Breakthrough Therapy

Posted date

From Paths of Progress 2016

Anthony Letai, MD, PhD, says cancer drugs known as Bcl-2 inhibitors represent "true game changers."

by Richard Saltus

In the fall of 2013, after a series of CT scans and tissue biopsies, Roy Jann, a 59-year-old insurance executive, walked into a Rhode Island hospital with his wife to learn the results.

"They showed us into the wood-paneled library," Jann recalls. "That's never a good sign."

This was a few weeks after he first had an inkling something was amiss. Jann, who lives in Dighton, Mass., is a self-described gym rat and a highly competitive fitness buff who enjoys adventure vacations. But biking up a mountain in Colorado in August with his wife and friends, he was short of breath and fell behind the others. Moreover, he had noticed a swelling the size of a peanut under the skin of his neck – but he dismissed it as a harmless fatty growth.


Still, his group biked 50 miles a day during the trip, and Jann did OK. In September, his doctor examined the neck lump and was concerned. A scan revealed other lumps inside his body. Next were the biopsies and, when he and his wife met with a physician, Jann was told he had chronic lymphocytic leukemia (CLL), a blood cancer and the most common adult leukemia, a type that typically grows slowly. "He said I might not need treatment for seven or eight years," Jann says. So, reassured, he went into watch-and-wait mode, and continued his daily workouts.

However, watching and waiting ended suddenly just four months later, when things went downhill – fast. Antibiotics failed to quell a stubborn cough and a stomach bug, then vomiting and weight loss put Jann in the hospital. His CLL was behaving aggressively and, in May 2014, when he was referred to oncologist Matthew Davids, MD, in the Center for Chronic Lymphocytic Leukemia at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC), he got even worse news.

Tests showed his CLL cells contained an ominous type of DNA damage – the deletion of a chromosome segment known as 17p – that makes chemotherapy much less effective and creates a very poor prognosis – historically two to three-year survival.

"I was shocked," Jann admits. "It was very scary. But Dr. Davids has a way about him. He just said, 'We're going to address this.'"


Davids had a reason for his confidence. He was leading a clinical trial of a new cancer drug that was showing exciting promise in CLL patients. Called ABT-199 (now known as venetoclax), it belongs to a class of drugs called Bcl-2 inhibitors that are just emerging from three decades of research. They disable the Bcl-2 "pro-survival" proteins that enable cancer cells to escape the "pro-death" signals that command abnormal cells to self-destruct through apoptosis, a natural quality-control process in the body. One member of Jann's treatment team referred to venetoclax as "the rock-star drug."

By the time Jann started on a venetoclax clinical trial in December 2014, two other drug therapies had failed and he had large lumps in his neck and inside his body. 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." The drug can have side effects, but Jann experienced only some mild nausea and bloating.

By May 2015, the raging leukemia had been driven into retreat, leaving only a barely detectable trace of cancer in his bone marrow. To be on the safe side, Davids recommended that Jann undergo a reduced-intensity donor stem cell transplant to wipe out any hidden cancer. Again, fortune shone on Jann. Stem cell transplants, even reduced-intensity ones, are risky procedures that require stem cell donors who are immunologically matched to the recipients. Jann's sister, Lisa Murphy, was a perfect match and he had a successful procedure in June 2015, under the care of Edwin Alyea, MD, at DF/BWCC.

"Many CLL patients on venetoclax achieve a minimal residual disease (MRD)-negative complete response, which means that even with highly sensitive techniques we cannot detect any leukemia in their body," explains Davids. "Although this is not necessarily equivalent to cure, it does suggest that venetoclax has curative potential, particularly if used in combination with other drugs."

Matthew Davids, MD, examines a scan of a cancer patient.

Striking Response Rate

The promising outcomes with venetoclax in the DF/BWCC-led phase 1 clinical trial for CLL were presented at the American Society of Hematology (ASH) meeting in December 2015 and published in the New England Journal of Medicine. Venetoclax was administered to patients with relapsed or treatment-resistant CLL. Almost 90 percent of the patients had high-risk genetic features – like Jann's 17p deletion – predicting a poor outcome. Of the 106 patients, 79 percent responded, meaning the amount of cancer was reduced significantly. In an impressive 20 percent, the leukemia went into complete remission. And, in several patients, the cancer became totally undetectable, even by very sensitive testing. The results were particularly remarkable considering how sick these patients were at first.


Bcl-2 inhibitors like venetoclax "are going to change practice across many cancers," says Anthony Letai, MD, PhD. Research in Letai's Dana-Farber laboratory has produced a series of discoveries and tools for the development of Bcl-2 inhibitors and for predicting which types of cancer might respond best. "Dana-Farber has been an academic leader at every part of this program, from understanding the basic biochemistry all the way to the clinic," he says.

Investigators predict that even though venetoclax worked well by itself, it will be more potent when combined with other drugs. In a phase 1B study presented at the ASH annual meeting in December 2015, venetoclax combined with a standard antibody drug, rituximab, achieved an overall response rate of 86 percent in CLL patients: An astonishing 41 percent went into complete remission, with similar results in various high-risk subgroups, including those with a 17p deletion.

Interestingly, notes Davids, eight patients who achieved MRD-negative complete response elected to stop taking venetoclax, and none of these patients has had clinical relapse. Some of them were still in complete remission approaching two years after their last dose. Davids says this suggests that combining venetoclax with other active drugs in CLL has the potential to achieve deep and durable responses without the need for continuous venetoclax dosing.


"I am very excited about venetoclax as a novel class of inhibitors that affects Bcl-2, particularly because some of its mode of action suggests that it may work well in combination with ibrutinib [another new CLL treatment]," says Jennifer Brown, MD, PhD, director of the CLL treatment center at DF/BWCC. "This could perhaps form the backbone for a potential combination therapy that is free of chemotherapy."

At left, Emily Su, Shruti Bhatt, PhD, and Jing Deng, PhD, work in the laboratory of Anthony Letai, MD, PhD. At right, patient Roy Jann enjoys the great outdoors with his wife, Karen Boch.

Fulfilling a Vision

The Food and Drug Administration (FDA) has designated venetoclax a "breakthrough therapy," for CLL and acute myeloid leukemia. If approved, as many expect in 2016, it will be, among other things, the fulfillment of a vision that Dana-Farber's Stanley Korsmeyer, MD, conceived but did not live to see realized.

Korsmeyer, who headed Dana-Farber's Program in Molecular Oncology from 1998 until his death from cancer in 2005, discovered the role of Bcl-2 in cancer nearly 30 years ago. In the 1980s, he and his colleagues at Washington University in St. Louis identified Bcl-2 (for B-cell lymphoma-2) as a gene and protein present at abnormally high levels in lymphoma cells that allowed them to defy the body's efforts to eliminate them through apoptosis, or programmed cell death.

The late Korsmeyer showed that Bcl-2 acted as a survival protein for cancer cells, which would normally self-destruct like other damaged, unwanted, or dangerous cells when ordered to do so by signals from within and outside the cells. Lymphoma cells harnessed Bcl-2 proteins, he demonstrated, to intercept and block apoptotic death signals. He went on to show that Bcl-2 was the ringleader of about 20 genes and proteins that regulate apoptosis, and that Bcl-2 is overexpressed in multiple cancers. In doing so, he was one of the founders of an entire field of research directed at understanding the program of cell death in normal and cancer cells.

Stanley Korsmeyer, MD (left), shown with Anthony Letai, MD, PhD, was a pioneer in Bcl-2 inhibitor research.

If cancer was dependent on these survival proteins, reasoned Korsmeyer and others, it might allow a new approach – designing drugs that blocked the survival signals so that apoptosis could destroy the cancer. While at Dana-Farber, he and Letai, who was then a postdoctoral fellow in Korsmeyer's laboratory, showed that CLL was dependent on – in fact, "addicted" to – Bcl-2. They found that CLL cells were very efficiently killed in the laboratory by Bcl-2 inhibitor compounds that were the forerunners of ABT-199. Letai would later discover Bcl-2 addiction in other cancers, including acute myeloid leukemia (AML)acute lymphocytic leukemia (ALL), and some types of non-Hodgkin lymphoma. These findings prompted expansion of clinical trials of ABT-199 to these diseases as well.

Discovering the importance of Bcl-2 in cancer was one thing: figuring out how to block it potently and selectively, to avoid serious side effects, was another. Korsmeyer helped found a company, and he and Letai also worked with Abbott Laboratories to devise potential Bcl-2 inhibitors.

Abbott – the predecessor to AbbVie – working with Genentech developed a series of compounds that bind to a particular site that Bcl-2 molecules use to prevent cancer cell death. The first compound to be given to patients in trials was ABT-263 (navitoclax) in 2009. While it was modestly effective, it also destroyed blood-clotting platelets, which limited the doses that could be given. As a next step, AbbVie re-engineered the compound to eliminate that problem, and the new drug, ABT-199, entered clinical trials in 2011.

"It's amazing how far they've come in being able to treat my disease," Jann says. "If I had gotten this cancer three or four years ago, I wouldn't be alive now."

But he is very much alive. He's begun working out with a personal trainer amid precautions to prevent infections because of his still-recovering immune system. He's also back to work part-time, dealing with clients remotely from home.

If all continues to go well, this June, nearly two years after he was first diagnosed, he plans to resume full-time work.

The Dana-Farber investigators are also working full-time to improve and expand the promising role of Bcl-2 inhibitors in this new attack on stubborn and life-threatening cancers.

Learn more about Dana-Farber breakthroughs.

Paths of Progress 2016 Table of Contents

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