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While most people living with follicular lymphoma—the most common subtype of slow-growing indolent non-Hodgkin’s lymphoma—respond to treatment, studies conclude that approximately 20 percent of patients relapse within two years of receiving first-line therapy. One area of research to understand this is the tumor microenvironment, which researchers have recognized as a significant driver of this blood cancer.

At the University of Texas MD Anderson Cancer Center in Houston, Dr. Loretta J. Nastoupil leads the Lymphoma Phase I Drug Development team, which is exploring the role of the tumor microenvironment in lymphoma. In this Q&A, she discusses how targeting the microenvironment may change how we treat follicular lymphoma and why treatment combinations may be helping to eliminate these tumor cells.

What is the tumor microenvironment?

DR. LORETTA J. NASTOUPIL

DR. LORETTA J. NASTOUPIL FROM THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER IS EXPLORING THE ROLE OF THE TUMOR MICROENVIRONMENT IN FOLLICULAR LYMPHOMA.

“Recently, researchers have been paying increased attention to the tumor microenvironment—the cells, molecules and pathways that surround and support the growth of tumor cells.

When B-cells, a type of white blood cell, become cancerous in follicular lymphoma, they have migrated from the bone marrow, where they are produced, to the lymph node. The microenvironment within the lymph node is essential in maintaining this disease. Complex interactions between cells in the nodes keep the cancerous B-cells growing.”

Why is targeting the microenvironment in follicular lymphoma worth studying?

“We tend to consider follicular lymphoma as more of a chronic disease than a fatal one. Patients generally do well with treatment, but we can’t cure it. Current therapies can put most people in remission, when there are no signs of cancer, but it usually comes back. If we can understand the tumor biology better, we hope to develop treatments that lead to a more durable remission.

We know that the microenvironment plays a critical role in maintaining this disease, helping it to thrive and to resist treatment. Right now, characterizing the microenvironment is our best predictor of how well someone with follicular lymphoma is going to do. If we can figure out better ways to target whatever structures support the lymphoma, instead of helping to stop DNA replication like some current therapies do, we might progress how we treat patients with follicular lymphoma.”

Why can’t we just target the genetic drivers of follicular lymphoma?

“With solid tumors, immune cells infiltrate in small numbers. If you can target or block that mutation, you can stop or slow that tumor from growing. But in follicular lymphoma, it’s not the same.

About 90 percent of patients with follicular lymphoma have an abnormal rearrangement between parts of two chromosomes, called a translocation. But you can’t target that abnormality for treatment. Acquiring the translocation is just the first in a multi-step process that leads to follicular lymphoma. The other steps lead to more genetic alterations, which provide some survival advantage to that cancer cell, including masking them from the immune system’s search-and-destroy process.”


Do any current therapies target the microenvironment?

“People with follicular lymphoma are often treated with anti-CD20 antibodies that interact with effector cells of the immune microenvironment. Essentially, you’re putting a flag on the follicular cancer cells, which express the CD20 proteins on their surface, and hope the other key immune system players see those flags and eliminate the cancer cells. Significant developments in treatment over the last two decades have led to an improvement in the relative five-year survival rate for patients with follicular lymphoma, which increased from 70 percent in 1990 to 89 percent in 2010.

Therapies that target the microenvironment offer a promising approach that has the potential to improve outcomes in follicular lymphoma.”

How important is combination therapy in helping the immune system to eliminate follicular lymphoma cells?

“With follicular lymphoma, when you block one pathway, usually cancer cells find another way to escape the immune system.

Now, it’s critical to be more rational about the combinations we’re studying. We could do a better job selecting combinations if we understood the key players in the microenvironment and their roles in maintaining the lymphoma.”

We want 100 percent of patients with follicular lymphoma to be looking at an average life expectancy, and we want to achieve that with as little impact on their quality of life as possible.

How important is targeting the microenvironment to the future of treating patients with follicular lymphoma?

“With follicular lymphoma, many patients do well with the current standard of care treatment options. So why do we focus so much on the 20 percent that relapse early, within the first couple years? Why do we talk about it so much at our meetings and in our research? It’s because we want 100 percent of patients with follicular lymphoma to be looking at an average life expectancy, and we want to achieve that with as little impact on their quality of life as possible. Targeting the tumor microenvironment is the next step forward towards accomplishing this goal.”

To learn more about novel combination approaches for some patients with lymphoma, read “The Goal to Treat Lymphoma without Chemotherapy.”

New research has helped scientists better understand the more than 60 different molecular subtypes of non-Hodgkin’s lymphoma (NHL), revealing just how diverse and complex this group of blood cancers is. And with better understanding comes the potential for different treatment pathways, which clinicians anticipate seeing at this year’s American Society of Hematology (ASH) Annual Meeting.

“From a biological standpoint, molecular lymphoma subtypes are very different from one another,” said Dr. Georg Lenz, Director of the Department of Hematology, Oncology and Pneumology at the University Hospital in Muenster, Germany. “These complexities potentially warrant different treatment approaches.”

Expanding our knowledge of these unique molecular drivers may open the door for targeted treatment approaches. Dr. Lenz expects we will learn more about these approaches during the ASH congress.

Dr. Georg Lenz

DR. GEORG LENZ FROM THE UNIVERSITY HOSPITAL IN MUENSTER, GERMANY BELIEVES THAT UNDERSTANDING THE SUBTYPES OF NON-HODGKIN’S LYMPHOMA IS HELPING RESEARCHERS TO IMPROVE TREATMENT.

A Tale of Two Characterizations

NHL subtypes can be divided into two broad categories based on how quickly the disease progresses: they can either be indolent or aggressive. Indolent lymphomas, such as follicular lymphoma (FL), are usually slow-growing and represent up to 40 percent of all NHL cases. Aggressive lymphomas grow at a much faster rate, such as one of the most frequent subtypes, diffuse large B-cell lymphoma (DLBCL).
 

Fast Progress in Slow-Moving NHL

The treatment landscape for indolent NHL, which includes follicular and marginal zone lymphomas, has been evolving quickly. While many patients still receive chemotherapy, targeted therapies have been making headway. At this year’s ASH Annual Meeting, Lenz expects to see more data from trials of these investigational therapies in combination with—or instead of—chemotherapy, opening the possibility for chemotherapy-free treatment.

“While we see increased interest in chemotherapy-free treatments, these approaches still have serious side effects,” Lenz said. “We still have a lot of work to do in managing these toxicities.”

Fortunately, most patients with indolent NHL respond well to treatment, but about 20 percent of FL patients relapse rather early after initiation of therapy. Since each patient responds to treatment differently, clinicians need to adapt treatment approaches accordingly, particularly for patients who do not initially respond well.

“This could be the next step for patients,” Lenz said. “It’ll be a challenge for years to come, but hopefully, we’ll see some progress in predicting treatment responses at this year’s ASH.”

It has been challenging to translate the biological knowledge of NHL into clinical practice.

New Avenues in Aggressive NHL Subtypes

Meanwhile, researchers are still grappling with the genetic complexity of aggressive lymphomas. Even previously identified subtypes are evolving into a collection of unique subtypes. For instance, DLBCL can be further broken down into additional subtypes, including activated B cell-like (ABC) DLBCL and germinal center B cell-like (GCB) DLBCL.  Different treatment approaches for the two are being tested in clinical trials.

“DLBCL encompasses unique molecular subtypes that behave differently, both biologically and clinically,” Lenz said. “It has been challenging to translate the biological knowledge of NHL into clinical practice.”

One investigational option being studied in patients with relapsed or refractory DLBCL and other aggressive NHL subtypes is chimeric antigen receptor (CAR) T cell therapy.

“Results on CAR T cell therapy are encouraging. However, we need longer follow-up to correctly assess its efficacy,” Lenz said.

To learn how patients and doctors are partnering to make treatment decisions in lymphoma, read “Developing Confidence in Lymphoma Treatment Decisions.”

A non-Hodgkin lymphoma diagnosis can come with many uncertainties, especially for patients with subtypes that remain chronic and incurable. Patients may feel anxious about not knowing when their lymphoma may progress or how their treatment may impact their lives. As a result, more than one-third of survivors experience symptoms of post-traumatic stress disorder.

Those uncertainties can make navigating diagnosis and treatment emotionally crippling. But a doctor who acts as a partner in their lymphoma care—educating patients on therapeutic options and supporting them throughout their treatment—can make all the difference in building confidence in their patients.

With that in mind, the theme of this year’s World Lymphoma Awareness Day, recognized on September 15, was “Small Things Build Confidence.” In recognition of this campaign, Dr. Nathan Fowler, associate professor at MD Anderson Cancer Center, discusses why taking the time to ensure people with lymphoma understand their therapeutic options can go a long way in strengthening their confidence in their treatment decisions.

DR. NATHAN FOWLER FROM THE MD ANDERSON CANCER CENTER BELIEVES IT IS IMPORTANT THAT PATIENTS WITH LYMPHOMA BUILD A HEALTHY PARTNERSHIP WITH THEIR DOCTORS.

How does understanding of their therapeutic options help lymphoma patients build confidence in their treatment?

“When people living with lymphoma understand their treatment options, they are better prepared to navigate what’s best for them. Fortunately, patients have multiple treatment options for lymphoma, and their participation in the decision-making process is important. They should be aware of the risks and benefits of any treatment that they’re starting.

There’s also a psychological benefit of understanding the path ahead, the chances of success and having confidence in the treatment choices made. From my observations, patients who approach treatment with understanding and confidence are less stressed and are in a better place psychologically.”

How important is the doctor-patient relationship to addressing uncertainties and building confidence for lymphoma patients?

“It’s paramount that patients feel their doctor is going to be a partner in their care throughout their entire treatment journey. Today, many patients take it upon themselves to search the internet and learn all that they can about their disease. But, they should also feel comfortable coming to their doctor with questions when things just don’t make sense. They shouldn’t feel like they have to figure it out all alone.

I’ve grown quite close to many of the patients I have treated over the years; I know details about their families, their friends and their lives. In fact, the close relationship that I’ve forged with my patients is one of the rewarding parts of being an oncologist.”

What are some common questions that your patients with lymphoma ask you?

“The most common question I get asked is ‘am I going to die from this?’ Patients also have concerns about treatment side effects, insurance coverage of their treatment and how the disease will affect their work and their families.

The best way to address these concerns is to be very honest and discuss both the good and the bad. While survival rates for lymphoma are generally increasing with new treatment options, some subtypes of non-Hodgkin lymphoma have varying outcomes for patients and remain incurable.”

Why is it important for patients with lymphoma to know their subtype?

“The more we learn about the over 80 different subtypes of lymphoma, the more we learn how dramatically different they are from each other. These diseases behave differently and respond differently to various treatments, which is why patients should have a basic understanding of their subtype.

Knowing their subtype is critical to balancing the risks of therapy against the risk of the disease. This information needs to be factored into a patient’s decision for treatment.”

What are some of the concerns that patients have about their treatment options?

“Almost every patient I see in the clinic has concerns about their treatment. I spend a great deal of time talking about how each treatment works. When a patient feels like part of the decision-making process, they can be more confident when they start their cancer treatment.”

It’s paramount that patients feel their doctor is going to be a partner in their care throughout their entire treatment journey.

After a patient has been treated, how do you address their concerns about their cancer returning?

“When a patient finishes treatment, they still need to see their doctor frequently. Return visits not only allow many of our patients’ questions to be answered but also allows us to monitor their progress and determine if their disease may have returned. Regular follow-up visits help reassure patients that multiple options exist should their cancer return, which can help relieve a patient’s concerns while furthering the doctor-patient relationship.”

To learn more about advances in lymphoma treatment, read “The Many Faces of Lymphoma.”

Disclosure: Dr. Fowler has received research funding from and is on a scientific advisory board of Celgene.

Most patients diagnosed with lymphoma discuss the possibility of chemotherapy with a healthcare professional at some point. Chemotherapy is a standard of care for many forms of lymphoma, but most patients will experience multiple relapses.

Chemotherapy is a broad spectrum treatment that stops cell growth and division throughout the body, which can lead to side effects. Chemotherapies cannot differentiate between cancer cells and normal cells, so they also attack fast-growing but healthy cells, such as hair follicles and the cells lining the gut. That damage can lead to both short and long-term side effects, such as fatigue, nausea, a compromised immune system, fertility loss and an increased risk of infection or a second primary cancer.

While the benefits of chemotherapy often outweigh the risks, patients are eager for alternative solutions. Thankfully, research continues to look at different treatment pathways.

Meghan Gutierrez

MEGHAN GUTIERREZ, CHIEF EXECUTIVE OFFICER OF THE LYMPHOMA RESEARCH FOUNDATION (LRF), EXPLAINS WHY RESEARCHERS ARE EXPLORING CHEMOTHERAPY-FREE TREATMENTS

“We are learning a great deal about lymphoma subtypes and making progress in the discovery and development of new approaches that may improve quality of life,” Meghan Gutierrez, chief executive officer of the Lymphoma Research Foundation (LRF), said. “There is meaningful interest in exploring potential new treatments and combinations, many of which are chemotherapy-free.”

Lymphomas are caused by changes in immune cells called lymphocytes. In patients with lymphoma, the body makes many of these defective lymphoma cells that may not be detected by normal immune cells, which can properly fight infection and disease, including cancer. Restoring the immune system’s ability to fight cancer is a growing trend that has led to the development of immunomodulatory therapies, which can boost the tumor-killing cells of the immune system.

Investigators continue to explore new approaches focused on stimulating the immune system for patients with lymphoma.

The inherent ability of some types of immune cells to attack tumors relies on “tags” called antibodies on the surface of cancer cells. This killing process is known as antibody-dependent cell-mediated cytotoxicity (ADCC). In fact, several approved lymphoma therapies are antibodies that attach to cancer cells, leading the immune system to better identify and attack them. Researchers are now studying whether combining these antibody therapies with immunomodulatory therapies might further enhance cancer-killing ADCC, without the need for chemotherapy.

With further understanding of how both of these types of treatment work, separately and in combination, there is a potential to improve outcomes.

“Investigators continue to explore new approaches focused on stimulating the immune system for patients with lymphoma,” Gutierrez said. “It’s an incredibly exciting time as research is constantly evolving.”

By Ed Svec

Lymphoma survivor Ed Svec and his wife Susan have participated in Light The Night walks for the past seven years.

Lymphoma survivor Ed Svec and his wife Susan have participated in Light The Night walks for the past seven years.

For seven years, I have been participating in the Leukemia & Lymphoma Society’s Light The® Night walks in Long Island, New York. Sometimes I’m asked why I walk. I say, “I don’t do it for myself; I walk for future blood cancer patients.”

There’s no screening. There’s no known prevention. Our best hope today rests in supporting research to find cures and making sure all patients get the best support and care possible.

My hope is that the treatment for those diagnosed with blood cancer in the future won’t be as invasive, debilitating or emotionally draining as what I went through.

My lymphoma was a journey to hell and back again. After being diagnosed with non-Hodgkin’s B-cell follicular lymphoma in 2009, I underwent eight sessions of chemotherapy in just four months.

During that time, I wasn’t allowed to drive. And I couldn’t go into public places because my immune system was compromised; it was like being under house arrest.

I lost 55 pounds and every hair that I owned, and my toenails started to peel. I felt like a soft shell crab.

In the end, though, my lymphoma went into remission, and I survived. So I’m grateful to the people who were participating in these walks years before I got sick, raising funds and supporting research in blood cancer. It was partly through their efforts that my odds of surviving lymphoma were as good as they were.

What I went through pales in comparison to what my friend experienced when he was diagnosed with the same disease 15 years prior.

Like the people who walked a decade before I was diagnosed, now it’s my turn to pay it forward by raising funds to improve treatment for blood cancer in the future.

You can see how far we’ve come in the treatment of blood cancer at the Light The Night events. The sheer number that participate in these walks today is inspiring. Survivors of every age and background come to share their journeys and to carry their white lanterns with pride. Hearing those stories and seeing those white lights is one of the most uplifting things that someone currently struggling with blood cancer can experience.

That’s why I decided to share my story in front of a large crowd of patients and survivors at my local walk in Nassau County on Long Island, NY last year. Afterward, a couple introduced me to their six-year-old daughter. She was being treated for lymphoma at the time but didn’t want to talk about it with her parents or anyone else. I understand; I’m 63, and it’s tough for me to talk about it.

I knelt down beside her and asked her if she was okay. She said “yeah” and hugged me. It’s small interactions like this at these walks that can make big differences to patients who need to know they are not alone in their journey. We are fighting against this disease right along side them.

Ed Svec gave a speed to current patients and survivors during last year’s Light the Night walk in Nassau County, New York.

ED SVEC GAVE A SPEECH TO CURRENT PATIENTS AND SURVIVORS DURING LAST YEAR’S LIGHT THE NIGHT WALK IN NASSAU COUNTY, NEW YORK.

By supporting continued research, we can improve the lives of patients like that little girl and stop losing loved ones to blood cancers. In the meantime, we remember those we have lost during the Light The Night walks. Participants write down and display the names of people who have lost their battles in the Remembrance Tent. This year, I’m up to three names. I don’t want to add anybody else.

Like the people who walked a decade before I was diagnosed, now it’s my turn to pay it forward by raising funds to improve treatment for blood cancer in the future. I hope that you will join us for a walk this year and make a difference in the lives of blood cancer patients.

Discover how you can participate in an upcoming walk near you by visiting the Leukemia & Lymphoma Society’s Light The Night website

In 2006, pitcher Jon Lester of the Boston Red Sox was undergoing chemotherapy for anaplastic large cell lymphoma, a potentially fatal cancer of the immune system, yet seven years later he won two 2013 W­­orld Series games.

Like Lester, many of the more than 70,000 people diagnosed with lymphoma each year survive because of advancements in chemotherapy and other treatments. However, most people don’t realize that this cancer is actually a  large group of distinct diseases. Which therapies they receive and how well they will respond to treatment depend on the type of lymphoma they develop.

Lymphoma, the most common form of blood cancer, occurs when the immune system produces too many of the cells called lymphocytes, which normally guard the body against viruses and bacteria. These cells multiply normally in the course of an infection, leading to swollen lymph nodes, such as in mumps or mono, but after the infection has subsided, the cells die off and the lymph nodes return to normal size. When these lymphocytes become malignant, they multiply continuously and lymph nodes become larger and larger even in the absence of an infection.  Hodgkin’s lymphoma, one of the many subtypes of lymphoma, is a remarkable treatment success story. The vast majority of patients are cured with chemotherapy and or radiation therapy.  Patients have a more than 80 percent chance of cure even when the cancer has widely spread throughout the body.

Hodgkin’s lymphoma is characterized by the presence of an abnormal cell called the Reed-Sternberg. All other lymphomas—those that do not have Reed-Sternberg cells—are lumped into a category called non-Hodgkin lymphoma (NHL).

There are more than 30 different types of NHL. Some forms are treated differently than others. For example, anaplastic large cell lymphoma, the type of lymphoma that Jon Lester was diagnosed with, often responds well to a chemotherapy regimen called CHOP, which includes four drugs:  cyclophosphamide, doxorubicin, vincristine and prednisone. CHOP also works against other NHL sub-types that fall within the same category as anaplastic large cell lymphoma, known as peripheral T cell lymphomas.

The most common type of NHL, diffuse large B cell lymphoma (DLBCL), is also treatable and potentially curable. This fast-growing lymphoma  accounts for about one third of NHL cases. For this lymphoma, it is typical for lymph nodes to double in size every month, and patients often present within a few months of having noted an enlarged lymph node. The typical first line treatment is a modified version of CHOP, known as R-CHOP, that adds a “targeted therapy” called rituximab which is  a monoclonal antibody, that homes directly to the cancer cells and promotes their destruction.  Over 90 percent of patients with localized, early stage DLBCL will be cured with a combination of R-CHOP and radiation therapy and approximately 50 percent of patients with advanced stage DLBCL will be cured with R-CHOP. Unfortunately for those patients who are not cured by R-CHOP there are less attractive second line therapies, including chemotherapy or high dose chemotherapy followed by autologous stem cell rescue, also known as bone marrow transplant. Many fewer can be cured at that point and the majority of these patients will not survive their disease.

The second most common subtype of NHL, follicular lymphoma (FL), grows slowly, with lymph nodes doubling in size approximately every six to 12 months, and patients often get diagnosed a year or later after they first noted an enlarged lymph node. Many patients may not require treatment initially and can just be observed. A small fraction never require treatment, however, eventually, the vast majority of  patients will require therapy which is typically rituximab combined with a chemotherapy. Unlike DLBCL, patients with FL are rarely if ever cured but may live many years  because of the slow growth of the tumor cells and the ability to treat with multiple therapies. Eventually, however, most patients will die of their disease and in about 25 percent of them their FL will transform to DLBCL which is typically not responsive to therapy in this setting.

Another type of NHL that responds to chemotherapy is Burkitt’s lymphoma. Doctors first noticed this cancer in children in Africa, but it also strikes people infected with human immunodeficiency virus (HIV), organ transplant recipients, and others. Chemotherapy combinations cure about 50 percent of patients, meaning there are many who need other choices. This lymphoma is very rapidly growing, and lymph nodes double in size within a few days to a few weeks. While it is rapidly growing, it is curable in many patients when diagnosed early.

Mantle cell lymphoma (MCL) only accounts for about five percent of the cases of NHL but it is a very aggressive type of lymphoma  and is typically diagnosed in very advanced stages of the disease. Treatments like R-CHOP have improved the prognosis for patients, who now survive for five to seven years on average, but the disease recurs in nearly all patients and cures are extremely rare.  Continued scientific advancements  are providing  additional options for patients

The picture however is continuing to improve for all of the lymphomas with the continued research and development of exciting therapies that specifically target the cancer cells, and agents that modify the immune system. These new therapies include monoclonal antibodies that target directly to the cancer cells and kill the cancer cells by a variety of immune mechanisms, monoclonal antibodies that are “packaged” with toxic chemicals that target directly to the cancer cells to deliver these toxic agents, and tyrosine kinase inhibitors that are small molecules that can be given orally and target different growth receptors in cancer cells and very effectively kill the cancer cells, and other agents to stimulate the immune system. This is perhaps the most exciting era in lymphoma history where basic science discoveries are becoming available to lymphoma patients with the hope of  improving their survival and  quality of life.