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Follicular Lymphoma Treatment Strategies Continue to Evolve, Unmet Needs Remain

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000527110.77865.f9
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follicular lymphoma

follicular lymphoma

Follicular lymphoma is a good news/bad news diagnosis. The good news is follicular lymphoma is generally a very treatable disease allowing many patients to outlive their diagnosis.

The bad news is there is a subset of patients who experience a more aggressive form of disease for whom it may spell a shortened lifetime. And still another percentage of patients will battle follicular lymphoma's own zombie apocalypse. The disease transforms, as if by the flick of a switch, to another type of lymphoma aptly named transformed lymphoma. Under a microscope it shows itself to be a different, diffuse, large B-cell lymphoma. For some, it will be beaten back by therapy, but for about 30-50 percent of those afflicted it will likely result in death within 2 years' time.

Because the “good news” side of follicular lymphoma is a primary hallmark, the disease may lag behind in some areas of funding, research, and molecular testing simply because it is not considered a “killer cancer” in the same way that pancreatic or lung cancers are. Experts in the field, however, are well aware of both the unmet needs and the progress that is being made despite any roadblocks, and they are proactively alerting others in oncology to demands and challenges that lie ahead.

Follicular lymphoma was described in a Sept. 17 FDA news release as “a slow-growing type of non-Hodgkin lymphoma, a cancer of the lymph system. The lymph system is part of the body's immune system and is made up of lymph tissue, lymph nodes, the spleen, thymus, tonsils, and bone marrow.” The FDA further noted, “The NCI ... estimates that approximately 72,240 people in the U.S. will be diagnosed with some form of non-Hodgkin lymphoma this year; approximately 20,140 patients with non-Hodgkin lymphoma will die from the disease in 2017.”

Brad Kahl, MD, Hematologist/Oncologist and Professor in the Department of Medicine, Oncology Division, at Washington University School of Medicine, St. Louis, Mo., offered another statistic. “Some 25,000 of our fellow Americans are diagnosed with follicular lymphoma every year. A substantial proportion of those patients will have their lives shortened by this disease. Although we have good treatments, we still don't know how to cure it,” he lamented.

Brad Kahl, MD

Brad Kahl, MD

That inconvenient truth of “no cure” was echoed by Jonathan W. Friedberg, MD, MMSc, Director of the Wilmot Cancer Institute, and Professor in the Department of Medicine at the University of Rochester, N.Y. Most recently, Friedberg was a featured presenter on the topic, “How I Treat Follicular Lymphoma” at the September 2017 ASH Meeting on Hematologic Malignancies in Chicago. “This remains for most patients an incurable disease. So at some level I think it is clear that improvements need to be made,” he told Oncology Times.

Jonathan W. Friedberg, MD, MMSc

Jonathan W. Friedberg, MD, MMSc

Because the cancer, in general, is not highly aggressive and often asymptomatic, it is often found “accidentally,” when a patient is having imaging done for another purpose and enlarged lymph nodes are discovered. “We can stumble upon it,” said Kahl. “But other patients present with palpable, painless lymph nodes in the neck, armpit, or groin. Still others may present with pain in their abdomen or back caused by lymph nodes that have grown large, probably over the course of years, causing discomfort.”

Kahl mentioned that, even in the diagnostic area, which has been straightforward and successful for a long time, there has been a pinprick. “The use of needle biopsies and the resulting small tissue samples have made it a bit more challenging,” he explained. “There are different grades of the disease—grade 1-2, 3A, 3B—referring to the number of large cells seen per high-powered field in the biopsy. Follicular lymphoma is usually made up of small cells; the more big cells there are, the more aggressive the disease tends to be. The pathologist has to count how many big cells there are to grade accurately and that requires ample material. Sometimes when a sample size is too small we have to send patients back to remove more tissue, and that causes anxiety. But we eventually get it nailed down.”

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Treatable, But Incurable

Why has follicular lymphoma proven to be incurable thus far? “We don't know exactly why it is so hard. We can control it, we can manage it, we can keep a lid on it for long periods of time, but making it go away once and for all is hard to accomplish,” admitted Kahl.

His own theory has to do with it being such a slowly proliferative cancer. “Think of cancer as a population of billions of cells in someone's body,” he said. “At any one moment in time, a huge fraction of that population of cancer cells is just sitting there doing nothing. It is when they are active, trying to multiply and divide, that cells are most vulnerable to drugs or radiation. But with follicular lymphoma, so many cells are sitting there quiescent, idling. It's just hard to kill every last little cancer cell in a patient.”

Friedberg said he is surprised we do not encounter this disease more often. “The immune system is a complex entity,” he explained. “Every day a human body is producing thousands and thousands of immune cells. If you get an infection, the body has to switch very quickly to produce cells that are targeting that infection. With all of that growth going on, it is rather remarkable we don't see lymphoma more frequently.”

The fact that follicular lymphoma is treatable, but not curable, carries its own implications on both treatment and education for patients—and providers.

“For those patients with symptoms, we can help nine out of 10 feel better very quickly,” said Kahl. “The trickier cases are those patients whose cancers are found incidentally and who feel fine. We stage them, find a relatively low amount of disease, and then tell them we are not going to treat them, but rather we are going to watch and wait. Studies have shown that long-term survival is not impacted by this approach; some patients can be watched for years.”

But mere observation can be a hard sell. “It is hard for some patients to accept non-treatment. Trying to convince a patient that just observation is the best strategy for them is one of my most frequent conversations. It seems counterintuitive to them.” Kahl said he typically sees these patients every 3 months initially, and repeats scans 6 months later “... because this disease behaves differently in every individual.”

Friedberg agreed that a period of watchful waiting is a powerful strategy. “When I talk to patients with follicular lymphoma, I emphasize they have to view this as a marathon. I tell them, “If you are going to have this disease for 20 or 30 years, you can't use all of your bullets in the first year or two. You need to keep options open.””

Friedberg stressed it is not only patients in need of education. “Some providers give a lot of chemotherapy up-front. But in doing that, they may not be focused on treating how patients feel, but instead are trying to make scans look good. It could be that 5 years later you have fewer open options to offer. Many patients feel well, despite having some degree of disease activity. This requires both patients and doctors to tolerate imperfect scans.”

One of the themes of Friedberg's talk at ASH suggested providers may be over-treating a large segment of patients with follicular lymphoma who are destined to do extremely well.

“The biggest message I want to pass along, which still is not well appreciated by general oncologists, is follicular lymphoma is a very heterogeneous disease,” he explained earnestly.

“Some patients have an aggressive disease and need aggressive treatment. But the majority of patients have a very indolent, slow-growing course and is unlikely to die or really be bothered by lymphoma. The old paradigm of treating every patient the same way with a single chemotherapy regimen is really incorrect; we must do much more individualization in our treatment of patients.”

Friedberg also mentioned another inevitable downside of over-treating—the cost factor. “Treatments are very expensive and becoming more so. The more of a “precision” approach we can give—treating only when necessary—the less costly it will be for the health care system,” he said.

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Risk Assessment

Precision is sorely needed at diagnosis to determine patients who will be at high risk for the more rare aggressive version of follicular lymphoma. However, that degree of personalization at diagnosis remains an unmet need that is squarely in the crosshairs of researchers.

“We need a way to determine who is at risk of dying from follicular lymphoma versus the patient who will have a normal life expectancy—two very different scenarios,” said Kahl.

“But the best we have right now is risk stratification by looking at the length of a patient's first remission following treatment. Powerful data in the last 3 years shows if first remission lasts fewer than 2 years, the patient has a 50 percent chance of death over the next 5 years. That is the high-risk group for follicular lymphoma. On the other hand, if the first remission lasts longer than 2 years, survival very closely mirrors age-matched healthy controls. This means life expectancy would be very similar to anyone else at the patient's age.”

The high-risk subset is about 20 percent of follicular lymphoma patients, said Friedberg. He noted important work is under way to discover, at genetic and molecular levels, who these patients are so that they can be identified at diagnosis and well before they reach that treacherous 2-year mark.

Asked if a biomarker has been identified to point the way, Friedberg answered, “The short answer is no, but we are making progress. For many years there have been clinical scoring systems based on all kinds of clinical prognostic indicators. For example, we know that older patients, patients with a lot of lymph node involvement, and patients with advanced grade tend to do a little worse.

“In the last 2 years, researchers have taken genetic information from the tumors and layered that onto the clinical information. Now we do have a score called the M7FLIPI [Follicular Lymphoma International Prognostic Index] that seems to be at least a starting point on how we might identify high-risk patients.”

A 2015 paper posited, “Follicular lymphoma is a clinically and genetically heterogeneous disease, but the prognostic value of somatic mutations has not been systematically assessed. We aimed to improve risk stratification of patients receiving first-line immunochemotherapy by integrating gene mutations into a prognostic model... Integration of the mutational status of seven genes with clinical risk factors improves prognostication for patients with follicular lymphoma receiving first-line immunochemotherapy and is a promising approach to identify the subset at highest risk of treatment failure” (Lancet Oncol 2015;16(9):1111-1122).

Friedberg cautioned that identifying risk by finding gene mutations that appear to be indicative of favorable or less favorable outcomes is still in an experimental stage. “This is not ready for primetime clinical use. But several groups are coming up with their own scores that are similar to M7FLIPI, and it is my sense that within 5 years one that is most predictive will rise to the top and we will have something robust. That is a major direction the field is moving.”

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And Then What?

Once the high-risk patients are identified, how should they best be treated? Kahl said there is no easy answer yet.

“How can you change the natural history of the disease? If you could identify them, would you start treatment earlier? We still don't know. We have to do research to figure out if early treatment in these patients can improve their outcome. It is an excellent research question.”

Friedberg is in fast agreement. “Three years ago we had a clinical trials planning meeting sponsored by the NCI where SWOG researchers from all around the country came together. One question rose quickly to the top of the list as the priority question in follicular lymphoma: How do we manage patients who have relapsed early after chemotherapy?”

Friedberg and the SWOG team are now leading a national clinical trial (Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma, No. S1608) that opened in late August. It is under the national leadership of Friedberg's Rochester colleague, Paul Barr, MD.

“It is a randomized trial looking at three different approaches to treat patients who progress early after immunochemotherapy. We hope to see if one of these three approaches is best for these high-risk patients,” detailed Friedberg. “Equally as important, we will be storing tumors to help develop the signature marker to predict who these patients are up-front. This is a big thing.”

Friedberg said there have been positive strides on the pharmaceutical front, with new drugs entering the market and under development to target follicular lymphoma in various ways.

Rituximab, a B-cell antibody, has been used for some 20 years along with chemotherapy and has significantly increased survival time for patients.

“Now we have obinutuzumab, which is like a next-generation of rituximab. Results from a large randomized trial were presented last winter. It found obinutuzumab combined with chemotherapy results in better remission durations for patients than rituximab combined with chemotherapy. For a subset of patients—not everybody—that is an advance that may be very important,” said Friedberg.

“There are also some new oral drugs that are quite exciting in follicular lymphoma,” he informed. “One is lenalidomide, a drug that has been used with myeloma, and which has significant activity in follicular lymphoma. There are some trials that are actually looking at lenalidomide for use up-front as a first therapy replacing chemotherapy.”

Additionally, there are a number of new drugs that are being used in the relapse situation. “These are a different classes of drugs, often oral drugs that have very much less toxicity than standard chemotherapy,” said Friedberg.

“Part of the challenge of managing this disease is due to the fact that many patients are older and often have other medical problems that make it harder to give necessary treatments. Even for patients in their 80s, these oral drugs seem to be tolerated well, much better than chemotherapy. So I would say it is certainly an exciting time in treating patients with follicular lymphoma.”

Proof of that assertion can be found in the accelerated approval of idelalisib, a first-in-class PI3K inhibitor, in 2014 for this patient population.

The safety and efficacy of idelalisib for the treatment of relapsed follicular lymphoma was established in a clinical trial with 123 participants with indolent non-Hodgkin lymphomas. Results showed 54 percent of participants with relapsed follicular lymphoma experienced objective response rate.

Further evidence of the continued growth of treatment options for follicular lymphoma, includes the Sept. 17 accelerated approval by the FDA of copanlisib for the treatment of adults with relapsed follicular lymphoma who have received at least two prior treatments known as systemic therapies.

“For patients with relapsed follicular lymphoma, the cancer often comes back even after multiple treatments,” said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, via news release. “Options are limited for these patients and [FDA] approval provides an additional choice for treatment, filling an unmet need for them.”

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The Big Hurdle

The remaining, and hulking, unmet need in follicular lymphoma is found in what Kahl called “the dreaded complication”—transformation.

For every year that a patient lives with the less risky follicular lymphoma, the chance of experiencing disease transformation and acquiring transformed lymphoma, a more lethal cancer, rises 2-3 percent.

“If you live with follicular lymphoma for 10-15 years, those percentages start to add up,” said Kahl.

“When cells do transform, they become larger and nastier in appearance, proliferating much more rapidly. For 25-50 percent of patients with transformed lymphoma, we can use aggressive treatment to change it back to regular old follicular lymphoma, and they can do well for a very long time. But that still means there is a sizeable proportion of patients for whom we cannot get the disease under control.”

He explained the DNA in these cells is very unstable. The cells are constantly dividing and multiplying and acquiring new mutations along the way. Sometimes they create resistant clones that become increasingly harder to kill. “They form all sorts of different resistance mechanisms and it doesn't seem to matter what we throw at them—they just won't die,” Kahl lamented.

Though transformation has been a topic of research for 30 years, there is still no strategy that has been conclusively shown to prevent transformation. Friedberg said the only upside to the current transformation discussion is found in newer treatment regimens that perform somewhat better than older regimens. He noted younger patients, more robust than their older counterparts, are even receiving stem cell transplants as a part of an aggressive treatment. But the fact remains, “Transformation is a major cause or morbidity and mortality of this disease. We need to learn how to prevent it. There is much more work to do,” Friedberg declared.

Kahl continued that battle cry. “There are still a lot of unanswered questions and unmet needs. We owe it to our patients to continue to do the work and continue to improve their outcomes.”

Valerie Neff Newitt is a contributing writer.

Wolters Kluwer Health, Inc. All rights reserved.
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