Making Headway Against Myeloproliferative Disorders

From OncoLog, January 2008, Vol. 53, No. 1

Making Headway Against Myeloproliferative Disorders

by Don Norwood

Until very recently, patients with myeloproliferative disorders—hematological diseases in which the blood-producing cells in the bone marrow undergo abnormal development and malfunction—faced an uphill battle in their treatment because of the relative rarity of these disorders.

As for other rare diseases, pharmaceutical companies have been hesitant to develop drugs for myeloproliferative disorders. Thus, even though these disorders cause myriad health problems and in some cases lead to acute leukemia, little headway had been made in finding effective therapies—that is, until a recent discovery. This discovery of a key gene mutation has led to the development of new drugs that appear to control myeloproliferative disorders and their symptoms, giving new hope to patients who suffer the diseases’ debilitating effects.

The three main myeloproliferative disorders are polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Patients often experience such symptoms as headache, fatigue, shortness of breath, easy bruising or bleeding, petechiae, unexplained weight loss, night sweats, and fever. The symptoms unique to the different disorders are no less debilitating. In those with polycythemia vera, overproduction of red blood cells can lead to swelling of the spleen; patients may also have widespread itching. For patients with essential thrombocythemia, excess platelet production can make the blood “sticky,” slowing blood flow. Patients with primary myelofibrosis develop scarring or thickening of the fibers in the bone marrow, leading to decreased red blood cell production, anemia, and low numbers of platelets and white blood cells; the spleen subsequently enlarges as it takes over the production of blood cells from the bone marrow.

Low incidence, big breakthrough

Because of the rarity of myeloproliferative disorders, most organizations that track disease incidence do not track these disorders. According to 2001-2004 Surveillance, Epidemiology and End Results data, the combined annual incidence of myeloproliferative disorders in the United States was 2.1 per 100,000 individuals. In comparison, the mean annual incidence of prostate, breast, lung, and colorectal cancers during that period was 172 per 100,000 men, 130 per 100,000 women, 63 per 100,000 population, and 51 per 100,000 population, respectively.

The progression of and prognosis for myeloproliferative disorders vary greatly, as some patients must undergo only close monitoring of their disease, whereas others have rapid progression to advanced-stage disease or even to acute myelogenous leukemia. Furthermore, myeloproliferative disorders can develop at any age, and researchers have yet to identify causes for them. Even with treatment, these disorders can be fatal.

The discovery that prompted pharmaceutical and biotechnology companies to develop more effective therapies occurred in 2005, when researchers found a mutation of the JAK2 gene in very large percentages of patients with the three main myeloproliferative disorders. While exact causes of the disorders remain unknown, the discovery of the mutation resulted in the development of JAK2 inhibitors, and this has paid significant dividends for patients.

Initially discovered by a group of researchers in France, the JAK2 gene is mutated in more than 90% of patients with polycythemia vera and about 50% each of patients with essential thrombocythemia and primary myelofibrosis. Physiologically, the JAK2 protein, a tyrosine kinase, plays an important role in cell growth. In patients with the mutation in the JAK2 gene, the JAK2 protein is autophosphorylated, meaning that it is always active, resulting in the overproduction of blood cells, said Srdan Verstovsek, M.D., Ph.D., associate professor in the Department of Leukemia at M. D. Anderson. “The JAK2 protein helps transfer signals from growth factors that usually circulate in the blood and attach to the growth factor receptors on the cell surfaces,” Dr. Verstovsek said. The receptors activate JAK2, which then carries signals through a cascade of proteins to the cell nuclei. This tells the cells to grow.

About half of patients with essential thrombocythemia or primary myelofibrosis do not have the JAK2 mutation. However, researchers have found that a small percentage of these patients have other mutations and that the JAK2 inhibitors may also be beneficial for them, said Dr. Verstovsek.

New hope for control

In the short period since the discovery of the JAK2 mutation, development and clinical testing of several agents that inhibit JAK2 have occurred. These agents include INCB18424, XL019, and CEP701, which are currently being evaluated in clinical studies for patients with advanced primary myelofibrosis.

M. D. Anderson has been at the forefront of clinical testing of JAK2 inhibitors for the treatment of myeloproliferative disorders, said Charles A. Koller, M.D., medical director of the Leukemia Center and professor in the Department of Leukemia. Currently, Dr. Verstovsek is conducting several clinical trials of JAK2 inhibitors for myeloproliferative disorders. Furthermore, the number of patients with myeloproliferative disorders seeking participation in clinical trials at M. D. Anderson has greatly increased, from 34 in 2003 to 214 in 2006.

“We realized the potential for developing medications for this particular abnormality and helped design and elicit approval of these studies through the U.S. Food and Drug Administration,” said Dr. Verstovsek. “So the studies were offered to patients rather quickly.” Dr. Koller emphasized this quick drug development by pointing out that the period from discovery of the JAK2 mutation to the first human trial of a JAK2 inhibitor was only about 2.5 years. This is significantly shorter than the typical time required to develop therapies in response to scientific discoveries.

Thus far, the JAK2 inhibitors that are being tested appear to be improving the quality of life of patients with myeloproliferative disorders, which is no small feat. Consider patients with primary myelofibrosis who suffer from an enlarged spleen. An enlarged spleen can intrude upon the space that the stomach normally takes up, said Dr. Koller. As a result, when the patient eats, he or she becomes full before sufficient amounts of food are eaten, resulting in weight loss. Before the development of JAK2 inhibitors, the only way to relieve an enlarged spleen in such patients was to perform a splenectomy. Now, however, JAK2 inhibitors can regulate the number of blood cells that pass through the spleen, preventing buildup of the cells in the spleen and the swelling that results. Researchers have observed significant and rapid decreases in the size of the spleen and the number of circulating white blood cells; this has led to the reduction or elimination of many other symptoms, including shortness of breath, fatigue, weakness, itching, bone pain, early satiety, and weight loss. The end result has been much improved energy level and performance status.

“We know that by inhibiting JAK2, we can get rid of the manifestations of myeloproliferative disorders,” said Dr. Koller. “I’m convinced that the JAK2 inhibitors will be key to controlling these diseases. I think that’s going to have a significant impact on the quality of life for these patients.”

The only drawback of these drugs is that they interrupt normal JAK2 function, which in turn interrupts normal cell growth. However, Dr. Koller believes that within the next 5 years, researchers will develop agents that do not have this negative effect.

Patient involvement driving advances

Dr. Verstovsek confirmed that the early results of the studies of JAK2 inhibitors are very positive. “Our preliminary results already show that these medications have the potential to affect the patients in a positive way in a rather short period of time,” he said. “Furthermore, many patients come to M. D. Anderson knowing about the potential of these medications, and thus they try to enroll in specific studies if they are eligible.”

Key ingredients in letting patients with myeloproliferative disorders know about such trials are patient advocacy groups such as the CMPD Education Foundation, an organization that Dr. Verstovsek knows well, as he serves on its six-person medical advisory board. The foundation publishes a Web site (www.mpdinfo.org) and a newsletter with information for patients with myeloproliferative disorders. This foundation, along with the MPD Foundation (www.mpdfoundation.org), is an important avenue for patients to learn about clinical trials.

Because of the rarity of myeloproliferative disorders, patients are not likely to encounter others with these diseases in their daily lives. However, through the efforts of the foundations and communication through M. D. Anderson’s Department of Leukemia Web site, patients with myeloproliferative disorders can learn about clinical trials offering new hope.

“We’ve been in contact with patients with myeloproliferative disorders for a decade,” said Dr. Koller. “That’s why there’s no shortage of patients. They’ve figured out that JAK2 is the key here and they want to get it inhibited.”

As the research in this field develops, the close relationship between the Department of Leukemia and these patient groups may pay even bigger dividends.

A clearer picture emerging

An additional achievement that has benefited patients with myeloproliferative disorders is the improved classification of these diseases. To help make diagnosis of myeloproliferative disorders more precise, M. D. Anderson has worked with other institutions to both update and streamline the diagnostic criteria for the diseases. Among the changes: a patient’s JAK2 mutation status is now determined as part of the diagnostic process. This determination, which can be accomplished with a simple blood test, helps significantly in making a proper diagnosis—previously, no single test could effectively differentiate between the myeloproliferative disorders and other similar bone marrow diseases, Dr. Verstovsek said. The results of this collaboration will be published in the next edition of the World Health Organization’s “blue book” for hematological neoplasms (World Health Organization Classification of Tumours: Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissues).

In addition, M. D. Anderson has organized and taken part in three meetings of the International Working Group for Myelofibrosis Research and Treatment. These were designed to help myelofibrosis experts come to a consensus regarding different issues in the treatment of the disorder. As a result, the experts decided on a set of clinical response criteria that should be used in clinical studies of myelofibrosis. These criteria were published in 2006 and are now in use across the board in clinical trials.

Also recently published as a result of these meetings is a definition of the transformation of essential thrombocythemia and polycythemia vera to myelofibrosis, a phenomenon that occurs in 25% of patients; these findings also will be published in the World Health Organization’s hematological neoplasms blue book. The transformation is important because myelofibrosis is associated with a much shorter life expectancy (5–7 years) than essential thrombocythemia and polycythemia vera (20 years or more).

“These are the issues that have troubled this community for a long time,” said Dr. Verstovsek. “Now, with the new findings and with the common effort from all sides to streamline procedures for diagnosis, for therapy, for definition, and so forth, the field is becoming clearer and physician-friendly so that we can enroll patients in studies and administer potentially effective therapies for myeloproliferative disorders in a uniform fashion.”

For more information, visit the Department of Leukemia’s myeloproliferative disorders Web site at www.mdanderson.org/diseases/mpd.

TOP

©2008 The University of Texas M. D. Anderson Cancer Center
1515 Holcombe Blvd., Houston, TX 77030
1-877-MDA-6789 (USA) / 1-713-792-3245
Patient Referral Legal Statements Privacy Policy