Treatment Is Waiting

A FEW DAYS  after a routine physical in July 2009, Geoff Grubbs got a phone call from his nurse practitioner. His white blood cell count was higher than normal, and she wanted him to come back in for a second blood test. “She thought maybe it was a mistake,” recalls Grubbs. He did, too. At age 58, he was “happy as a clam,” he says, exercising regularly and spending a lot of time outdoors with his wife and children. He had the second blood test, expecting everything to be fine. Instead, his nurse practitioner called to say he should see an oncologist—soon.

Several anxiety-filled weeks later, Grubbs learned he had chronic lymphocytic leukemia (CLL), a type of blood cancer that begins in the bone marrow when certain white blood cells, called lymphocytes, begin multiplying too rapidly. Not feeling at all ill, Grubbs was stunned by the diagnosis. But even “harder to get my mind around,” says the Washington, D.C., resident, was his oncologist’s recommendation: waiting to treat the cancer until it advanced. “You are afraid you are going to die,” he says, “and then the doctor tells you the best thing to do is nothing at this time.”

Not treating a potentially deadly cancer seems counter-intuitive. But for some patients with slow-growing (indolent) blood cancers, an approach known as “watchful waiting”—or as some patients call it, “watchful worrying”—is the standard of care. For some, the watchful waiting period may last a decade or more. For others, it may be two years or less before symptoms appear and drug therapies are needed to put the cancer into remission—when watching and waiting for symptoms begins again.

Why Wait?

It’s not always easy for patients—or their loved ones—to trust a doctor who says watch and wait. But for certain blood cancers, the research shows starting treatment before symptoms develop doesn’t improve survival. Instead, it exposes patients to unnecessary treatment-related side effects.

Uma Borate, a medical oncologist and hematologist at Oregon Health & Science University in Portland, says when she treats patients diagnosed with a slow-growing blood cancer, one of her first goals is to ease their anxiety. “I try to help them understand the nature of the disease,” she says. “I explain that this is not something that happened overnight and that it is not likely to get out of control soon.”

Watchful waiting isn’t actually the same as doing nothing. Patients like Grubbs who are put on watch-and-wait protocols are observed closely, typically coming in for blood tests every three to six months. By testing patients regularly, says Loretta Nastoupil, a medical oncologist and hematologist at the University of Texas M. D. Anderson Cancer Center in Houston, “we learn about the tempo of their disease.” It is not until the pace at which the cells are dividing picks up, she says, that “the risk of disease outweighs the risk of therapy.”

Symptoms also relay the news that treatment is near. Grubbs had been having blood tests every six months for five years when, in late 2014, he found himself extremely exhausted, losing weight quickly and with a white blood cell count doubling rapidly. “It was quite clear I was no longer watch and wait,” he says.

Grubbs enrolled in a study at the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., comparing a standard CLL treatment—the chemotherapy drug Treanda (bendamustine) and the targeted therapy Rituxan (rituximab)—with the standard treatment accompanied by Zydelig (idelalisib), a new type of targeted therapy that had been approved recently for previously treated CLL. He was randomly assigned to the group that received the standard treatment and Zydelig. Partway into the trial, Grubbs developed severe side effects and was taken off Zydelig, but he remained on the standard treatment. (Ultimately, trials testing Zydelig as a first-line treatment for CLL were halted because of the side effects it caused.) Even so, Grubbs says he doesn’t regret his decision to take part in the clinical trial. The treatment put his cancer in remission, and he says he intends to look for another trial if and when he needs treatment again. “Without new data, the science can’t advance,” he says.

After two years of watchful waiting, John D’Orazio, who was diagnosed with CLL in 2005 at age 35, had a similar experience. “When you start getting lymph nodes the size of tennis balls popping out of you, you know you need treatment,” says the Medford, Massachusetts, resident and father of four. D’Orazio entered a study at the Dana-Farber Cancer Institute in Boston investigating whether Revlimid (lenalidomide), a drug in trials for many different types of blood cancer, was effective in treating CLL. His cancer didn’t respond to the drug, and he switched to a standard-of-care regimen known as FCR—Fludara (fludarabine), Cytoxan (cyclophosphamide) and Rituxan—that put him into remission. (Revlimid is no longer being studied in CLL. It has been approved to treat multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma.)

In 2010, D’Orazio’s symptoms returned. This time, he enrolled in a study investigating the benefit of using the targeted therapy Imbruvica (ibrutinib) along with Treanda and Rituxan. (Imbruvica, which comes in pill form, was approved for use in patients with relapsed CLL in 2014; in March 2016, it was approved as an initial treatment for CLL.) When that trial ended, D’Orazio enrolled in a study in which he would take Imbruvica daily to prevent recurrence. He’s now been on the drug for six years. In terms of side effects, he says, “my skin is not great. But really, it seems stupid to complain about anything. This drug has been a miracle for me.”

New Treatments, New Possibilities

Rituxan, which both Grubbs and D’Orazio received, was the first targeted therapy to be used for lymphoma. Since its approval in 1997 as a blood cancer treatment, 29 other targeted therapies have been approved for use in different types of blood cancer. Clinical trials now underway are investigating the best way to use these new treatments—in what combination and in what order—to extend not only how long patients stay in remission but overall survival. Other studies are following patients as their cancers progress, looking for biomarkers that might suggest new treatment targets. (Data from a natural history study led researchers to discover that the protein Bruton’s tyrosine kinase helped certain types of blood cancers grow and to develop the drug Imbruvica, which blocks it.)

The National Institutes of Health (NIH) National Heart, Lung and Blood Institute, for example, launched an ongoing large observational study in April 2008 to learn more about the natural history of slow-growing B-cell lymphomas. The trial, currently led by Clare Sun, a hematology and oncology fellow at the NIH, is open to patients who have been diagnosed with one of four types of lymphoma. One goal, says Sun, is to study blood and tissue samples and learn “what makes these cells tick and thrive.” Another is to identify biological pathways that help a cancer grow or provide information about how treatments are working that could assist researchers in developing new therapies.

Irene Ghobrial, a medical oncologist and hematologist at Dana-Farber, is another researcher investigating these questions. In 2014, Ghobrial launched Dana-Farber’s new Center for Prevention of Progression of Blood Cancers, which sees patients with early myelodysplastic syndromes (MDS), early CLL, monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma, which can progress to multiple myeloma, in order to learn more about the natural history of these cancers and develop therapies that could potentially prevent progression.

The same year, in conjunction with the Leukemia & Lymphoma Society, Ghobrial launched a study focused on uncovering new information on the natural history of myeloma. Known as the Precursor Crowdsourcing study, or PCROWD, it has enrolled more than 600 people with MGUS or smoldering myeloma, which MGUS turns into before becoming a cancerous myeloma.

Dana Holmes, a 58-year-old human resources specialist from New York City, was diagnosed in December 2010 with MGUS and then, following a bone marrow biopsy, with smoldering myeloma in 2012. She enrolled in the PCROWD study after hearing about it in a radio interview featuring Ghobrial and Jenny Ahlstrom, founder of the website Myeloma Crowd.

“This study is so important to me,” Holmes says. “I understand why treatment doesn’t start until there are overt symptoms. I’m also intrigued by the question of whether there might be benefits to starting new treatments earlier.” Holmes encourages others to enroll and has posted information about the study to the Faceb​ook asymptomatic smoldering myeloma group she started in 2013.

Ghobrial has also launched five clinical trials enrolling patients with high-risk smoldering myeloma whose cancers are likely to progress within two to three years. Typically, these patients do not receive any treatment, and Ghobrial wants to learn whether starting treatment in the smoldering stage can change the natural history of the disease and prevent a potentially deadly cancer from ever developing.

Tracy DeMaggio, who was diagnosed with smoldering myeloma in January 2015, just seven months after being diagnosed with MGUS, has a high-risk strain of smoldering myeloma called IgA lambda. She enrolled in Ghobrial’s phase II study that randomly assigns high-risk patients to receive Empliciti (elotuzumab) and Revlimid with dexamethasone, a steroid used to treat inflammation, or Empliciti and Revlimid. For DeMaggio, the treatment combination resulted in numerous side effects, including fatigue, nausea, a facial rash, chronic bowel issues and shaking hands. The 45-year-old, who manages a human resources team, says that while on the treatment, she sometimes wondered if entering the trial had been the right choice. But when blood tests showed the treatment had slowed the blood cells’ growth, her doubt ended immediately. Now, she takes Revlimid daily and will continue to do so until her cancer progresses, if it ever does. “It’s challenging,” she says, “but I think that if I had waited, at this point I would probably have active signs of multiple myeloma.”

Only time will tell whether DeMaggio’s treatment did what Ghobrial hoped it would: keep her from ever getting myeloma. Meanwhile, D’Orazio will continue to hope Imbruvica keeps him in remission. Holmes will have lab work done every three months. And Grubbs, now 65, is back to where he started. “There are a lot of us—including those of us who have already been treated,” he says, “watching and waiting.”

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