polycythemia vera, and thrombocythemia.

Last medically reviewed on June 9, 2023

Study Unveils Family Risk for Certain Types of Blood Cancers

Posted on August 15, 2019August 15, 2019 by mpn_admin

Individuals with a parent, sibling or child with blood cancer appear to have a higher likelihood of also being diagnosed with the disease, according to study results published in Blood.

Moreover, age of diagnosis; whether the relative is a parent, sibling or child; and the number of affected first-degree relatives were substantially associated with familial risk for certain blood cancers.

“Although many hematological malignancies are individually rare, collectively they contribute significantly to the overall cancer burden in the population,” the researchers wrote, adding that the etiological basis of most blood cancers is poorly understood.

Therefore, they analyzed data from over 16 million individuals from the Swedish Family-Cancer Database to determine the familial risk of the different blood cancer and their possible inter-relationship.

Those with a familial link to the disease represented 4.1% of all blood cancer diagnoses – higher than patients with cancers of the nervous system, kidney and pancreas. However, this was lower than those with cancers of the breast, colon and prostate, which ranged from 8% to 15%.

In total, the researchers identified 153,115 patients who were diagnosed with a primary blood cancer, including myeloproliferative neoplasms (MPN; polycythemia vera, essential thrombocythemia, myelofibrosis and MPN not otherwise specified), chronic myeloid leukemia, myelodysplastic syndrome, acute myeloid leukemia, acute lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, Burkitt lymphoma, small lymphocytic lymphoma, hairy cell leukemia, chronic lymphocytic leukemia and multiple myeloma.

The researchers found the highest relative risks for familial risk among patients with certain Hodgkin lymphoma subtypes (lymphoplasmacytic lymphoma and mantle cell lymphoma) and with polycythemia vera, myelodysplasia and essential thrombocythemia.

“This information improves our understanding of the causes of – and potential inherited predisposition to – blood cancers and should inform the identification and characterization of genetic risk factors for blood cancer, as well as how we best clinically manage patients and their relatives,” lead study author Dr. Amit Sud, from The Institute of Cancer Research in London, said in a press release. “The results should also encourage conversations among families, clinicians and patients about familial risk.” (Cure Magazine)