From One Patient to the World
A single case during fellowship spurred hematologist Jason Gotlib to develop a drug that’s now helping patients around the world.
It was a winter day that began like any other in Jason Gotlib’s hematology fellowship: There were patients to see, notes to write and papers to read. Then the attending in charge of the Stanford hematology clinic that day, Stanley Schrier, told Gotlib that he had one more patient to add to his schedule. The patient’s records, Schrier told him, were on a table behind him.
“I turned around,” Gotlib recalls, “and there was a stack of rubber-banded papers that literally was around two feet high.” The patient, it turned out, was a 39-year-old man with a rare blood disease called idiopathic hypereosinophilic syndrome, characterized by a surplus of a kind of white blood cell, which can lead to inflammation, organ damage and even cancer. This patient’s disease had transformed into acute myeloid leukemia. “He had gone through many treatments, including multiple rounds of chemotherapy,” says Gotlib, now a professor of hematology at Stanford. “He had fluid in his lungs and abdomen, an enlarged liver and spleen, and large disease masses abutting his spine.”
Gotlib and Schrier decided to try something for the patient — a course of imatinib (Gleevec), a drug that blocks a group of proteins called tyrosine kinases which some cancers need to survive. Imatinib had been formally approved by the FDA only a few months prior for treating a different type of blood cancer. Within a month, Gotlib’s patient was in remission.
“We were completely astonished,” says Gotlib. But when colleagues started treating other hypereosinophilic syndrome patients with imatinib, they had dramatic responses as well.
To find out exactly why imatinib had worked so well, Gotlib sent blood samples from his patient to a lab at Harvard that specialized in discovering new mutations for blood cancers.
That Harvard team, led by physician-scientist Gary Gilliland and postdoctoral fellow Jan Cools, discovered that many patients with hypereosinophilic syndrome have two genes that have been smashed together by mutations, causing a fusion oncogene called FIP1L1-PDGFRA. Imatinib binds to and blocks the activity of the fusion protein. Gilliland, Cools, Gotlib and other collaborators published their findings in the March 27, 2003, issue of the New England Journal of Medicine.
In the meantime, though, Gotlib’s original patient relapsed and died. The Gilliland group used a new blood sample from the time of the patient’s relapse to uncover a mutation that prevented imatinib from binding. Using a mouse with the same mutation, the group found that an alternative drug — midostaurin (PKC412) — treated the resulting, imatinib-resistant leukemia. Their results appeared in Cancer Cell in May 2003.
In the back of his mind, Gotlib kept pondering the new results. He wondered whether other diseases might also be successfully treated by midostaurin once the drug was approved by the FDA. One possibility, he thought, would be systemic mastocytosis (SM), a rare and debilitating disease caused by the accumulation of mast cells in the skin, bone marrow and internal organs. About 90 percent of SM patients have an imatinib-resistant mutation in the gene for a tyrosine kinase called KIT.
“I said, well, if it’s resistant to imatinib, maybe midostaurin will work in these patients,” remembers Gotlib. A few months later, Gotlib’s hematology colleague Caroline Berube came to him asking for ideas for a patient with an advanced form of SM called mast cell leukemia who was not responding to imatinib. Gotlib called Novartis, the manufacturer of midostaurin, and asked to use the drug on a compassionate use basis.
“It took some time, and a few months went by,” says Gotlib. “The patient became sicker and sicker and ultimately needed to be hospitalized.” But when the clinicians finally got the OK to give her midostaurin, her mast cell disease improved immediately, although she ultimately died from separate complications of her SM.
Based on the dramatic response that the one patient with mast cell leukemia had to midostaurin, Gotlib worked with Novartis, Tracy George of Stanford’s hematopathology division, and doctors at two other institutions to launch a phase II investigator-initiated trial. They began enrolling people in July 2005 and eventually recruited 26 patients with advanced SM and evidence of mast cell–related organ damage.
While the trial was still ongoing, Gotlib and George presented interim data from the study at a large mast cell research meeting in Budapest, generating excitement from investigators around the world. At the same meeting, Novartis, encouraged by these data, asked for researchers to help with a global trial. Gotlib and other scientists began developing a protocol and, within a year, started recruiting patients at 29 sites around the world.
Fast forward eight years, when encouraging results of the international trial using midostaurin to treat advanced SM were published in the June 30 issue of the New England Journal of Medicine: Sixty percent of patients responded to the drug, with not only decreased signs of their disease based on lab tests and scans, but improvements in symptoms and quality of life as well.
“It’s definitely a positive study,” says Gotlib, who was the first author. Forty-five percent of patients who received the drug in the trial had a major response, with at least one type of organ damage completely resolving.
2017 and beyond
So what’s next? Gotlib is ready to publish the results of the investigator-initiated trial that began in 2005, which demonstrates long-term responses with midostaurin. With more than eight years of data on some patients, it provides more evidence on how much difference midostaurin can make. The response rate in that group, he says, is similar to what was seen in the global trial — around 69 percent — and the responses often last.
Louise Rabel, the longest surviving patient in the world who’s been treated with midostaurin, is in that trial; she started the drug on February 2006, and she’s still on the drug now more than 10 years later, he says.
But Gotlib also wonders whether other compounds more specifically designed to target the KIT mutation in advanced SM could work even better than midostaurin.
“In the global trial, there were no complete remissions. Clearly whatever targets midostaurin is hitting do not yet translate into deep remissions or cures.”
Gotlib indicated that a second-generation group of drugs, KIT D816V-selective inhibitors, are being developed. Trials have already commenced, and 2017 should be a banner year for understanding their efficacy and safety profile. But already, patients with advanced SM who previously had no treatment options have new hope.
“This really highlights the importance of a single patient observation,” says Gotlib. “Fourteen years later we’ve gone from a single patient with a different disease to a global trial which demonstrates very encouraging results in these poor-prognosis SM patients.”