A New Cancer Drug — in the Nick of Time

When Roy Jann was diagnosed with cancer in 2013, it never crossed his mind that he would be a model for the life-saving potential of venetoclax, a new type of cancer drug that had recently entered human testing.

The first inkling that something was amiss had come a few weeks earlier, while Jann was biking up a mountain in Colorado with friends. As a 59-year-old competitive fitness buff, exercise like that was routine, but on this outing he lacked his usual energy and fell behind the others. After returning home to Dighton, Mass., Jann saw his primary care doctor, mentioning his unaccustomed fatigue and pointing out a small lump he had noticed under the skin of his neck a month or so earlier. The physician ordered a CT scan, which spotted other enlarged lymph nodes, leading to a biopsy.

“When I went to the hospital for my results, the doctors met with me and my wife in the wood-paneled library,” Jann recalls. “That’s never a good sign.”

His intuition was accurate: the tests revealed chronic lymphocytic leukemia (CLL). The good news, his doctor said, was that the blood cancer was in a slow-moving stage and might not need treatment for seven or eight years. So Jann went into watch-and-wait mode and resumed his daily gym workouts.

However, that approach ended suddenly just four months later, when his health went downhill fast. Antibiotics failed to quell a stubborn cough and a stomach bug, then vomiting and weight loss put Jann in the hospital. Unbeknownst to his local physicians, Jann had a highly aggressive form of CLL and he was referred in May 2014 to oncologist Matthew Davids, MD, MMSc, at Dana-Farber. Tests showed his CLL cells had an ominous type of DNA damage – the deletion of a segment known as 17p – that has a very poor prognosis.

“I was shocked,” Jann admits. “It was very scary. But Dr. Davids has a way about him – he said, ‘we’re going to address this’.”

Davids was leading a clinical trial of a new cancer drug called ABT-199 (now known as venetoclax) that was showing promise in CLL patients, even those with 17p deletion. Venetoclax belongs to a novel class of drugs called Bcl-2 inhibitors that force cancer cells to self-destruct through apoptosis, a natural quality-control process in the body. One member of Jann’s treatment team called it, simply, “the rock star drug.”

Research leading to the development of Bcl-2 inhibitors goes back nearly 30 years, and Dana-Farber scientists like the late Stanley Korsmeyer, MD, and Anthony Letai, MD, PhD, have made critical contributions. Korsmeyer was among the first to show that Bcl-2, a “survival protein,” helped cancer cells thwart treatment, and blocking Bcl-2 could be a new anti-cancer strategy. Drugs like venetoclax “are going to change practice across many types of cancer,” predicts Letai.

Anthony Letai
Research leading to the development of Bcl-2 inhibitors goes back nearly 30 years, and Dana-Farber scientists like the late Stanley Korsmeyer, MD, and Anthony Letai, MD, PhD, (above) have made critical contributions.

By the time Jann started on the trial in December 2014, two other drug therapies had failed and he had large lumps in his neck and elsewhere. Venetoclax is an oral drug; Jann took four pills every morning.

“Within the first month, I could feel the lumps going down, and then they were all gone,” recalls Jann. “I felt normal.”

For a patient with CLL and a 17p deletion, this was a stunning outcome, and recent results from a clinical trial of venetoclax show that an impressive 80 percent of relapsed CLL patients had significant tumor shrinkage, with 20 percent going into a complete remission. Remarkably, the response rates were equivalent in patients with 17p deletion compared to others with less aggressive variants of CLL, a result that would be unheard of with chemotherapy.

Venetoclax eradicated all but the most minuscule trace of CLL in Jann’s bone marrow, but to be on the safe side, Davids recommended he undergo a stem cell transplant, which he did in June 2015. His sister was a perfectly matched donor.

“This is amazing,” Jann says. “If I had gotten this cancer a year and half earlier, I probably wouldn’t be around.”

Many believe the Food and Drug Administration will approve venetoclax for CLL patients like Jann sometime this year. When this happens, it will be a milestone in the Bcl-2 inhibitor story – and a reminder that basic molecular discoveries about cancer may translate into new weapons decades later.

For Jann, it’s a different kind of milestone. With his recovery going smoothly and no evidence of remaining cancer, he’s begun working out with a personal trainer. He hopes to return to full-time work in June.