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From a single patient to a global clinical trial: One hematologist’s journey

Confronted in 2002 by a medical record that was literally two feet in height, Stanford hematologist Jason Gotlib, MD, had no idea that his career path had just been established. Chasing down a treatment for his 39-year-old patient with a rare blood disease — which transformed into acute myeloid leukemia — Gotlib turned to a newly-approved therapy for a different blood cancer, imatinib, and within one month the patient was in remission.

Seeking to learn why imatinib worked so well, Gotlib sent a sample of the patient’s blood to a lab at Harvard that specialized in finding mutations in blood cancers. They soon had an answer – imatinib blocked a crucial pathway of an oncogene, stopping its activity altogether – but the patient soon relapsed and died.

I tell the story of Gotlib's quest to improve care for blood disease patients in the Department of Medicine's 2017 Annual Report.

Gotlib then wanted to learn why the drug stopped working, so he sent another sample of the patient’s blood, this one from the time of the relapse. The Harvard lab found that a mutation had occurred that prevented imatinib from working. That led to a study in a mouse model with a similar mutation, and the finding that another drug, midostaurin, could treat the leukemia that resisted imatinib. Gotlib then postulated that midostaurin might work in other imatinib-resistant diseases, such as systemic mastocytosis, a severe condition caused by an increase in cells known as mast cells. He tried this on a patient (on a compassionate use basis) and treatment with midostaurin helped her improve immediately.

In 2005, Gotlib and others began a phase II trial of midostaurin in 26 patients with advanced systemic mastocytosis. When they presented interim results from their trial in 2008, both investigators and the manufacturer of the drug, Novartis, were encouraged enough to initiate a trial at 29 sites around the world. Eight years later they reported very hopeful results, with 60 percent of patients responding to midostaurin. And the phase II trial that began in 2005 has had similarly positive results, with 69 percent of patients responding, many of them for years. But there were no complete remissions in either trial. “Clearly whatever targets midostaurin is hitting do not yet translate into deep remissions or cures,” Gotlib said.

Patients with systemic mastocytosis now have hope that midostaurin and second-generation drugs currently in trials will improve their prognoses. Looking back over the 15 years since meeting his patient with the voluminous medical record, Gotlib reflected: “This really highlights the importance of a single patient observation. We’ve gone from a single patient with a different disease to a global trial which demonstrates very encouraging results in these poor-prognosis systemic mastocytosis patients.”

Previously: New Stanford-developed tool allows easier study of blood cancers and A recipe for disaster: Stanford researchers identify mutations that contribute to rare blood cancers
Photo of former patient Louise Rabel and Jason Gotlib by Norbert von der Groeben

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