Jakafi Targets Faulty Mechanism in Polycythemia Vera

Jakafi represents a paradigm of advances in pharmacology.

We live in wondrous times where we not only better understand the mechanisms of disease but also how to target these mechanisms with newly discovered drugs. For instance, Jakafi (ruxolitinib) became the first FDA-approved drug to treat polycythemia vera, and it works by inhibiting enzymes Janus Associated Kinase 1 (JAK-1) and Janus Associated Kinase 2 (JAK-2). Along with other cellular changes, these enzymes go haywire in people with polycythemia vera.

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What Is Polycythemia Vera?

Polycythemia vera is an uncommon blood disorder. It's an insidious disease that usually presents later in life (people in their 60s) and eventually causes thrombosis (think stroke) in one third of all people affected. As we all know, stroke can be deadly thus a diagnosis of PV is pretty serious. 

The story of how PV works begins in the bone marrow. Our bone marrow is responsible for making our blood cells. Different types of blood cells in our body have different roles. Red blood cells deliver oxygen to our tissues and organs, white blood cells help fight infection and platelets stop bleeding. In people with PV, there's a mutation in multipotential hematopoietic cells which results in excess production of red blood cells, white blood cells, and platelets. In other words, in PV, progenitor cells, which differentiate into red blood cells, white blood cells, and platelets, are thrown into overdrive.

Too much of anything is no good, and in the case of PV, too many blood cells can muck up our blood vessels causing all kinds of clinical problems including the following:

  • headache
  • weakness
  • pruritis (itching which classically presents after a hot shower or bath)
  • dizziness
  • sweating
  • thrombosis or excessive blood clotting (Blood clots can clog arteries and cause stroke, heart attack, and pulmonary embolism, or clog veins like the portal vein which feeds the liver thus causing liver damage.)
  • bleeding (Too many blood cells—many of which are defective platelets—can cause bleeding)
  • splenomegaly (The spleen, which filters dead red blood cells, swells due to an increased number of blood cells in PV.)
  • erythromelalgia (Pain and warmth in the digits are caused by too many platelets impeding blood flow in the fingers and toes which can lead to digit death and amputation.)

PV can also complicate other diseases like coronary heart disease and pulmonary hypertension both on account of an increased number of blood cells jamming circulation and smooth muscle hyperplasia or overgrowth that further constricts blood flow. (Smooth muscle makes up the walls of our blood vessels, and an increased number of blood cells probably releases more growth factors which cause smooth muscle to thicken.)

A minority of people with PV go on to develop myelofibrosis (where the bone marrow becomes spent or "worn out" and filled with functionless and filler-like fibroblasts leading to anemia) and eventually even acute leukemia. Keep in mind that PV is often referred to as myeloproliferative neoplasm or cancer because like other cancers it results in a pathological increase in cell numbers. Unfortunately, in some people with PV, leukemia represents the end of the line on a continuum of cancer. 

Jakafi: A Drug That Combats Polycythemia Vera

People in the plethoric phase of PV or the phase characterized by an increased number of blood cells are treated with palliative interventions which mitigate symptoms and improve the quality of life. Most well-known among these treatments is probably phlebotomy or bleeding to reduce blood cell counts.

Specialists also treat PV with myelosuppressive (think chemotherapeutic) agents—hydroxyurea, busulfan, 32p and, more recently, interferon—which inhibit the excess production of blood cells. Myelosuppressive treatments increase a patient's sense of well-being and are thought to help people with PV live longer. Unfortunately, some of these drugs like chlorambucil carry a risk of causing leukemia. 

For people with PV who have trouble tolerating or are unresponsive to hydroxyurea, a first-line myelosuppressive agent, Jakafi was approved by the FDA in December 2014. Jakafi works by inhibiting the JAK-1 and JAK-2 enzyme which is mutated in most people with PV. These enzymes are involved in blood and immunological functioning, processes which are abnormal in people with PV. 

In 21 percent of people who are intolerant or unresponsive to hydroxyurea, studies show that Jakafi decreases spleen size (decreases splenomegaly) and reduces the need for phlebotomy. Research suggests that even with the best alternative treatments available, only 1 percent of such people would have otherwise experienced such benefit. Of note, Jakafi had been previously approved by the FDA for the treatment of myelofibrosis in 2011. Jakafi's most common adverse effects (which the FDA curiously terms "side effects") include anemia, low blood platelet counts, dizziness, constipation, and shingles.

It should be noted that as is the case with other myelosuppressive treatments, it's unclear whether Jakafi will help people live longer.

If you or someone you love has PV that doesn't respond to hydroxyurea, Jakafi represents a promising new treatment. For the rest of us, Jakafi represents a prime paradigm of how more drugs will be developed going forward. Researchers are getting better at figuring out exactly which mechanisms are messed up by disease and targeting this pathology.

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  • "Therapy for myeloproliferative neoplasms: when, which agent, and how?" by HL Geyer and RA Mesa published in Blood on 12/4/2014.
  • Prchal JT, Prchal JF. Chapter 86. Polycythemia Vera. In: Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT. eds. Williams Hematology, 8e. New York, NY: McGraw-Hill; 2010.

By Naveed Saleh, MD, MS
Naveed Saleh, MD, MS, is a medical writer and editor covering new treatments and trending health news.