Gleevec Lights Its Fifth Birthday Candle

Turn back the clock to December 1999, to the 41st ASH Annual Meeting in New Orleans. The final plenary abstract of the day is being introduced by Dr. Owen Witte. The abstract is presented by Dr. Brian Druker, describing a so-called Abl specific tyrosine kinase inhibitor that is supposed to be a targeted therapy for CML. Dr. Druker refers to this compound as STI571, formerly known as CGP57148B.

Nobody, not even Dr. Druker, predicted what was witnessed in this phase I dose escalation trial in chronic phase CML patients who had failed interferon therapy. The dose escalation was to proceed from 25 to 500 mg daily. A funny thing happened. Any patient receiving more than 140 mg got a hematologic response, and 96 percent of patients treated with 300 mg or more got a complete hematologic response. All this with basically no toxicity and responses within the first few weeks of therapy. Thus ushered in the Gleevec era. Physicians, scientists, and virtually the entire NCI lauded it as proof that mechanism-based, molecularly-targeted therapy was an achievable goal. Patients and their families cheered that the day had finally arrived when cancer therapy came in the form of a very potent pill with virtually no side effects.

Within six months after that ASH meeting, Novartis had launched the IRIS trial which would accrue over 1100 patients worldwide in about eight months. The IRIS trial would eventually show that STI571 or imatinib or Glivec or Gleevec should replace interferon as the standard therapy for CML. Story after story started springing up from patients, who had long ago exhausted all chemotherapy options, given up hope, and were literally on their death beds. Within months of starting Gleevec, these same patients were healthy, eating, interacting with their families, and even active, going back to playing golf and tennis. And it wasn’t just limited to CML. Philadelphia chromosome positive ALL patients also were responding, even though we quickly learned that these responses were short-lived. But then there were the scientific data that Gleevec also inhibited other tyrosine kinases such as c-kit and PDGFR. All of a sudden, patients with an obscure tumor known as GI stromal tumors (GISTs) started having responses, and man, did they ever respond. There were PET scan images of tumors turning metabolically inactive within 48-72 hours after starting Gleevec – talk about turning out the lights! The Gleevec era turned into Gleevec mania.

And the FDA even got in on the act, approving Gleevec in 2001, months before Novartis anticipated it (one of the few times I have ever seen a pharmaceutical company caught off guard). But they quickly cranked into gear and have been going full speed ever since. So where are we now? A little of the new kid luster has worn off. Instead of curing almost everyone, we now know that only a small fraction of CML patients will remain PCRnegative. Blast crisis and ALL patients generally only get months of benefit from Gleevec alone, so one has to formulate plan B as soon as they are started on Gleevec. But, even still, Gleevec remains the ‘wonder pill’ of the cancer world. So far, none of the other new kids on the block can claim to have replaced it. And we hematologists can rightfully claim that we ushered in this new era.

Thanks Drs. Druker, Sawyers, Talpaz, and others for your perserverance.