A Fortunate Turn of Events in Chronic Lymphocytic Leukemia

November 2013 marked the start of Sonia Dolinger’s struggle with severe fatigue, headaches and tremendous sinus pain. “I felt like I had mononucleosis,” she says. “I slept for hours, and when I woke up, I felt like I needed to sleep more.”

Dolinger, then 39, had enrolled in a master’s nursing program at the University of Maryland with the aim of caring for patients with cancer. She was a mother three — the youngest just 5 years old — and had been a full-time caregiver to her mother, who had just died of ovarian cancer. “I tried to attribute the fatigue to grief or stress, but cancer was always in the back of my mind,” she says.

She visited her primary care doctor, who discovered swollen lymph nodes near Dolinger’s ear. Blood tests revealed a high white blood cell count. Desperate to get to the bottom of her symptoms, Dolinger asked an ear, nose and throat specialist to remove and test one of the nodes. The diagnosis: chronic lymphocytic leukemia (CLL), a cancer of the lymphocytes, or B cells, that begins in the bone marrow and migrates to the blood and sometimes to lymph nodes.

CLL strikes more than 20,000 people in the United States each year, according to the American Cancer Society, and affects more men than women. Some studies suggest that people who were exposed to Agent Orange, a toxic herbicide used in the Vietnam War, have a greater risk of developing CLL. Others point to genetic risk factors: People who have a first-degree relative with CLL are two to four times more likely to develop the disease. But for most people with CLL, including Dolinger, the disease stems from being dealt a bad hand.

In CLL, leukemia cells build up slowly in the bone marrow, eventually crowding out normal white cells, red blood cells and platelets. Because the hallmark of CLL is abnormal bloodwork, most patients discover they have the disease almost by accident during a routine checkup. “The analogy I use with my patients is that leukemia cells are like weeds growing in your garden. If it’s chock-full of weeds, the good stuff can’t grow through,” says Dr. David L. Porter, Jodi Fisher Horowitz Professor of leukemia care excellence at the Perelman School of Medicine and director of cell therapy and transplant at Penn Medicine in Philadelphia.

Historically, doctors considered CLL an incurable disease with limited treatment options, none of which were curative. Patients either responded to initial treatment, sometimes for many years, before ultimately relapsing or their disease worsened within six months of initial therapy (refractory CLL). Now doctors have more tools than ever in their arsenal to combat CLL, including more than half a dozen chemotherapy-free regimens.

“The treatment landscape for CLL has dramatically changed over the past decade, both for people with relapsed disease as well as people who are getting front- line treatment,” says Dr. Nitin Jain, associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “With the development of targeted therapies, including single-agent and combination regimens, patients are achieving more durable remissions and better quality of life.”

Scientists still don’t fully understand what triggers CLL or how to definitively stop it from progressing. They don’t know why CLL often returns after treatment or why some patients don’t respond at all. Many people experience recurrent disease for years and require multiple treatment courses. Fortunately, with novel treatment options and combination therapies, CLL is increasingly shifting from an incurable chronic disease to a once-and-be-done cancer.

TREATMENT ODYSSEY

When patients like Dolinger receive a CLL diagnosis, they often feel like their future is being erased. “Hearing the words ‘incurable disease’ was like getting a kick in the gut,” Dolinger says.

After scouring the internet for answers, Dolinger learned about a potentially curative treatment called Imbruvica (ibrutinib). “I remember reading about a patient who took Imbruvica while he was on hospice. Within weeks he had his life back,” Dolinger says. “That gave me hope.”

She joined an online support group where veteran patients with CLL all said the same thing: See a CLL specialist. Within two months, Dolinger was sitting in front of Dr. Bruce Cheson, deputy chief of the Division of Hematology/Oncology at Georgetown the Lombardi Comprehensive Cancer Center in Washington D.C. Cheson has been treating patients with CLL for decades, yet during Dolinger’s first visit with him, he told her the best course was to do nothing. He prescribed Adderall, a medication for attention deficit hyperactivity disorder, to alleviate her fatigue and put her on a check-in schedule to monitor her blood levels.

Unlike solid tumors — of, say, the breast, prostate and lung — in which the focus is early detection and immediate treatment, the first-line approach for CLL is sometimes to watch and wait. Dating back to the 1980s and 1990s, several studies reported no survival benefits from treating CLL upon diagnosis. “If we jump into treatment too quickly, we risk exposing patients to toxicities without any benefit,” says Dr. Tanya Siddiqi, a hematologist-oncologist at City of Hope in Duarte, California.

Doctors base the decision to treat on evidence of disease progression according to guidelines established by the International Workshop on Chronic Lymphocytic Leukemia. Factors include things such as, enlarged lymph nodes, spleen or liver; decreased blood and platelet counts; evidence of autoimmune hemolytic anemia; and debilitating, flu-like symptoms. When

it’s time for treatment, doctors have a slew of medication options, such as:

• Chemotherapy, such as Fludara (fludarabine), Bendeka (bendamustine) and Cytoxan (cyclophosphamide).
• Targeted therapies — kinase inhibitors to block the growth pathways of cancer cells, such as Imbruvica and Zydelig (idelalisib), and BCL-2 proteins to regulate cell growth and cell death, such as Venclexta (venetoclax).
• Monoclonal antibodies that attach to a specific protein (CD20) on the surface of B cells contributing to the disease and kill the cells, such as Rituxan (rituximab), Arzerra (ofatumumab) and Gazyva (obinutuzumab).

When 71-year-old Terry Evans received a diagnosis of CLL in 2000, the most effective treatment options were chemoimmunotherapy (a three-drug cocktail of Fludara, Cytoxan and Rituxan, more commonly known as FCR) and a bone marrow transplant. A computer technology manager for the city of Long Beach, California, Evans sailed by for years with almost no symptoms.

“I assumed I was part of the lucky 20% to 30% of patients who don’t need treatment,” he says. Evans retired in 2005. Then, in 2007, his white blood cell count doubled within a month. It doubled again the following month. He began experiencing night sweats, fatigue and muscle weakness and lost weight. “I was so weak that I had to sit down after a shower just to dry off,” he says.

That’s when he decided to see a specialist. Turns out Evans had developed autoimmune hemolytic anemia, a complication of CLL in which the immune system attacks its own red blood cells. “The doctor looked at my blood under the microscope and admitted me to the hospital,” Evans says. “If I hadn’t come in, the doctor said, I would have been dead within 48 hours.”

Once his autoimmune condition was under control, Evans joined a three- drug clinical trial investigating a BCL-2 inhibitor called navitoclax (formerly ABT-263), Bendeka and Rituxan. His blood levels all returned to normal during treatment, but the regimen wreaked havoc on his liver enzymes, forcing him to drop out of the trial.

Two years later, he enrolled in another trial comparing Imbruvica with Arzerra. He participated in both groups of the trial, then relapsed again. In May 2017, Evans joined a third trial, in which he stayed on Imbruvica and added Venclexta. “Within one month on the combined regimen, my blood numbers were the lowest they’d been in eight years,” Evans says. “My doctor did a test for minimal residual disease (MRD), testing one in 100,000 cells, and couldn’t find any CLL in my body.”

This sort of treatment merry-go-round is the norm for patients with CLL, but evidence of MRD among treated patients is also becoming increasingly common. By the time Dolinger dipped her toes in the treatment pool in November 2016, chemotherapy regimens for CLL were falling out of favor and novel agents like Evans’ latest drug cocktail were becoming standard therapy. Several studies reported that these agents produced better outcomes with fewer toxicity concerns.

LAUNCHING A TARGETED ATTACK

There’s evidence that targeted therapy, such as Imbruvica, can reduce the rate of infections over time and may help reconstitute patients’ immune systems. Experts like Dr. John Allan, assistant professor of medicine in the Division of Hematology and Medical Oncology at New York-Presbyterian and Weill Cornell Medicine in New York City, argue that Imbruvica, in particular, is so effective at altering CLL’s natural history that treated patients may approach the life expectancy of the general population.

In July, a trial that included more than 500 patients with newly diagnosed CLL showed that the combination of Imbruvica and Rituxan stopped the progression of leukemia in 89.4% of participants about three years later compared with 72.9% of those who received the traditional chemotherapy combination — FCR. In addition, at three years, 98.8% of people who received the combination were compared with 91.5% of those who received traditional treatment.

Currently, researchers are investigating a combination therapy pairing Imbruvica with Venclexta, the same regimen Evans has been taking. In a 2019 New England Journal of Medicine study, researchers reported that after 12 cycles of the combined medications, 88% of participants had no signs of cancer and 61% had remission with undetectable MRD. Researchers are also testing whether a three-drug therapy — Imbruvica, Venclexta and Gazyva — can further enhance responses.

“The downside is that many of these options are lifelong therapies, and every option introduces some level of toxicity,” Porter says. “That’s why ‘watch and wait’ is the preferred first-line strategy.” Because there are two types of CLL — fast growing and slow growing — watching closely is key. Both types of patients look alike in the clinic but have different blood, genetic and protein markers.

These markers help doctors identify not only which patients are most likely to progress but also which form of therapy might work best. “Some of these risk features change over time and in response to different agents,” Siddiqi says. “So before a patient starts treatment, switches drugs or goes on a new treatment, they should get prognostic markers checked again.”

When the waiting is over, the best initial treatment depends on the patient’s age, medical issues, reason for treatment and personal preferences. Some patients prefer an oral drug over infusions, others want to avoid lifelong therapy, and still others have a low tolerance for side effects. “So we can pick and choose and tailor treatments given these different options,” Allan says.

When Dolinger’s time arrived, she was working full time as a senior campaign manager for the Leukemia & Lymphoma Society. She started researching clinical trials and, with her doctor’s guidance, enrolled in a three-drug trial at The Ohio State University investigating Gazyva, Imbruvica and Venclexta. “It was one of the first clinical trials with a definitive stop point: 16 months,” Dolinger says. “I told the children I was going to get treatment in a different state, and I would come back and get better — and that’s what I really believed.”

But her foray into the treatment space was harrowing. Like most patients, Dolinger had an infusion reaction after her first dose of Gazyva. As cancerous cells die off in droves, patients often experience nausea, flu-like symptoms and tightness in the chest. The night of her first treatment, Dolinger woke up in her hotel room drenched in sweat, feverish and hurting all over. “I headed straight to the ER,” she says. “I had significant liver damage from the treatment, so they held me for observation. Then I became septic and one of my lungs collapsed.”

Dolinger recovered from the reaction, discovered her white blood cell count had dropped to the normal range and continued the trial. Six months after her first treatment, a bone marrow biopsy showed no evidence of disease in her system — 90% of her cells had been CLL positive at the start of the trial. She completed the 16-month trial. She maintained her MRD-negative status after the trial but experienced severe side effects ranging from infections to adrenal insufficiency that lasted a full year. “I’m just now starting to feel normal again,” she says.

A BIG QUESTION MARK

Every patient with CLL has a different disease trajectory. Some patients watch and wait for decades. Others receive an initial treatment with chemotherapy or a targeted treatment and go into remission indefinitely. But the typical CLL course involves periods of disease-free remission interspersed with treatment.

No matter which camp patients fall into, data on long-term outcomes is lacking. “Some of these new agents like Imbruvica have only been around since 2010, so we don’t know what the effects of long-term, continual treatment are,” Allan says. “Plus, many of these therapies are used indefinitely, as long as they’re effective. At a cost of more than $100,000 each year, that’s tremendously expensive.”

Even when treatment works, patients often relapse. When that happens, chimeric antigen receptor (CAR)-T cell therapy may be an option. With this therapy, doctors remove a person’s

T cells, re-engineer them to recognize a CLL-specific protein called CD19 and place them back into the patient to help fight cancer cells. But unlike lifelong targeted therapy, CAR-T cell therapy is a one-time treatment — one that will likely continue to be tested and pushed farther up the treatment chain.

“There have been astounding results in highly refractory patients who have no other options. Some patients are many years out, with no detectable disease in their bodies,” Allan says. The biggest issue: Just 25% to 35% of patients achieve durable remissions, or no signs of cancer for a reasonable amount of time.

Even those figures are starting to shift. At City of Hope, Siddiqi’s team followed 23 patients with refractory CLL for a median of nine months and discovered that more than 80% of them achieved overall remission with about 45% complete remissions and about 70% had MRD-negative results in their blood and bone marrow biopsies within a month of receiving CAR-T cells. These results were durable at three-, six- and nine-month follow-ups and three patients have now been followed for more than one year without relapse. “Now we’re investigating whether combining CAR-T cell therapy with Imbruvica can produce even better responses,” Siddiqi says.

In the meantime, people like Dolinger and Evans feel a bit like they’re playing Russian roulette. Dolinger’s trial wrapped up in February 2018, and she has focused on bolstering her immune system ever since. Evans has been on the Imbruvica/Venclexta regimen for almost 14 months, and his blood markers remain in the normal range. “But I’m always looking one step ahead, just in case I relapse again,” he says.

Scientists increasingly believe there’s reason for hope. Although these newer, more powerful agents are not yet known to be curative, the number of patients with refractory CLL is beginning to shrink. “There are still patients that develop resistance even to the newer agents, but they make up a smaller and smaller percentage of CLL patients,” Porter says.

With the introduction of new and better therapies, CLL is slowly transforming from a chronic disease requiring lifelong treatment to a cancer that doctors can eradicate. “We don’t know if we’re there yet, but I do think we can start thinking about potentially curing it,” Porter says.

People like Evans and Dolinger are championing the cause, participating in clinical trials, increasing awareness about novel therapeutics and even raising money to advance research toward a cure. Since starting treatment in 2008, Evans has been helping patients with newly diagnosed and refractory disease in the support group setting. Through his work with the CLL Society, Evans helped establish more than 31 CLL-specific support group chapters across the U.S. and two in Canada. “Training support group facilitators has become like a second career for me,” he says.

Through her work at the Leukemia & Lymphoma Society, Dolinger, too, has a career in the CLL world. For her, it’s about taking action rather than sitting on the sidelines — and it has become a family affair. “My sons have collectively raised $60,000 for CLL research,” she says. “It’s their way of doing something to help Mom.”