Trial of telomerase inhibitors points to lasting treatments for myeloproliferative disorders
September 2, 2015

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Trial of telomerase inhibitors points to lasting treatments for myeloproliferative disorders
Study in New England Journal of Medicine highlights City of Hope research on novel-acting drug

DUARTE, Calif., September 2, 2015 — A multinational team of physicians and scientists from City of Hope, the San Francisco Bay area, and Europe recently reported success of a phase II clinical trial of a novel drug against essential thrombocythemia (ET), one of three myeloproliferative neoplasms (MPNs). That study, published in the Sept. 3 edition of the New England Journal of Medicine, represents the first human trial of a drug targeting telomeres in a blood neoplasm and paves the way toward more durable treatments of these disorders.  
 
MPNs, which also include myelofibrosis and polycythemia vera, are blood diseases akin to leukemia, each marked by overproduction of a particular blood cell type. ET patients, for example, make too many platelets, cells essential for blood clotting, which puts them at risk for thrombosis and bleeding. Even when effective, existing ET treatments reduce platelet counts but do not provide a long-lasting cure, and some patients are resistant to them. A small percentage of patients progresses to acute leukemia.
 
The new study reports that all 18 ET patients treated with the drug imetelstat exhibited decreased platelet levels, and 16 showed normalized blood cell counts. Eight patients participated at City of Hope and the rest were treated at hospitals in Germany and Switzerland. Most participants experienced only transient mild or moderate adverse affects. City of Hope physician David Snyder, M.D, associate chair and professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation, was senior author of the paper.

“Our trial was a first look at what happens when you treat ET patients with a drug that has a totally novel mechanism of action,” said Snyder, a co-principal investigator on the trial. “These studies open the door to test imetelstat effects in myelofibrosis, an MPN whose prognosis is much worse than ET.”
 
Imetelstat was developed by the Bay-area biotech company Geron, which sponsored the study and whose scientists were co-authors. Imetelstat inhibits the enzyme telomerase, which elongates telomeres — repetitive DNA and RNA structures that encase chromosome tips. Telomere length serves as a molecular clock to control cell growth: Normally, as cells age, telomeres shorten, slowing the overall rate of cell division. However, telomerase becomes overactive in 90 percent of all cancers, keeping telomeres from eroding and permitting uncontrolled tumor cell proliferation.
 
Previously, researchers had treated cultured human cells derived from breast or blood tumors with imetelstat and observed shortened telomeres and decreased tumor cell growth, sparking intense interest in anti-telomerase drugs as therapeutics. Imetelstat is the first anti-telomerase molecule to be evaluated clinically.
 
The 18 ET patients chosen for the study displayed high platelet counts at study entry, and many were resistant or intolerant of other ET treatments. Initially, participants received weekly imetelstat injections, and most were treated less frequently as the trial progressed. Not only did 100 percent show decreased platelet counts but many maintained that response for more than a year while on the drug.
 
“Patients at City of Hope generally tolerated the infusions well,” Snyder said. “Some experienced flu-like symptoms a few days later, which then cleared. For most, things got easier over time.” All patients, however, exhibited elevated liver enzyme levels, which normalized once treatment ended, and one elderly patient died of liver failure during the trial and imetelstat could not be conclusively excluded as a contributory agent. The Food and Drug Administration, however, concluded that the benefits of drug treatment outweighed any risk of harm.
 
Nonetheless, Snyder said that “more dots need to be connected” to nail down how imetelstat acts molecularly. For example, it remains to be proven that positive patient responses were attributable to telomerase inhibition or how and whether positive responses correlate with particular mutations associated with MPN disease.
 
“We also don’t yet know whether imetelstat eradicates early progenitor cells or just more mature blood cells,” he said. However, patients’ platelet levels rose after drug withdrawal. “That suggests that in ET, imetelstat may target an early stem cell population within bone marrow, but not irreversibly.”
 
Killing those cells will likely be required for a long-term anti-cancer response, or remission. Intriguingly, a pilot study conducted at Mayo Clinic hinted that imetelstat can promote remission in a subset of myelofibrosis patients. Snyder said this discovery, also reported in the Sept. 3 issue of the New England Journal of Medicine, shifts the focus of anti-telomerase therapies for MPNs from ET to myelofibrosis. Both studies were released online Sept. 2.
 
Gabriela M. Baerlocher, M.D., the study’s lead author and a hematologist at University Hospital and the University of Bern in Switzerland, concurred. “There is a greater need for drugs in more devastating diseases like myelofibrosis, where there are no other good treatment options,” she said. “The goal is now to confirm these effects in a larger cohort of patients and evaluate if imetelstat has effects in other precancerous or malignant blood diseases.”
 
Geron in partnership with Janssen Biotech Inc., is now conducting such trials focusing on myelofibrosis.

Snyder, whose practice includes a sizeable proportion of MPN patients, eagerly awaits their outcome. “My patients get really excited when I tell them about the Mayo study that showed remission in some patients,” Snyder said. “This drug has gotten a lot of attention in the patient population. We’re anxious to get these studies going.”
 
Other collaborating authors include Elisabeth Leibundgut, PharmD., and Michael Daskalakis, M.D., of University Hospital and University of Bern, Switzerland; Oliver Ottmann, M.D., of Johann Wolfgang Goethe University in Frankfurt, Germany; Gary Spitzer, M.D., of Upstate Oncology Associates, Greenville, South Carolina; Olatoyosi Odenike, M.D., of University of Chicago; Michael McDevitt, M.D., Ph.D., of Johns Hopkins University School of Medicine, Baltimore; Alexander Röth, M.D., of University Hospital in Essen, Germany; Bart Burington, Ph.D., and Monic Stuart, M.D. of Geron in Menlo Park, California.
 
Snyder is supported by City of Hope’s Gehr Family Center for Leukemia Research and the Hematologic Malignancies and Stem Cell Transplantation Institute.

About City of Hope
City of Hope is an independent research and treatment center for cancer, diabetes and other life-threatening diseases. Designated as a comprehensive cancer center, the highest recognition bestowed by the National Cancer Institute, City of Hope is also a founding member of the National Comprehensive Cancer Network, with research and treatment protocols that advance care throughout the nation. City of Hope’s main hospital is located in Duarte, California, just northeast of Los Angeles, with clinics in Antelope Valley and South Pasadena. It is ranked as one of "America's Best Hospitals" in cancer by U.S. News & World Report. Founded in 1913, City of Hope is a pioneer in the fields of bone marrow transplantation and genetics.