New Treatments May Be Worth the Wait in CLL

Statistically speaking, Raye Murphy figures she’s lucky to be alive.

The 64-year-old kindergarten teacher from San Pedro, Calif., was first diagnosed with chronic lymphocytic leukemia (CLL) in 2003. The most common adult leukemia, CLL is a typically slow-developing cancer diagnosed in about 16,000 Americans a year. In CLL, the bone marrow’s production of white blood cells — specifically, the lymphocytes that help the body fight infection — spirals out of control, crowding out other healthy blood cells.

Abdominal discomfort first sent Murphy to the doctor. Labs showed her white counts were elevated. A few months later, during an annual physical, they had spiked further.

She was officially diagnosed the day before Thanksgiving. The disease was considered to be early-stage, and her doctor’s advice was standard: watch and wait. We tend to think of cancer treatment as an aggressive and ASAP affair, but because early treatment has not been shown to improve survival and standard chemotherapies have not been considered curative, watchful waiting until patients develop an indication for treatment is the current standard of care. Indeed, one of every three patients diagnosed with CLL never require treatment.

Raye Murphy, who has CLL, believes that recently approved therapies for the disease have extended her life. [Photo by Mariesam Sanchez Photography]

But within a year Murphy’s CLL began to escalate, and her doctors made a discouraging discovery: Her cancer was ZAP-70 positive. While doctors use other tools to predict the course of CLL, patients without the ZAP-70 protein often have a mutated immunoglobulin heavy chain variable (IGHV) gene, which is associated with an average prognosis of more than 25 years after diagnosis. Murphy’s second-opinion doctor estimated she probably had 10 years to live.

That was 12 years ago, and Murphy has since benefited from extraordinary developments in both understanding and treating CLL. In the last two years alone, four new drugs — two targeted therapies and two immunotherapies — have been approved by the U.S. Food and Drug Administration for CLL, and there are still more in development. In January, the American Society of Clinical Oncology recognized that progress with its inaugural Cancer Advance of the Year award.

Chemical Warfare

Murphy had good luck with her initial treatment, but after a relapse and a difficult second round, she swore off chemo. Since then she’s tried three of these four new agents, two in a clinical trial. It wasn’t until her third drug that her CLL became manageable again. “I would theoretically already be dead if these new therapies hadn’t come to light,” she says.Effective treatment for CLL with chemotherapy began with — of all things — the use of mustard gas in the First World War. In the 1940s, researchers trying to prepare for possible advances in chemical warfare in World War II began poring over the records of soldiers exposed to mustard gas. They noticed that these patients produced fewer white blood cells, and wondered if this clue could help them shut down the overproduction of lymphocytes in diseases like CLL.

In the 1950s, two distant chemical cousins of mustard gas, chlorambucil and cyclophosphamide, were developed and shown to have some effect on CLL. Fludarabine was added to the arsenal of chemotherapies in the 1980s. At the turn of the 21st century, treatments grew more sophisticated with the addition of Rituxan (rituximab), an antibody against a cell surface protein on white blood cells called CD20. Instead of poisoning cells outright, this immunotherapy tricks the immune system into targeting the cancer.

Fludarabine, cyclophosphamide and Rituxan together are known as FCR, the most common first-line treatment regimen for younger patients. Less common, and more aggressive, is stem cell transplant, where the bone marrow is treated with chemotherapy and then replaced. Both treatments can be successful, but CLL is primarily a disease of the elderly and the transplant regimen is challenging for older patients.

That’s a big part of the appeal of the four newly approved drugs for CLL. Fewer and less severe side effects have provided viable treatment options for a broader swath of patients.

Arzerra (ofatumumab) and Gazyva (obinutuzumab) are immunotherapy agents. By targeting the protein CD20 — as does Rituxan — these drugs can turn a patient’s own immune system against the cancer. Arzerra was approved in 2009 to treat patients for whom all other chemotherapy had stopped working, and then, in 2014, it was approved for frontline use. Gazyva was approved in 2013 as a first-line treatment. Both received expedited review by the FDA as potential breakthrough therapies.

In a trial comparing Gazyva and chlorambucil to Rituxan and chlorambucil, patients in the Gazyva arm experienced a significantly longer period without their disease worsening (an average of 27 months compared with 15 months). And more than a quarter of patients showed no evidence of disease in their blood after treatment, compared with less than a tenth on the Rituxan plus chlorambucil treatment. When compared with chlorambucil alone, the addition of Gazyva nearly doubled progression-free survival time, to 27 months. Similarly, in a phase 3 trial of Arzerra, the median progression-free survival was 22.4 months with Arzerra plus chlorambucil compared with 13.1 months for chlorambucil alone.

Common side effects for Gazyva and Arzerra include lowered white cell count, a reduction in blood platelets, anemia and fever. Gazyva may also cause muscle and bone pains and fever, while Arzerra may cause pneumonia and trouble breathing.

The other new agents, Imbruvica (ibrutinib) and Zydelig (idelalisib), are targeted therapies, which means they’ve been designed to hit certain protein targets in the leukemia cells that the cancer needs to grow. Imbruvica works by blocking BTK, an enzyme that plays a role in the maturation of B cells — another name for the cells that grow out of control in CLL. Zydelig targets what’s called PI3-kinase, a family of enzymes involved in cell growth that get hijacked by some cancers. As a group, doctors sometimes call these drugs B cell receptor (BCR) pathway inhibitors.

Imbruvica received accelerated approval from the FDA in early 2014, for treatment after one previous therapy has stopped working, based on how quickly it reduces visible disease. “The BCR inhibitors just shrink the nodal disease before your eyes, within a couple of days,” says medical oncologist Jennifer R. Brown, director of the CLL Center at Dana-Farber Cancer Institute, in Boston. “And then (the patients) have durable remissions. They don’t clear blood and bone marrow quite as well, but despite that, the remissions tend to be stable.” The CLL becomes quiescent while patients remain on treatment, just sitting there rather than dividing or growing.

Less than six months after giving the green light to Imbruvica, the FDA confirmed the drug’s long-term benefit and expanded its approval to include treatment of CLL patients who don’t respond to standard therapy because of a common chromosome abnormality in the cancer cells called a 17p deletion. Imbruvica’s most common side effects include diarrhea and bruising. More serious issues can arise with bleeding and infections.

Zydelig, meanwhile, offers a line of defense for patients for whom all other treatments have stopped working. The clinical trial that led to its approval in combination with Rituxan, compared Rituxan alone with Zydelig and Rituxan, and patients who received Zydelig were without disease worsening for nearly four times as long (19.4 months). Some common side effects include diarrhea and pneumonia, along with fever, fatigue and nausea. Some patients develop liver function abnormalities and drug-induced hepatitis.

Older Drugs Remain Available

William Wierda, center medical director for the Leukemia Department at MD Anderson Cancer Center, in Houston, calls the BCR inhibitors “major, major advances for treatment of the disease.” For many older patients, a cure may not even be necessary. Simply managing the disease will provide adequate relief. The drawback is that, for most patients, there is still residual disease. “If you stop the drugs, the disease will progress, and so patients must stay on those drugs continuously.” Cancer drugs are expensive, and the new CLL drugs are extremely expensive, so money can quickly become an issue with ongoing treatment. And, ultimately, the cancer can develop a resistance. Because the drugs are so new, we don’t have long-term data yet, but, says Wierda, “we’re starting to see more patients developing resistance.”With so many new options, might it be possible to move away from chemo, maybe even ditch the watch-and-wait approach? For now, the data doesn’t support it. Trials comparing waiting versus early treatment of patients without any symptoms have yet to show any improvement in overall survival.

“This is the major challenge with treating CLL,” says Brown. “People usually get diagnosed, they feel fine, they have plenty of time to do research. They want to do something. It feels a little like the sword of Damocles hanging over your head, waiting for something to happen.”

But, she adds, “I really think that it’s premature to decide that the new drugs change the balance between surveillance and active treatment.”

To understand, we need to go back to FCR, the chemo plus immunotherapy. In use for nearly 20 years now, the long-term data is beginning to show great promise.

“FCR appears to cure,” says Susan O’Brien, associate director for clinical science at the Chao Family Comprehensive Cancer Center at the University of California at Irvine. It won’t cure all subtypes, but among the 60 percent of CLL patients who have a mutated form of the IGHV gene, as many as 50 to 60 percent are cured after treatment with FCR.

And that treatment is likely to get better results as time goes on. “We’re working on clinical trials to fine-tune the amount needed for that group,” says O’Brien.

But the real excitement comes when doctors contemplate using all of these new agents in combination. For example, Arzerra and Gazyva use the same molecular levers as Rituxan, but seem to work better. What might they accomplish in the FCR regimen? Is there another combination with even greater potential?

“It’s great to wait, because your options are only going to get better,” says O’Brien. “Clinical research is so active, there are so many new drugs. If you don’t need treatment for three more years, there are going to be more options.”

Expert Treatment is Crucial

People with CLL need to be treated by specialists, cautions CLL survivor Terry Evans, pictured with his wife, Donna, and their grandchildren. [Photo by Mariesam Sanchez Photography]

“It used to be a harder conservation,” says Wierda of the watch-and-wait debate. “Now it’s a little bit easier. The options and opportunities today will be different and probably better, even in six months to a year.”Terry Evans looks back on his CLL diagnosis in 2000 with a critical eye. “I got the standard local oncologist’s spiel that this was the good cancer if I was going to have one,” he remembers. “Kind of downplayed the whole thing.” Evans checked in every six months with his doctor, and they watched his white counts slowly climb. Then, after about six years, the count jumped, and he got other symptoms — an enlarged spleen, enlarged lymph nodes, night sweats, weight loss, fatigue.

Looking back, Evans wishes he’d used that time to find a doctor who was better prepared to treat his disease. But because of his local oncologist’s soft-pedaled approach, and because CLL was rare and slow-growing, he didn’t. The decision nearly killed him. Evans had a rare complication, and by the time he got to a specialist, he was an estimated 48 hours from cardiac arrest.

Since then, Evans has immersed himself in research and advocacy. The slow course of the disease has one surprising advantage, and that is that the patients who deal with it can form long-lasting support groups. Murphy and Evans belong to the same group in Orange County, and both have learned to flex their muscles. They’ve changed doctors when the care wasn’t right. They’ve aggressively sought clinical trials and supported genetic research. They’ve spoken out about sky-high drug prices. They’ve even participated in medical conferences to help educate doctors about patients.

Evans’ primary advice: Find a doctor with experience treating CLL. It may be a sluggard, but there is no such thing as a good cancer. And it’s devilishly complicated.

O’Brien recuses herself at first — she’s biased, she says. But then she agrees. “I don’t think there is any question about it. It’s becoming even more complicated,” she says. If she were a cancer patient she would see her local oncologist, then get a second opinion. “That would be my approach for myself with any type of cancer.”

Even with all of these advances, there is still more on the horizon. A number of clinical trials will be rolled out to assess the many possible new combinations of treatment. A few more promising drugs are working their way through trials, including navitoclax, which inhibits a protein made by cancer cells that may prevent chemotherapy from killing them; next-generation BTK and PI3K inhibitors; and Revlimid (lenalidomide), which helps to activate the immune system against cancer and is approved for the treatment of some other blood cancers.

Researchers are also excited about a new class of immunotherapy drugs — these are called checkpoint inhibitors — first developed for melanoma. Particularly exciting is their ability to reconstitute the immune system. “CLL is very immune compromising,” says Wierda. “If you can correct that, you can also improve quality of life and morbidity and mortality from other things, particularly infections and second cancers.”

Wierda is also working on a more advanced form of immunotherapy called CAR T cell therapy, in which a patient’s T cells are collected, engineered in a lab to recognize and attack a specific type of cancer cell, and then reinfused into the patient’s body. While much of this research is focused on acute lymphoblastic leukemia (ALL), a clinical trial for CLL is currently ongoing.

A specialist is more likely to be aware of these options, and may have better access to trials. The difference is huge for a patient like Evans, who’s now been through a half dozen treatment options. “The changes that have happened just in the last three years have been so amazing,” he says. “As long as I’m in remission and my numbers look good, I’m a happy camper.”