Novel Approaches Create a Bridge to Transplant in MPNs

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.”

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