The treatment landscape for myeloproliferative neoplasms (MPNs) has evolved significantly over the past decade, with advances in molecular diagnostics, risk stratification, and targeted therapies transforming clinical decision-making.

The discovery of driver mutations like JAK2, CALR, and MPL has not only enhanced diagnostic accuracy but also opened doors to mutation-specific therapeutic strategies.

While JAK inhibitors have revolutionized symptom management in myelofibrosis and agents like interferon alpha show disease-modifying potential in polycythemia vera, clinicians still face the fundamental challenge of balancing therapeutic intervention against the risk of treatment-related complications.

Amid this evolving therapeutic landscape, Dr. Ayalew Tefferi at Mayo Clinic is urging clinicians to return to clinical fundamentals: risk-adapted care, minimal intervention, and patient-centered decision-making.

Korea Biomedical Review met with Tefferi during the International Congress of the Korean Society of Hematology 2025 held at Grand Walkerhill Seoul from March 27 to 29. Tefferi, who also delivered the keynote lecture at the congress, shared his insights on current treatment approaches, particularly focusing on the importance of minimalist intervention for certain patients.

A minimalist approach to MPN treatment

Tefferi's keynote lecture at the congress was particularly notable for challenging the increasingly complex approaches to MPN management.

In a field dominated by molecular markers and sophisticated genetic profiling, his emphasis on simple clinical indicators and minimalist treatment strategies represents a distinctly patient-centered philosophy that resonated with many attendees.

"Don't let the treatment kill the patient before the disease does," Tefferi said. "To date, no one has demonstrated that survival can be improved in low-risk essential thrombocythemia or polycythemia vera patients. Their survival is already excellent.”

These patients can live for decades and a young patient under the age of 50 can have a life expectancy exceeding 30 years, the Mayo Clinic professor added.

As a result, Tefferi stressed that physicians must be extremely cautious not to administer treatments that could shorten the patient's life expectancy.

His approach is particularly relevant for patients with essential thrombocythemia (ET) and polycythemia vera (PV), two common forms of MPNs. Traditional risk assessment classifies patients as low-risk if they are under 60 and have no history of blood clots. But even this landscape is changing.

"With the growing availability of mutation testing, we can further stratify patients," he said. "Those with JAK2 mutations may be at higher risk, while those with type II CALR mutations or triple-negative status may be at lower risk."

The AAAA risk score, a new predictive model based on Mayo Clinic data, uses just four indicators: age, neutrophil count (ANC ≥8), monocyte count (AMC ≥0.8), and lymphocyte count (ALC <1.7). Patients with scores of 0-1 showed remarkable 20-year survival rates of approximately 80%, while those with scores of 6-7 had survival rates approaching zero.

"Simple is best," Tefferi emphasized. "This model performs comparably to complex genetic models but can be used anywhere, even in primary care settings."

Given these survival statistics, Tefferi's treatment philosophy becomes clear.

"Every time I see a low-risk patient, my mindset is how can I avoid giving them medication?” he said. “No drugs are always better than drugs."

This approach translates to practical treatment decisions. For most low-risk patients, Dr. Tefferi recommends only a single daily low-dose aspirin, sometimes twice daily for those with additional cardiovascular risk factors or JAK2 mutations.

When asked about platelet count thresholds that might trigger cytoreductive therapy, his answer was surprising.

"There is no fixed numerical threshold for me. It's all about the symptoms," he said. "If a patient's platelet count is 1.5 million but they have no symptoms, I don't automatically start treatment.”

Interestingly, patients who are called platelet millionaires may actually have a lower risk of blood clots, though their bleeding risk may increase if on aspirin, he added.

Different approaches for myelofibrosis

While Tefferi champions restraint for low-risk conditions, his approach shifts dramatically when discussing myelofibrosis, a more aggressive form of MPN.

"Myelofibrosis is a completely different disease," he said. "Unlike ET and PV, which are relatively indolent, myelofibrosis is not benign and these patients have a significantly reduced life expectancy, averaging around five years."

Patients with myelofibrosis struggle with enlarged spleens, debilitating fatigue, weight loss, and severe anemia that often requires regular blood transfusions.

The pharmaceutical industry has responded with numerous drugs, but Tefferi remains skeptical about their impact.

"There are many drugs available for myelofibrosis, but most are inadequate," he stated bluntly. "They don't prolong life or alter the natural course of the disease.”

The value of such drugs lies primarily in symptom improvement, he added.

Tefferi stressed that current approved JAK inhibitors like ruxolitinib, fedratinib, pacritinib, and momelotinib can reduce spleen size and alleviate constitutional symptoms, but they rarely extend survival.

“Of these options, momelotinib shows some advantages for anemic patients by potentially reducing transfusion needs, while ruxolitinib demonstrates a comparatively favorable side effect profile,” he said. “The treatment approach for myelofibrosis should be based on established prognostic scoring systems like DIPSS-plus or MIPSSv2.”

Recent clinical trials have investigated combination therapies such as JAK inhibitors with navitoclax or pelabresib.

While these show improved clinical responses in some measures, Tefferi noted that their study designs leave questions about their place in treatment guidelines and definitive evidence for survival extension or disease modification remains insufficient.

Despite recent enthusiasm about these experimental approaches, Tefferi remains unconvinced that they represent true breakthroughs.

"When I see a patient with myelofibrosis, I ask myself is my primary goal to improve survival? If yes, then I focus on transplant," he said. "Stem cell transplantation remains the only option for meaningful disease modification—the only path to prolonging survival or achieving a cure."

For those who cannot undergo transplantation due to age or other health issues, symptom management becomes the focus. But even here, Tefferi approaches clinical trials with caution.

"I always ask would I take this drug myself? Would I enroll myself in this clinical trial? If not, why would I do that to a patient?" he said, emphasizing that many trials serve drug development goals rather than patient needs. "I focus on the patient first—not whether they match a trial protocol."

For low-risk patients or those with contraindications to transplantation, the standard approach focuses on JAK inhibitor therapy for symptom control.

Tefferi noted that newer options like momelotinib or pacritinib offer advantages for patients with low platelet counts or anemia, providing additional tools for managing challenging cases.

As the interview concluded, Dr. Tefferi reflected on what he sees as a disconnect between current treatment trends and patient needs.

"MPN treatment is always about selecting 'which patient to treat' first," he said. "Whatever medication you give might not cause issues in the next five years—but it could lead to serious problems 30 years down the line.”

These are long-lived patients and physicians need to consider what could happen when these patients reach their 60s, not just when the patients are in their 30s or 40s, he added.

His message to the hundreds of hematologists gathered at the ICKSH 2025 was clear.

"Especially for PV and ET patients, unnecessary side effects from treatment can be more harmful than the disease itself,” he said.