Clinical Strategies for Diagnosing and Treating MPNs

Andrew Kuykendall, MD Moffitt Cancer Center | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• Secondary causes of elevated blood cell counts must be ruled out when diagnosing polycythemia vera (PV) or essential thrombocythemia (ET).

• Molecular profiling is a major component of the diagnostic workup for suspected myeloproliferative neoplasms (MPNs), as the majority of patients will carry one of the common driver mutations.

• Low-dose aspirin is a standard treatment for both PV and ET, although additional cytoreductive therapy may be recommended to reduce risk of thrombosis or decrease symptom burden.

Treatment Algorithms for Patients With MPN

Andrew Kuykendall, MD, of Moffitt Cancer Center, reviewed the diagnosis and treatment algorithm for patients with MPNs, specifically PV and ET, with the cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center.

PV Diagnosis and Stratification

When investigating potential PV, physicians must rule out secondary causes of erythrocytosis, including cardiac abnormalities, lung abnormalities, smoking, sleep apnea, emphysema, living at a higher altitude, prior lung resection, or SGLT2 inhibitor therapy. If secondary causes are unapparent, lab testing is the basis for the diagnostic workup. Elevated white blood cell or platelet counts in conjunction with erythrocytosis may be suggestive of PV. 

Erythropoietin (EPO) level can be a key breakpoint for further investigation, Dr. Kuykendall said. Most patients with PV will carry a JAK2 mutation, but molecular profiling may not be needed in patients where EPO levels are normal and the erythrocytosis has a likely secondary cause. Bone marrow biopsies are recommended to confirm a PV diagnosis, but are typically reserved for after a positive JAK2 mutation test result.

For stratification of confirmed PV, patients aged 60 years or older or with a prior history of a thromboembolic event are considered high risk. “About 60% of patients are going to be high risk, a lot of them by age,” Dr. Kuykendall said.

PV Treatment Algorithm and Indicators for Additional Therapy

The standard of care for every patient with PV is typically once-daily low-dose aspirin based on the ECLAP study plus regular phlebotomizing to maintain a hematocrit level under 45% based on the CYTO-PV study. High-risk patients are recommended for additional cytoreductive therapy via hydroxyurea or interferon formulations or, in the second-line setting, ruxolitinib. 

Notably, some patients that would otherwise be considered low-risk may benefit from cytoreductive therapy if they have risk factors like high JAK2 allele burden or white blood cell count, or if frequent phlebotomy requirements or disease-related symptoms are especially burdensome. “Historically, we wanted to avoid starting cytoreductive therapy early because we didn’t know that any of our treatments had disease-modifying potential, but now we’re seeing a consistent ability with interferon formulations to reduce the variant allele fraction over time,” Dr. Kuykendall said. 

When selecting between cytoreductive therapies, the disease-modification potential of interferon formulations can be a significant upside if patients can tolerate the treatment long term. Dr. Kuykendall favors starting younger patients with interferon formulations if they do not have contraindications, while he said hydroxyurea is a perfectly valid approach for older patients where disease progression is more likely to occur over decades. 

Although hydroxyurea and interferon formulations are comparably effective for controlling blood counts, they are largely ineffective at improving symptoms of the disease, Dr. Kuykendall said. For highly symptomatic patients, ruxolitinib in the second line can provide a huge benefit, especially for those with constitutional symptoms or itching. 

ET Diagnosis and Stratification

The initial workup for ET is similar to PV, and secondary causes of elevated platelet counts must be excluded, the most common of which is iron deficiency. Molecular profiling is also a primary tool for diagnosing ET, as 95% of patients will carry a JAK2, CALR, or MPL mutation, although there is a small subset of triple-negative patients without any of the three. Bone marrow biopsies can distinguish ET from prefibrotic or primary myelofibrosis and inform long-term expectations when counseling patients, Dr. Kuykendall suggested. 

Risk stratification in ET is based on the patients’ history of thrombosis and age, much like PV, but is further differentiated by presence or absence of a JAK2 mutation, as follows:

• Very low-risk: no history of thrombosis, under 60 years of age, and no JAK2 mutation.
• Low-risk: no history of thrombosis, under 60 years of age, and with JAK2 mutation.
• Intermediate-risk: no history of thrombosis, aged 60 years or older, and no JAK2 mutation.
• High-risk: history of thrombosis or aged 60 years or older with JAK2 mutation.

ET Treatment Algorithm

The recommended therapeutic approach for patients with ET varies based on risk stratification. For very-low risk disease, once-daily low-dose aspirin is recommended if patients have cardiovascular risk factors. Otherwise, observation alone may be appropriate. Twice-daily aspirin is recommended for patients with low-risk disease, and once-daily aspirin with or without concurrent hydroxyurea or interferon therapy is recommended for those with intermediate-risk disease. For patients with high-risk disease, hydroxyurea or interferon therapy plus twice-daily aspirin is recommended for those with a history of arterial thrombosis, while hydroxyurea or interferon therapy plus anticoagulation is recommended for those with a history of venous thrombosis.

While low-dose aspirin is a standard treatment across risk groups, it should be avoided in patients with extreme thrombocytosis or acquired von Willebrand’s Disease, or in patients who are already on a direct oral anticoagulant, barring any specific recommendations for dual treatment, Dr. Kuykendall said.