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From OncoLog, January 2011, Vol. 56, No. 1

New Drugs Control Symptoms of Myeloproliferative Disorders and Improve Quality of Life for Patients

By Bryan Tutt

Photo: Dr. Srdan Verstovsek
Dr. Srdan Verstovsek examines a patient whose symptoms from myelofibrosis improved during his participation in a clinical trial of a JAK2 inhibitor.

Recent clinical trials have demonstrated that a new class of drugs can effectively treat myeloproliferative disorders. These disorders are a diverse group of diseases in which the blood-producing cells in the bone marrow start to grow without control and function abnormally.

Myeloproliferative disorders can be classified into two main categories according to the presence or absence of the Philadelphia chromosome abnormality, which can be identified by bone marrow karyotyping.

“Any patient who has the Philadelphia chromosome abnormality—a translocation between chromosomes 9 and 22—in the bone marrow cells is considered to have chronic myelogenous leukemia,” said Srdan Verstovsek, M.D., Ph.D., an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. “None of the other myeloproliferative disorders can be identified by a specific test.”

The three main Philadelphia chromosome–negative myeloproliferative disorders—polycythemia vera, essential thrombocythemia, and primary myelofibrosis—are sometimes referred to as the classic myeloproliferative disorders, and they are most often diagnosed in patients aged 60–70 years. Patients with any of these disorders may experience disease progression over time. For example, patients with polycythemia vera or essential thrombocythemia can develop secondary myelofibrosis, called post-polycythemia or post-thrombocythemia myelofibrosis. Also, any of the three classic myeloproliferative disorders can progress to acute myelogenous leukemia.

Complications from myeloproliferative disorders

Patients with essential thrombocythemia, characterized by excess platelet production, have a normal life expectancy in general, although they face an increased risk of blood clots that may affect their quality of life. Each year, 6,000–7,000 new cases of essential thrombocythemia are diagnosed in the United States.

In patients with polycythemia vera, an abnormal proliferation of all hematopoietic bone marrow elements increases the total blood volume. The main complication this causes for patients is a high red blood cell count, which leads to increased clotting similar to that caused by essential thrombocythemia. Patients with polycythemia vera have a somewhat shorter life expectancy than is normal for their age group. Polycythemia vera has about the same incidence rate as essential thrombocythemia.

Primary myelofibrosis is less common than the other two classic myeloproliferative disorders. Each year, about 3,000 people in the United States are diagnosed with myelofibrosis, including patients with post-polycythemia and post-thrombocythemia myelofibrosis (who account for up to a quarter of all patients with myelofibrosis). In patients with myelofibrosis, bone marrow cells grow without control, and the bone marrow stromal cells react by secreting a number of different proteins that lead to the formation of fibers in the bone marrow. This scarring prevents the bone marrow from being able to produce enough blood cells.

As the body tries to compensate for the lack of red blood cells produced by the bone marrow, the spleen enlarges and contributes to the production of blood cells. Abnormal blood cells can also infiltrate the spleen and other organs (e.g., the liver). As a result, spleen enlargement occurs in about 80% of patients with myelofibrosis. These patients’ spleens may double or even triple in size. The liver is enlarged in about 40% of myelofibrosis patients.

Fatigue is the most common symptom of myelofibrosis. Many myelofibrosis patients also experience decreased appetite, weight loss, and malnutrition as a result of the enlarged spleen pressing on the stomach. These patients tend to have decreased performance status and poor quality of life. As the disease progresses, patients may have increasing weakness, progressive enlargement of the liver and spleen, liver failure, portal hypertension causing bleeding in the gastrointestinal tract, pulmonary hypertension, lung failure, and cardiac failure. “Most of these patients die from body wasting, organ failure, and similar disease complications within 5–7 years,” Dr. Verstovsek said. About 20% of cases of myelofibrosis progress to acute myelogenous leukemia, he added, and the average patient survival after such progression is only 5 months.

Atypical myeloproliferative disorders include hypereosinophilic syndrome (an excess number of eosinophils in the blood and bone marrow) and systemic mastocytosis (an infiltration of mast cells into non-skin tissues). Eosinophilic infiltration of the organs is a potentially deadly characteristic of hypereosinophilic syndrome. Mastocytosis is usually confined to the bone marrow and may be indolent or aggressive. Because eosinophils and mast cells are part of normal allergic reactions, patients with hypereosinophilic syndrome and systemic mastocytosis experience allergic reactions and skin rashes. Both of these disorders tend to affect patients in their 40s. “These disorders are very rare,” Dr. Verstovsek said. “Nobody has a good data base of these patients, and it is believed that there are only a few thousand people living with these diseases in the United States.”

Treatment

Systemic mastocytosis and hypereosinophilic syndrome are usually managed with prednisone or other steroids, while hydroxyurea or other chemotherapeutic agents may be used to treat more aggressive cases.

For chronic myelogenous leukemia, imatinib is the first-line treatment, and phase III trials demonstrating the effectiveness of two newer drugs—dasatinib and nilotinib—were described in the August 2010 issue of OncoLog.

Photo: Splenomegaly before treatment Photo: Splenomegaly before treatment
Photo: Splenomegaly after treatment Photo: Splenomegaly after treatment
ABOVE: Photos of a patient before therapy with an experimental JAK2 inhibitor show the distended abdomen caused by the enlarged spleen, a common symptom of myelofibrosis. BELOW: Photos taken after 2 months of therapy with a JAK2 inhibitor show a marked reduction in the patientís splenomegaly.

Treatment of the three classic myeloproliferative disorders varies. In patients with polycythemia vera, phlebotomies are used to reduce the red blood cell count. This is typically done every 2 weeks until the patient’s hematocrit is stabilized at below 45%, after which phlebotomies are done as needed. Low-dose aspirin is given to reduce clotting in patients with polycythemia vera and in those with essential thrombocythemia. Patients with either of these disorders who are at high risk for clotting may also receive hydroxyurea to decrease elevated blood cell counts.

There are no treatments approved by the U.S. Food and Drug Administration for myelofibrosis, but medications prescribed off-label for its treatment include hydroxyurea, thalidomide, lenalidomide, steroids, and growth factor injections. Low-intensity stem cell transplantation is also used to treat myelofibrosis, but this is considered risky, resulting in death in about 15% of patients.

None of these treatments for myelofibrosis has been found to be both safe and effective, and none has been proven to change the natural course of the disease. However, recent studies have shown the effectiveness of a new class of drugs in patients with the three classic myeloproliferative disorders.

JAK2 inhibitors

In 2005, researchers discovered a mutation in the JAK2 gene that occurs in about 80% of patients with the three main Philadelphia chromosome–negative myeloproliferative disorders. The JAK2 gene produces an enzyme that is inside all cells, attached to receptors for blood growth factors that signal the production of blood cells. In patients with the mutation, the JAK2 enzyme is produced even when the receptors are not activated by blood growth factors, causing abnormal cell growth. Several drugs have been developed to inhibit the activity of the JAK2 enzyme.

So far, eight JAK2 inhibitors have been tested in clinical studies in patients with primary or secondary myelofibrosis. Dr. Verstovsek has been the lead investigator for trials of most of these drugs. He and his colleagues recently published in the New England Journal of Medicine the results of a phase I/II trial of the JAK2 inhibitor INCB018424 in patients with myelofibrosis. Half the patients in the study had their enlarged spleens reduced by about 50%. Another quarter of the patients had their spleens reduced by 25%. The spleen reduction improved the patients’ appetites, and other general symptoms such as fatigue and weakness improved as well. Patients gained weight and were able to walk more. The most common adverse effect was myelosuppression, which occurred in less than 10% of the patients.

A phase III placebo-controlled study of INCB018424 in patients with myelofibrosis was recently conducted at MD Anderson and other centers, and the results will be available soon.

“Clinically, with JAK2 inhibitors we see good control of the signs and symptoms of myelofibrosis in the majority of patients,” Dr. Verstovsek said. “Some of my patients whose activities had been severely limited by fatigue and weakness have experienced marked improvement and said they’re able to go dancing or play golf again.”

In another phase II study led by Dr. Verstovsek, INCB018424 was given to patients with hydroxyurea-resistant or hydroxyurea-refractory polycythemia vera. Dr. Verstovsek was amazed by the results: all but one patients’ hematocrit decreased to below 42%, a goal of therapy. On the basis of these results, a phase III study of INCB018424 in patients with polycythemia vera has been approved. “I suspect that in a year or so we might be talking about this drug being a very effective, approved therapy for both myelofibrosis and polycythemia vera,” Dr. Verstovsek said.

Importantly, JAK2 inhibitors are not specific to the mutated JAK2 enzyme; they inhibit the activity of the normal JAK2 enzyme as well. This means that patients with Philadelphia chromosome–negative myeloproliferative disorders are likely to benefit from JAK2 inhibitors regardless of whether they have a JAK2 mutation.

“When the JAK2 mutation was first discovered, we thought it was the cause of these disorders,” Dr. Verstovsek explained. “We now know of at least eight other mutations that are present in patients with myeloproliferative disorders and can cause the activation of the JAK2-initiated intracellular signalling cascade of proteins that leads to the abnormal cell growth. Multiple mutations can be present in the same patient, but clinically these patients present in the same way regardless of their mutation profile.”

Because JAK2 inhibitors affect normal JAK2 production, the drugs cannot be given in doses sufficient to completely eliminate myeloproliferative disorders because that would completely suppress normal blood cell growth. Long-term follow-up of the patients in the recently completed studies and in ongoing studies will determine whether JAK2 inhibitors prolong patients’ lives. However, the studies have already shown that JAK2 inhibitors can improve patients’ quality of life and reduce their symptoms. These drugs are currently available only in clinical studies, so Dr. Verstovsek urges doctors to make these studies known to their patients with any of the three classic myeloproliferative disorders.

For more information, contact Dr. Srdan Verstovsek at 713-745-3429 or sverstov@mdanderson.org. For more information about clinical trials in myeloproliferative disorders, visit clinicaltrials.org.

Other articles in OncoLog, January 2011 issue:

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