Assistant Professor of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York
Assistant Attending Physician, NewYork-Presbyterian Hospital
Visiting Faculty Member, Weill Cornell Medicine-Qatar
“The general symptoms of MPNs include fatigue, headaches, weight loss, and night sweats.”
Dr. Ghaith Abu-Zeinah is an Assistant Professor of Medicine in the Division of Hematology and Oncology at Weill Cornell Medicine in New York, an assistant attending physician at NewYork-Presbyterian Hospital, and a visiting faculty member at Weill Cornell Medicine-Qatar (WCM-Q). Dr. Abu-Zeinah, an alumnus of WCM-Q, specializes in myeloproliferative neoplasms (MPNs), a rare type of blood cancer. He teaches, conducts workshops, and collaborates with discussion groups to raise awareness about MPNs, other chronic conditions, and premalignant states that can lead to leukemias. Dr. Abu-Zeinah spoke with “Hospitals” magazine on the importance of raising awareness about myeloproliferative neoplasms (MPNs)—blood cancers that can cause life-threatening conditions.
Can you describe myeloproliferative neoplasms (MPNs)?
Myeloproliferative neoplasms (MPNs) are rare blood cancers of stem cell origin that differentiate into myeloid lineage. MPNs are characterized by abnormal proliferation of blood cells and can manifest as either chronic or acute conditions.
Patients with MPN experience an overproduction of white blood cells, red blood cells, and/or platelets. The three classical types of MPNs include essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). ET and PV are the most common MPNs. PV is characterized by high red cell counts, with or without elevations in white cells and platelets, whereas in ET, the elevation in platelets is the sole blood count abnormality. In both conditions, more so with PV, patients are at greater than average risk of having venous or arterial blood clots, including potentially fatal pulmonary emboli, heart attacks, and strokes.
PMF is considered the most aggressive MPN, where the mutated stem cells cause bone marrow inflammation and scarring. As a result, some PMF patients develop very low blood counts (cytopenias), enlarged spleens, and infrequently, acute myeloid leukemia.
ET, PV, and PMF are driven by genetic mutations that augment hematopoiesis (stimulating blood cell production). The most common mutation is in the Janus kinase 2 (JAK2) gene, followed by calreticulin (CALR) and the thrombopoietin receptor (MPL).
Although these blood cancers are rarely fatal, some may cause life-threatening conditions such as heart attacks, strokes, transfusion-dependent anemia, or acute leukemia.
Unlike other types of cancers, there is no formalized screening guideline for MPNs. These conditions are typically detected during annual health check-ups, where Complete Blood Count (CBC) and other tests are performed. Since many individuals carry mutations without knowing, early detection and treatment in the premalignant state may be useful to prevent the condition from worsening. Further research is needed on the role and benefit of early screening and preventative strategies.
What are some common symptoms of MPNs?
The general symptoms of MPNs include fatigue, headaches, weight loss, and night sweats. A specific symptom more common in PV is aquagenic pruritus, which is itching triggered by contact with water, typically after showers.
That said, the World Health Organization (WHO) has set criteria for diagnosing MPNs. For example, one major criterion for PV diagnosis is an elevated red blood cell count, indicated by high hemoglobin levels (over 16 grams per deciliter (g/dl) for females or 16.5 g/dl for males). Confirmation of PV involves the presence of the JAK2 mutation and requires a bone marrow biopsy.
Who is impacted by MPNs?
The prevalence and incidence of MPNs in the Middle East and Asia “were estimated to be 57-81 and 12-15 per 100,000 hospital patients per year,” according to the MERGE Registry analysis by Dr. Yassin et al in 2020. The prevalence of the premalignant state known as clonal hematopoiesis of indeterminate potential (CHIP), where individuals carry the mutation without a formal MPN diagnosis, is likely much higher.
The median age of diagnosis for MPNs is in the early 60s, but the median age at some academic centers is in the 50s. MPNs have also been diagnosed less commonly in children, adolescents, and young adults.
Genetic research has identified that the most common underlying mutation for these blood cancers, usually in the JAK2 gene, can develop up to 20 years before clinical diagnosis. In some cases, this mutation can occur in utero, meaning a baby can develop the mutation in the womb and be diagnosed with MPNs later in life.
How do you treat patients with MPNs?
MPNs patients undergo cytoreductive treatment to help reduce blood counts. Additionally, those with PV undergo phlebotomy therapy to reduce the red blood cell count and decrease the risk of blood clots. The first-line cytoreductive therapies depend on the type of MPN one has, age, symptoms, and other clinical factors. The approved treatment options include oral chemotherapy (such as hydroxyurea), oral targeted JAK inhibitors (such as ruxolitinib), and subcutaneous injection of an immunotherapeutic drug (interferon alfa). Clinical trials of investigational agents with or without standard treatments may also be available. The approved drugs can lead to clinical remission but are not curative. If patients can remain on these drugs for years or decades without disease progression, they do not need a transplant. However, if the disease progresses, a bone marrow transplant may be required. An allogeneic, matched-donor stem cell transplant is typically carried out for myelofibrosis patients (PMF or secondary myelofibrosis after ET or PV) or patients with MPNs that are accelerating to leukemia. Providing the best standard of care to MPNs patients also involves collaboration with various health professionals, including hematopathologists, bone marrow transplant hematologists, oncologists, cardiologists, neurologists, and other specialists. These collaborations are crucial for identifying gaps in care, understanding patient needs, determining how best to support patients, and planning the most effective steps toward progress.
Beyond medical interventions, MPNs patients may benefit from lifestyle modifications such as regular exercise, a balanced diet, yoga, and meditation, which may help manage symptoms.
What are the advancements in treating MPNs?
Current treatments include chemotherapy, immunotherapy, and targeted agents. These treatments help ease symptoms and reduce the risk of MPNs developing into a more
serious disease. The JAK2 mutation was discovered in 2005, and several years later, research led to a series of newly approved Food and Drug Administration (FDA) drugs, primarily JAK inhibitors. Three JAK inhibitors—fedratinib, pacritinib, and momelotinib—have been approved after ruxolitinib.
While some of these inhibitors are more specific for JAK2 or target additional pathways, none are curative. Research is ongoing to determine whether there is a better JAK inhibitor or whether another drug must be added in combination. Different classes of drugs, including inhibitors of BET, BCL2/BCLxL, MDM2, telomerase, PIM1 kinase, CALR, and others, are currently being explored in clinical trials.