NEJM study suggests novel drug approach to myeloproliferative neoplasms

September 2, 2015 | by Elise Lamar

Myeloproliferative neoplasms, or MPNs, are a trio of blood disorders that if unchecked can develop into full-blown leukemia. All three MPNs, including myelofibrosis, polycythemia vera and essential thrombocythemia (ET), are caused by overproduction of a particular blood cell. ET patients, for example, make too many platelets, cells required for clotting, and are thus at risk for clotting disorders.

myeloproliferative neoplasms Myeloproliferative neoplasms are caused by overproduction of a particular blood cell. (Shown here, red and white blood cells.) The novel-acting drug imetelstat could be a promising treatment approach for these disorders.

About half of the patients that hematologist David Snyder, M.D., sees in his City of Hope practice have a myeloproliferative neoplasm. Snyder says that currently available drugs can manage symptoms and, in the case of ET, protect many patients from thrombotic events such as heart attack, stroke or other vascular problems.

“But some ET patients are intolerant or resistant to these drugs,” says Snyder, who is also associate chair and professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation. “Plus, existing drugs don’t impact molecular defects so their effects are not durable. We still need treatments that have more long-term benefits.”

In that effort, Snyder recently joined a multinational team of researchers from the San Francisco Bay area and Europe in announcing success of a phase II clinical trial of a novel anti-ET drug. That study, published in the Sept. 3 edition of the New England Journal of Medicine, reported that 18 ET patients treated with the drug imetelstat exhibited reduced platelet levels and 16 showed complete normalization of blood cell counts. Eight patients were treated at City of Hope; the rest were treated in Germany and Switzerland. Most participants suffered only mild or moderate adverse reactions.

Research could 'open the door' to new options for patients

“Our trial was the 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 of the trial. “These studies open the door to test imetelstat effects in myelofibrosis, an MPN whose prognosis is much worse than ET.” Considered by some a chronic leukemia, myelofibrosis can progress to acute myeloid leukemia in approximately 10 percent of patients.

Developed by the Bay-area pharmaceutical company Geron, imetelstat inhibits the enzyme telomerase, which elongates repetitive DNA and RNA structures capping chromosome tips called telomeres. Telomere length controls cell growth: As normal cells age, their telomeres shorten, slowing cell division. However, telomerase is overactive in most cancers, keeping telomeres long and permitting uncontrolled tumor cell proliferation. As a result, there is intense interest in telomerase inhibitors as therapeutics, and imetelstat is the first such molecule to reach clinical trials.

All 18 ET patients enrolled in the trial displayed high platelet counts, and many were intolerant of other treatments. Participants received weekly imetelstat injections, followed by less frequent doses 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.

“Some experienced flu-like symptoms a few days later, which then cleared,” Snyder said. “For most, things got easier over time.” All patients, however, exhibited elevated liver enzymes, which normalized once treatment ended, and one elderly patient died of liver failure. The Food and Drug Administration, however, concluded that the benefits of drug treatment outweighed any risk of harm.

Moving forward

Snyder says more work is needed to nail down whether positive patient responses were attributable to telomerase inhibition. “We also don’t yet know whether imetelstat eradicates early progenitor cells or more mature blood cells,” he said, cautioning that patients’ platelet levels rose after drug withdrawal. “That suggests that in ET imetelstat does not target an early stem cell population.”

Killing those cells is likely required for a long-term anti-cancer response, or remission. Intriguingly, a different study conducted at the Mayo clinic study hints that imetelstat can promote remission in some myelofibrosis patients. Snyder said this discovery shifts the focus of anti-telomerase therapies for MPNs from ET to myelofibrosis.

Gabriela M. Baerlocher, M.D., the study’s lead author concurred. “There is a greater need for drugs in more devastating diseases like myelofibrosis, where there are no other good treatment options,” said Baerlocher, a hematologist at University Hospital and the University of Bern in Switzerland. “The goal is now to confirm these effects in a larger cohort of patients.” Geron and Janssen Pharmaceuticals are now conducting such trials.

Snyder eagerly awaits their outcome. “My patients get really excited when I tell them about the Mayo study that showed partial remission,” Snyder said. “These drugs have gotten a lot of attention in the patient population. We’re anxious to get these studies going.”

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Learn more about becoming a patient or getting a second opinion at City of Hope by visiting our website or by calling 800-826-HOPE (4673). You may also request a new patient appointment online. City of Hope staff will explain what's required for a consult at City of Hope and help you determine, before you come in, whether or not your insurance will pay for the appointment.

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