ESSENTIAL THROMBOCYTHEMIA (ET) is one of the classical myeloproliferative neoplasms (MPNs), along with polycythemia vera and primary myelofibrosis (MF). Together, the blood cancers share characteristics such as an overproduction of blood cells; tendencies toward coagulation disorders that, paradoxically, include both blood clotting or bleeding; and a potential for disease progression, rarely including transformation to acute forms of leukemia (less than 10 percent).

An estimated 135,000 individuals in the United States are living with ET. The disease is more common in women than men (60 percent versus 40 percent) and most often diagnosed in older people. However, 20 percent of people who receive a diagnosis are under age 40. An official diagnosis, according to the World Health Organization, includes a sustained increase in platelets; a characteristic mutation seen in affected cells, such as JAK2 V617F, CALR or MPL; exclusion of other mimicking diseases, including early or prefibrotic MF; and characteristic features on a bone marrow test.

In some cases, patients with ET are asymptomatic (show no symptoms) at diagnosis and are recognized only after a high platelet count is noted on an annual physical. In other cases, patients present with fatigue, headaches, visual change, numbness, itching and/or color changes in their extremities. Blood clotting, another symptom that can lead to the diagnosis, has a major impact on prognosis and treatment. Therefore, it is important to understand symptoms, risk factors and treatment of ET-associated blood clotting, which can affect arteries and veins, as well as small and large blood vessels.

Counseling patients about the signs and symptoms of blood clotting can make them aware of the health risks associated with ET. For instance, small vessel disturbances may affect quality of life by leading to headaches; transient visual loss; or numbness, tingling, burning or discoloration of the extremities, (which may appear red blue or purple). Small vessel disturbances usually do not influence prognosis.

On a more serious scale, occlusion (blockage or closing) of a large vessel can affect arteries or veins. Arterial blood clotting can lead to stroke, ministroke and/or heart attacks. Signs of arterial blood clotting include facial droop, difficulties with speech, weakness on one side of the body, chest pressure and shortness of breath.

Venous blood clotting, more commonly known as deep vein thrombosis (DVT), can affect the legs, resulting in tightness, strain, redness and/or swelling. A DVT can break off and travel to the lungs, potentially leading to a pulmonary embolism, which can be very serious. A blood clot in the lungs may cause chest pain, difficulty breathing, fast heartbeat and, sometimes, a bloody cough. Venous clotting can also affect veins that drain the liver, intestines and spleen (abdominal venous thrombosis). These tend to be more common in women than men and can present with abdominal pain, bloating and fluid retention.

After learning the signs and symptoms, patients are assigned a blood clotting risk category — very low, low, intermediate or high &mdash; based on age over 60 years, blood clotting history and presence of the JAK2 V617F mutation. For example, high-risk patients are older than 60 and have a JAK2 mutation or a prior history of blood clotting.

Risk classification has a strong impact on treatment decisions. For those with high-risk disease, hematologists recommend medications such as Hydrea (hydroxyurea), a type of chemotherapy; Pegasys (pegylated interferon); or Agrylin (anagrelide), a platelet-lowering agent. For patients with disease that’s less than high risk, either observation alone (for very low-risk patients) or aspirin may be sufficient, particularly for those with small-vessel disturbances, JAK2 mutations or cardiovascular risk factors.

Prescribing aspirin should be selective rather than universal. In some patients, aspirin may bring more risk, such as bleeding, than benefit, especially for those with CALR mutations and extremely high platelet counts. It is important to note that the platelet count itself does not enter into the risk grouping; higher counts can associate with bleeding; and in asymptomatic, lower-risk patients, drugs to lower platelet count are not given without reason. Blood thinners are often prescribed for patients who develop deep vein thrombosis and/or pulmonary embolism.

Coumadin (warfarin) has been the standard, but newer agents are increasingly used, including direct oral anticoagulants. The hematologist will decide on the type of anticoagulant and duration of therapy. Arterial blood clotting events are co-managed with cardiologists and neurologists; if not already used, anti-platelet therapies also play an important role.

Although medications can help treat blood clotting, patients can lower their risk by maintaining a healthy lifestyle. Because ET is a vascular disease, it is important to maintain excellent vascular health. Such a strategy involves smoking cessation, maintaining a healthy weight, following a moderate diet, exercising and monitoring levels of blood pressure, glucose and cholesterol.

It is crucial that patients be proactive and educate themselves about ET. They must be their own best advocate and remain optimistic, because the pace and progress of ET/ MPN research are unprecedented.

BRADY L STEIN, M.D., M.H.S., is an associate professor of medicine in the division of hematology and oncology at Northwestern University Feinberg School of Medicine in Chicago. He received his medical degree from Emory University in Atlanta and completed his residency and fellowship at the Johns Hopkins Hospital in Baltimore.

Articles

Speaking Out

Patients with essential thrombocythemia should know the signs and symptoms of blood clots.

Through Thick and Thin: Monitoring Blood Clots With ET

THE CORRECT TREATMENT AND team are key components to fighting cancer, and support is equally important. For patients with rare types of the disease finding the connections may be more challenging. Organizations such as the Cutaneous Lymphoma Foundation have been founded to address this need. 

Cutaneous lymphomas are a subset of non-Hodgkin lymphoma that primarily affect the skin. Created by a newly diagnosed patient, a caregiver and a physician, the Cutaneous Lymphoma Foundation offers clinically vetted information about the disease. 

“With a rare disease, people often feel isolated and alone,” Susan Thornton, CEO, tells 

® in an interview. “We offer a place for them to come to, meet others, get individual support and help. We offer live educational programs that are now delivered through streaming technology so anyone can participate from the comfort of their home.” 

For any disease a correct diagnosis is critical. But, unfortunately, cutaneous lymphomas are often misdiagnosed because they mimic other skin diseases, such as eczema, dermatitis and psoriasis. “Most community dermatologists have not seen a patient with this disease and may not consider it as a possible diagnosis given its rarity,” Thornton says. “A second opinion, with a specialist in the field of cutaneous lymphoma, is important. These specialists have seen many cases, know what to look for and what to ask about an individual’s history, work with the pathology report and put the puzzle pieces together.” 

Although there is no curative therapy, people with a cutaneous lymphoma have treatment options. Topical and skin-directed treatment, such as ultraviolet B light, can be used for early stage disease, according to Thornton. She explains that with more resistant or aggressive disease treatment combinations with an oral drug or an infusion treatment are recommended. 

“The next five or so years look very promising for us to have new treatments that are targeted, more effective with longer lasting positive outcomes,” says Thornton, who is living with cutaneous lymphoma. 

Clinical trials are one of the ways advancements are being made. The Cutaneous Lymphoma Foundation works to help people understand the significance of clinical trials and get them into the right one if they are a good candidate. “We have a list of most of the open clinical trials on our website,” Thornton says. “(Patients) can search by geographic location. Although we don’t have every clinical trial listed, we do our best to make sure we have up-to-date information for most of the major clinical trials that are currently recruiting for participation.” 

In addition, the foundation has an online learning center with clinical videos and content, resources and patient stories. It also hosts a monthly Facebook live interview series with guests that include physicians, researchers, insurance experts and patients. 

“Today, this is a chronic disease that requires treatment over a long period of time for most people,” Thornton says. “Finding new ways to stop the disease, keep it from progressing and arresting its growth in advanced disease is critical to enabling people to live full lives.” 

The Advocate

The Cutaneous Lymphoma Foundation connects patients with guidance and resources for this rare cancer.

The Cutaneous Lymphoma Foundation Builds Bridges to Fight the Disease

RON GROSS met with LINDA ALEXANDER, the Northwest region manager for Be the Match, during the Stanford Blood and Marrow Transplant Program's 30th BMT Reunion, which took place in May 2018. - COURTESY RON GROSS

Ron Gross thought nothing of getting bloodwork before undergoing fusion surgery for damaged discs in his neck. But he now considers that routine procedure a miracle.

The blood test picked up a rare form of cancer called myelodysplastic syndrome, which occurs when the blood-forming cells in the bone marrow grow and mature abnormally.

In 2012, Gross, who is retired and lives in Las Vegas, began transfusions and chemotherapy. However, that wasn’t enough to keep his blood counts up. Doctors told him that he needed a bone marrow transplant to live. He started his search for a donor within his family, but no one was a match.

Five months later, his lifeline came from across the Atlantic Ocean. Gross received a phone call on Christmas Eve that a match had been found — a woman in Poland. “I was overwhelmed,” says Gross, a married father of four. “I just had to find a way to stay alive until I had it done a couple of weeks later.”

In February 2014, Gross underwent high-dose chemotherapy followed by a stem cell transplant. “I stayed in a pretty good train of thought,” he says. “I always felt blessed that I lived a great life and did everything I ever wanted to do.”

The 67-year-old also credits the “unbelievable support” of health care providers at Stanford Cancer Center, Las Vegas Cancer Center and Be the Match, which manages the largest and most diverse bone marrow registry in the world.

A stem cell transplant, sometimes referred to as a bone marrow transplant, replaces unhealthy blood-forming cells with healthy ones. It can be performed on patients with hematologic malignancies, such as leukemia, lymphoma, myelodysplastic syndrome and multiple myeloma.

To determine a patient’s suitability for this treatment, a health care provider considers the person’s overall health and age and the likelihood the disease will respond, according to the Leukemia & Lymphoma Society. Transplants are being done in patients up to 75 years old, according to some experts.

Two main types of stem cell transplants can be used: autologous and allogeneic. An autologous transplant involves removing a patient’s own stem cells from their blood before they receive treatment, such as chemotherapy or radiation, that may destroy them.

In an allogeneic stem cell transplant, a donor’s cells are used. A close family member is the ideal candidate, but if there is no match among relatives, a donor may be found through a national registry. “Since patients can use their own stem cells in an autologous transplant, it’s easier and quicker than an allogenic (transplant),” says Auayporn Nademanee, M.D., Jan & Mace Siegel Professor in Hematology & Hematopoietic Cell Transplantation and director of the Matched Unrelated Donor Program at City of Hope in Duarte, California.

Donors and patients are matched by their human leukocyte antigen (HLA) tissue type. HLAs are proteins, or markers, found on most cells in the body. A simple cheek swab can help determine whether an individual is a close bone marrow match.

The best marrow transplant outcomes occur when a patient and donor’s HLA closely match. If there is more than one match, factors such as the donor’s age, gender, blood type, height and weight will be considered, according to Be the Match.

In some cases, however, mismatched or haploidentical (half-matched) donors might be used. This has become increasingly common and safer with new transplant techniques, says Andrew Brunner, M.D., of Massachusetts General Hospital in Boston. A haploidentical donor, such as a parent, child or sibling, can more readily be used if the recipient is given a conditioning regimen — certain chemotherapy before and after the transplant is infused. “If we can diminish the transplant risk with a half-match by using this specific cocktail, perhaps this approach also will work for a mismatch donor,” says Brunner.

Siblings will be perfectly matched 25 percent of the time; half-matched, 50 percent; and totally different, 25 percent, says Dennis Confer, M.D., chief medical officer of the National Marrow Donor Program and its Be the Match registry. Parents are half-matched to their children.

Another consideration for stem cell transplantation includes a patient’s ethnicity. Caucasians have a 97 percent likelihood of finding a match, whereas African-Americans have a 66 percent chance, according to Be the Match.

“Efforts to increase the number and diversity of donors, as well as new techniques for alternative donor transplants such as using half-matched donors or umbilical cord stem cells, have improved the chances of finding a match for patients who identify as a racial or ethnic minority, but disparities remain,” Brunner says.

Cord blood, bone marrow and peripheral blood stem cells provide sources of blood-forming cells used in these procedures.

AMY MARSH received a cord blood transplant in 2015. - PHOTO BY EMILY INGALLS

The newer cord blood transplants proved beneficial for Amy Marsh, who received one in 2015, the year after she got a diagnosis of acute myeloid leukemia. Then 37 and a professional triathlete, Marsh felt something was off physically through her training. “I just wasn’t feeling good,” says Marsh, who lives in Austin, Texas.

“I was more tired than usual, but who isn’t tired when they’re training 20 to 25 hours a week for Ironman triathlons? Instead of taking a 30-minute nap, I would take two-hour naps, and my husband would have to come and wake me.” Her breathing also felt more labored during what she considered easy runs.

“When the doctor told me the diagnosis, I was in shock,” she says. “I was a professional triathlete and was healthy, or so I thought. I worked out, ate healthy and was at the peak of my athletic career. However, I knew something was wrong. I wasn’t feeling well. But I never thought it would be cancer.”

Cord blood contains stem cells that can cure diseases such as blood disorders, immune deficiencies, metabolic diseases and some certain cancers.

In preparation for an umbilical cord blood transplant, an expectant mother should make a plan with her OB-GYN. Cord blood is collected from the umbilical cord and placenta after a baby is delivered. It can be saved, frozen, in a private bank for the child or family members; however, there is a maintenance fee.

Cord blood can also be donated to a cord blood bank for public use, at no cost to the donor’s family, Nademanee says.

Because it requires less immunological match than other sources, cord blood opens the door to transplant for those who wouldn’t normally have a donor, says Joshua Sasine, M.D., director of the chimeric antigen receptor (CAR) T-cell therapy program at UCLA’s Jonsson Comprehensive Cancer Center.

The downside is that cord blood transplants generally take longer to engraft — when the body accepts the transplanted bone marrow or stem cells &mdash; increasing the risk of infections.

The rate of graft failure is also higher than with a matched sibling. If that occurs, graft failure could leave a patient unable to make blood cells.

“Although quite uncommon, this scenario’s often fatal and something we take extremely seriously and discuss with the patient prior to transplant planning,” Sasine says.

In addition, cord blood donation involves smaller cell doses, which might be insufficient for a transplant, especially for adults, according to Nademanee. Typically, cord blood is used for young children because cell doses are the key factor in engraftment. The cost of cord blood is quite expensive — about $25,000 per unit. Furthermore, the rate of blood count recovery is slower because of cord blood’s immaturity, Nademanee notes.

“We believe that cord blood plays a critical role in transplants, but it’s going to take time to sort out how it compares (with) these mismatched family donors in the long run,” Confer says.

Patients are monitored closely before, during and after transplant.

Most of the procedure will be performed over the course of an approximately four-week hospital stay, according to Brunner. It includes roughly a week of pretransplant chemotherapy and then a few days for the body to rest before the stem cells are infused.

Next, a patient waits for the cells to engraft and then start to multiply and make new blood cells. Brunner says it may be several weeks until blood counts recover to a safe level, allowing the patient to leave the hospital. “This requires ongoing monitoring at a transplant center, which most frequently occurs during the first 100 days of a transplant but typically continues out for at least six to 12 months, then intermittently for years after a transplant,” he says.

Cure rates following stem cell transplantation vary widely, according to Confer. For instance, he says, highrisk leukemia is about 35 to 40 percent, and standard-risk leukemia is 60 percent.

The procedure, although potentially curative, also comes with other risks — some deadly. Graft-versushost- disease (GVHD), an associated risk with allogeneic transplants, occurs when the new immune system, made up of donor stem cells, sees the patient’s tissues and organs as something foreign and then attacks them. Acute GVHD happens in the first months after transplant.

The chronic type develops later and can include symptoms like joint or muscle pain, vision changes, a yellow tint to the skin or whites of the eyes, dry mouth, oral sores, diarrhea, nausea and vomiting. “Preventing GVHD typically requires giving immunosuppressive medications at the time of transplant and slowly weaning those off as the graft ‘grows up’ inside the recipient,” Brunner says.

Data suggest that patients who develop GVHD may have a slightly lower risk of relapsing with their disease, which is thought to be due to a graft-versus-leukemia effect, Brunner adds. In graft-versustumor effect — in this example, leukemia &mdash; the new donor cells recognize the tumor as foreign, giving the patient an extra therapeutic boost. “The optimal outcome is a transplant with no relapse and no GVHD,” he says. “However, for many patients, if they stay in remission without disease relapse but have mild/tolerable GVHD that doesn’t significantly interfere with their life, this is also considered a favorable outcome.”

Other immediate side effects include bleeding, graft failure, lung inflammation, and mouth and throat pain. Organ damage, relapse, secondary cancers, abnormal growth of lymph tissues, infertility, hormone changes and cataracts may arise later.

Over the past few decades, transplants have become more readily available to every patient, Nademanee says. She is also encouraged by the role of CAR-T cell therapy in treating patients where conventional chemotherapy has not maintained a remission. CAR-T cell therapy involves removing a patient’s T cells, genetically modifying them to recognize antigens on the malignant cells, and then reinfusing them into the body. “(In the future), we expect that more and more patients can be cured with stem cell transplant,” she says.

There also is mounting interest in tolerable maintenance chemotherapies — particularly, targeted agents &mdash; as post-transplant maintenance. “Even today, the main reason a patient doesn’t benefit from a transplant is because the disease returns,” Brunner says. “Among the areas the field should focus on is identifying those at highest risk of relapse and finding new methods to prevent relapse from happening.”

Patients like Marsh and Gross will continue to hope for new advancements and focus on the power of positivity. “You have to be confident in yourself and believe,” Gross says. “You can (have a) best friend, a husband or wife, and everyone in the world who loves you, but they can’t get you through it. You have to prepare yourself to fight the odds and not give up. It’s all about you and intestinal fortitude.”

Features

Techniques open a field of opportunity for stem cell transplant recipients.

Striking a Match for Stem Cell Transplants

MARIEBETH HEROFF, who is living with multiple myeloma, continued working full time thanks to few side effects. - PHOTO BY ALY WILLIS

When Mariebeth Heroff couldn’t stay awake during her nursing shifts in late November 2017, she thought she simply needed more sleep. She slept as soon as she returned home, at 5 p.m., waking briefly to eat dinner and help her 8-year-old daughter get ready for bed. Then she began experiencing back pain and nausea.

Heroff, 43, had a history of high cholesterol, and she worried that these were symptoms of a heart attack.

Heroff, of Oak Harbor, Washington, made an appointment to see her primary care doctor. Blood tests revealed that her protein levels were slightly elevated, but the physician was not concerned, and he suggested retesting in a week. When the second round of results also showed elevated protein levels, Heroff was desperate to gather more information, so she turned to the internet. Suspecting that she could have multiple myeloma, a cancer of plasma cells, Heroff was overcome with fear — especially about the implications for her daughter. In March 2018, further testing confirmed her diagnosis: stage 1 multiple myeloma.

Heroff was eager to begin treatment, which included subcutaneous injections of Velcade (bortezomib), a targeted chemotherapy that was offered only intravenously before 2012. Her oncologist explained that injections of the medication were preferable because she would have a lower chance of developing peripheral neuropathy, or tingling, numbness, burning or weakness in the hands or feet. Heroff had witnessed the effects of neuropathy in her husband, who has diabetes.

Although Velcade is the only chemotherapy drug offered subcutaneously for patients with multiple myeloma, studies are underway to evaluate whether subcutaneous injections could be also be an option for an intravenous (IV) monoclonal antibody therapy known as Darzalex (daratumumab).

This drug works by attaching itself to multiple myeloma cells and killing them directly or by allowing the immune system to destroy them. Patients with certain forms of lymphoma and leukemia — relapsed or refractory follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia &mdash; also started reaping the benefits of the trend toward injections in June 2017, when the Food and Drug Administration (FDA) approved subcutaneous Rituxan Hycela (rituximab), a drug that has been given intravenously in the United States since the late 1990s.

“The fact that we can administer these drugs subcutaneously is a very big deal,” says Jason Valent, M.D., the director of plasma cell disorders at Cleveland Clinic in Ohio. “Infusions of rituximab used to take hours, and now patients can be done in a matter of minutes. And reducing the rate of peripheral neuropathy with subcutaneous bortezomib allows more patients to stay on the drug longer.”

Researchers started exploring the possibility of reformulating IV medications as subcutaneous injections to reduce the toxicity of the drugs and to improve convenience for patients, says Stephen Ansell, M.D., Ph.D., a hematologist at Mayo Clinic in Minnesota. With the subcutaneous method, a drug is injected with a needle into the tissue under the skin in the abdomen or other area typically known to have ample subcutaneous tissue, and nurses are trained to give these injections, says Kathleen Wiley, RN, MSN, AOCNS, an oncology clinical specialist with the Oncology Nursing Society. In contrast, IV medications travel through the vein directly into the circulatory system, and they act more quickly than injections under the skin, Wiley says.

When medication is absorbed by tissue under the skin, usually there is a lower level of the drug in the body sustained for a longer period of time than with IV administration, Ansell explains. “The peak levels of the drug may be higher with an IV infusion. This may be good for killing cancer, but this can also cause more toxicity,” he says. Although the peak levels may vary with these two forms of administration, studies suggest that both methods are equally effective.

Researchers compared the effectiveness of these two forms of administration in a 2011 study of 222 patients with relapsed multiple myeloma who were assigned to receive subcutaneous or IV Velcade. The results showed that patients in both groups had an equal overall response rate to the medication, but 38 percent in the subcutaneous group experienced peripheral neuropathy, compared with 53 percent in the IV group. Velcade works by blocking or slowing down the action of proteasomes in cells, which break down proteins in healthy and cancerous cells. The buildup of protein can cause cancer cells to stop growing, dividing and multiplying.

Heroff and her doctor have been encouraged by her response to Velcade in combination with the oral chemotherapy Revlimid (lenalidomide) and a steroid called dexamethasone, which increases the response to Velcade.

After two months, her myeloma protein, sometimes called the M protein or M spike, dropped from 3.1 to 0.6 g/dL — the goal is to get that number as close to zero as possible.

Her low albumin/globulin ratio jumped from 0.7 to 1.2, which meant her body’s overproduction of the globulin protein was slowing. She noticed a red, itchy skin reaction at the injection site, but the reaction has not been painful. She’s grateful to have minimal side effects from treatment and the ability to continue working full time.

While reducing the incidence of neuropathy is the main advantage of injecting Velcade subcutaneously rather than intravenously, studies are showing different benefits of this route of administration for Darzalex. The drug can be used to treat patients with relapsed or refractory multiple myeloma and also in combination with Velcade in newly diagnosed patients with multiple myeloma who are ineligible for autologous stem cell transplant.

“When the drug is administered intravenously, one of the big problems is that many patients experience an infusion reaction,” Valent says. “It is almost like an allergy, with symptoms such as shortness of breath, cough, scratchy throat, itchy skin or wheezing. With the subcutaneous administration, the risk of such infusion reactions seems to be much less.”

In December 2016, Saad Usmani, M.D., presented study results at the American Society of Hematology annual meeting in San Diego, showing that only 22 percent of patients who received the drug subcutaneously experienced infusion reactions, compared with 46 percent for those who received the drug intravenously. The efficacy of the drug is equal with both forms of administration, and the subcutaneous method is far more efficient, says Usmani, the director of plasma cell disorders and clinical research at Carolinas Healthcare System in North Carolina.

“The weekly infusions can take seven hours the first day, then more than four hours the second and third days, and then three and a half hours after that,” he says. “The injection is given within five minutes.”

Now there is a large randomized phase 3 trial underway comparing IV and subcutaneous Darzalex, and the results will ideally lead to FDA approval of subcutaneous Darzalex, Usmani says.

Long IV infusion times have also been one of the disadvantages of taking Rituxan. Studies have shown comparable clinical efficacy between the two forms of administration, and one study showed that 81 percent of patients preferred subcutaneous over IV administration because it required less time in the clinic. Rituxan binds to the CD20 protein on the surface of normal and malignant B cells and recruits the body’s immune and other defenses to attack and kill the marked B cells.

A phase 3 trial of 410 patients with previously untreated follicular lymphoma who received the drug either intravenously or subcutaneously showed that the overall response rate at the end of treatment was 84.9 percent with the IV group and 84.4 percent with the subcutaneous group. The study also showed that the frequency of severe side effects was similar between the groups, with 34 percent in the IV participants and 37 percent in the subcutaneous participants.

Before starting subcutaneous injections, patients must receive one full dose of IV Rituxan to give nurses an opportunity to watch for any reactions, including headache, rigors (sudden feeling of cold), fever, chills, stomach pain, nausea and diarrhea. If the patient is cleared to start injections, the volume of medication in the syringe will be larger than nurses are accustomed to giving subcutaneously, Wiley says. Fortunately, the addition of hyaluronidase to Rituxan increases the permeability of the tissue and helps the body absorb and distribute the high volume of medication, she says.

CRAIG NATZKE and his wife, MORGAN, drove two hours for monthly infusions to treat his follicular lymphoma. - PHOTO BY CHRISTA REED

Craig Natzke, 37, was relieved when his doctor said he could switch from IV to subcutaneous administration. For the past year, Natzke and his wife had been driving two hours from their home in Savage, Minnesota, to Mayo Clinic for monthly infusions. Natzke was diagnosed with stage 4 follicular lymphoma in December 2015 after he noticed a bump increasing in size on the left side of his neck. During the previous six months, the bump had become as large as a Ping-Pong ball, and family members suggested that he see a doctor. His physician noticed swelling under his left armpit and on the left side of his chest and immediately ordered a series of tests.

“My body was lit up like a Christmas tree on the first PET scan because there was so much cancer,” Natzke says. “I was shocked because I had gotten physicals every year and had been completely healthy.”

Natzke started on a combination of Rituxan and Treanda (bendamustine), and his first infusion appointment lasted eight hours. Eventually the appointment times decreased to two hours, and he was thrilled when his second PET scan showed no cancer in his body after three months of treatment. After six months on the drug combination, Natzke started going to his doctor every other month for infusions of Rituxan as maintenance therapy. A year later, the drug was available subcutaneously.

“I’m really happy that the appointments take 20 minutes now instead of two hours,” Natzke says. “I’ve been in remission for two years, and that is a major milestone.”

Natzke, who sells software to law firms, continued working full time throughout his treatment. He and his wife have rekindled their love of travel, and they’ve visited New York City, Costa Rica, Iceland, London and Jamaica in the last two years. Now they’re eyeing Machu Picchu, in Peru, and a few other places in South America.

Doctors like Valent are pleased to see that subcutaneous options for medications are giving patients more time to enjoy their lives with fewer side effects. “There is excitement about the very good response rates patients are having with these drugs in combination with other drugs,” Valent says. “They are very well tolerated for the most part, which is good news for patients.”

Injectable forms of medication may benefit patients with blood cancers.

Taking a Shot to Treat Blood Cancers

KELLY FURGASON's disease appeared first in her bones, which rarely occurs. - PHOTO BY CAYLIN MARIE PHOTOGRAPHY

At age 40, Kelly Furgason developed a persistent limp. The problem arose during a stint as a zookeeper at a small facility for exotic animals in Harford County, Maryland, where she lives. “I was doing very physical work, cleaning and restraining animals,” she says. “I just thought, ‘I’m getting older, and my body’s telling me to slow down.’” But even after Furgason got cortisone shots and saw one specialist after another, her leg continued to bother her.

Over the next 18 months, as the limp became an all-over aching of the joints, Furgason saw nine doctors. Most believed that she had arthritis, but she wasn’t satisfied with that explanation. Eventually, she found herself in the office of a reputable orthopedist at the University of Maryland Medical Center in Baltimore, who assured her, “We’re going to figure out what’s wrong with you.”

“He ordered a PET scan,” she says, “and when I had that done, I lit up like a Christmas tree.” Before PET scans are done, patients receive a radioactive form of glucose through an intravenous (IV) injection. Because they are more active than normal cells, any existing tumors attract the glucose and “light up” on the scan.

By then, due to the severity of her pain, Furgason was using a wheelchair. X-rays showed hairline fractures in her femur and a rib. The doctor sent Furgason to Johns Hopkins Hospital in Baltimore for a bone marrow biopsy, and the results revealed that she had diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma, involving bone. “I had no idea that cancer was even on the table,” Furgason says. “I had a family history of breast and colon cancer, but I never imagined they’d say I had lymphoma.”

Because the cancer was in the bone marrow, it was considered stage 4. Although DLBCL is the most common type of non-Hodgkin lymphoma, it very rarely appears first in the bones. Still, Furgason’s prognosis was good.

“In other cancers — solid tumor cancers &mdash; we tend to think of stage 4 disease as incurable,” says Christopher Flowers, M.D., director of the Emory Lymphoma Program at Winship Cancer Institute of Emory University in Atlanta. “But that’s not true for diffuse large B-cell lymphoma or some of the other aggressive lymphomas. Even when it’s advanced stage, the goal of treatment is cure.”

Nearly 75,000 adults and children in the United States will get a diagnosis of some form of non-Hodgkin lymphoma this year. For the vast majority, the chance of cure or long-term remission is very high. For those who don’t respond to standard treatments or who relapse, many promising treatment options are in the pipeline, including targeted therapies, immunotherapies and new combinations of existing drugs.

“It is an exciting time in the field of lymphoma,” says Ann LaCasce, M.D., director of the Dana-Farber/Partners CancerCare Hematology-Medical Oncology Fellowship Program at Dana-Farber Cancer Institute in Boston. “Patients often live a very long time with (slow-growing) lymphomas or we cure many patients with aggressive lymphomas, but (the outlook) keeps getting better.”

Lymphoma is a cancer of the lymphocytes, a subset of white blood cells that fight certain types of infection. Lymphocytes travel in the lymphatic system, the blood, bone marrow and through the body. In Hodgkin lymphoma, mature B cells become cancerous and unusually large, with more than one nucleus. Enlarged lymph nodes are typically the first sign of disease. Non-Hodgkin lymphoma, on the other hand, can arise from B cells or T cells and first appear in lymph nodes or other organs, including the skin or bones.

Non-Hodgkin lymphoma is not a single cancer but, rather, a broad category that includes more than 60 diagnoses. DLBCL, accounting for 1 in 3 cases of non-Hodgkin lymphoma, is the most common type, followed by follicular lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma. Other subtypes include marginal zone, mantle cell, peripheral T-cell, Burkitt, hairy cell and lymphoplasmacytic lymphoma. “The major challenge is that each type should be managed individually and a little bit differently,” Flowers says.

Nearly 90 percent of patients who have DLBCL respond to the standard of care, a combination of chemotherapy and immunotherapy drugs dubbed R-CHOP: Rituxan (rituximab) plus cyclophosphamide, Adriamycin (doxorubicin), vincristine and prednisone. Furgason received R-CHOP and reaped the benefits right away. “Within five to 10 days of receiving the first treatment, I was able to stand up and walk,” she recalls.

More than 60 percent of people go into complete remission after treatment, as Furgason did, but 35 to 40 percent relapse. A small minority — just over 10 percent &mdash; don’t respond at all.

People who have follicular lymphoma, which is typically very slow growing, or indolent, might not need treatment right away — if at all. If treatment is necessary, radiation is the preferred course for stage 1 and selected patients with stage 2 disease. Rituxan alone or in combination with chemotherapy is typically used for patients with more extensive disease.

Unlike DLBCL, follicular lymphoma is very difficult to cure except in patients with early-stage disease. However, it might be years before treatment is needed and, after it is completed, years before relapse occurs. “It has a long natural history where patients oftentimes live for many, many years,” says LaCasce. “The median survival is approaching 20 years.”

Although Rituxan, approved for follicular lymphoma in 1997 and for DLBCL a few years later, represented a major advancement in lymphoma treatment, it doesn’t help everyone. “For patients with T-cell lymphomas that don’t have the marker (CD20, a cell surface protein expressed on B lymphocytes) that rituximab attacks, there’s still a dramatic need to change survival with new therapies,” says Flowers.

Of course, not everyone who is a candidate for R-CHOP responds to treatment. “There need to be approaches that are more targeted to select groups of patients who don’t do well with standard therapies,” Flowers says.

A current clinical trial, which includes people with DLBCL who are at high risk of relapse, compares R-CHOP with a regimen that replaces the chemotherapy drug vincristine with the targeted drug polatuzumab. In a previous study, 78 percent of patients had no sign of disease after completing treatment with this combination.

Polatuzumab attaches to CD79b, a protein found in high quantities on B cells, and delivers a chemotherapy drug directly into the tumor cells, causing cell death. “Other approaches look at targeted subgroups of diffuse large B-cell lymphoma and add targeted agents such as Imbruvica (ibrutinib) or Revlimid (lenalidomide) to see if that improves outcomes,” Flowers says. Imbruvica binds to and blocks Bruton tyrosine kinase, a growth-signaling protein that promotes B-cell cancers. Revlimid is a chemotherapy already used in multiple myeloma and mantle cell lymphoma.

In mantle cell lymphoma, a less common and more aggressive subtype, a recent small study found that Imbruvica and Venclexta (venetoclax) produced better results together than either drug used alone. Venclexta, a targeted therapy already approved by the Food and Drug Administration (FDA) for chronic lymphocytic leukemia, blocks a protein called BCL-2, which can otherwise prevent cancer cells from dying in lymphoma. About 20 percent of people who use just one of these drugs show no signs of disease after treatment.

When the drugs are combined, 42 percent of people treated go on to have no signs of disease.

“There (are) some very interesting-looking complete remissions that you wouldn’t necessarily expect with just the ibrutinib alone,” says LaCasce, “so, we are hopeful about some of these new drug combinations.”

Other targeted drugs show promise in relapsed non-Hodgkin lymphoma. In an early phase trial, when combined with Rituxan, the drug 5F9 (Hu5F9-G4) brought about complete remission in 36 percent of patients with relapsed DLBCL or follicular lymphoma. 5F9 blocks CD47, a protein that promotes the spread of lymphoma. The drug interacts with cancer cells and macrophages — immune cells that consume harmful or threatening cells. Cancer cells, which are masters at escaping the immune system’s built-in defense mechanisms, thwart macrophages by giving off a tailored “don’t eat me” signal. 5F9 blocks this signal so that macrophages can destroy the cancer cells. The FDA has granted 5F9 fast-track designation to treat relapsed or refractory &mdash; meaning it does not respond to standard treatments &mdash; DLBCL and follicular lymphoma.

Among the DLBCLs that don’t respond as well to R-CHOP are double-protein-expression and double-hit DLBCLs. “In the past, when people relapsed and didn’t respond to second-line chemotherapy, we had a very, very difficult time treating them,” LaCasce says. “Now we are seeing remarkable results with CAR-T cells.”

Because cancer cells are expert at evading the immune system, chimeric antigen receptor (CAR)-T cell therapy — a type of immunotherapy &mdash; involves reengineering T cells to outsmart cancer cells. T cells are removed from the body, genetically modified and cultivated outside the body to fight certain types of cancer, and then reinfused to the body to attack the disease. Two types of CAR-T cell therapies have FDA approval to treat non-Hodgkin lymphoma.

Yescarta (axicabtagene ciloleucel) is approved for aggressive, relapsed and/or refractory DLBCL; primary mediastinal B-cell lymphoma; and once indolent follicular lymphomas that transform into aggressive disease. In clinical trials, 82 percent of people responded to Yescarta, 54 percent went on to show no further signs of cancer, and 40 percent remained in remission after 15 months.

Kymriah (tisagenlecleucel) is approved for relapsed or refractory DLBCL, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma. In clinical trials, 53 percent of participants responded to treatment, with 40 percent going on to show no signs of cancer. Their responses continued after 14 months. Kymriah is also approved for patients up to age 25 with relapsed or refractory B-cell acute lymphoblastic leukemia. “These are patients for whom we previously had no good treatment options,” LaCasce says, “so this is a huge advance in the field.”

Researchers are now studying the effects of CAR-T cell therapy in mantle cell, marginal zone, lymphoplasmacytic, angioimmunoblastic T-cell and anaplastic large cell lymphomas.

“Lymphomas, because they are part of the immune system, are actually exquisitely sensitive to activation of the immune system to attack the cancer, and this is a revolutionary form of immunotherapy that does that,” Flowers says.

Although CAR-T cell therapy has dramatically improved the prognosis for many people facing non-Hodgkin lymphoma, the treatment has risks that can be lifethreatening. Once CAR-T cells are placed back in the body via IV infusion, they begin to multiply, and the recipient can develop a dangerously high fever and low blood pressure, known as cytokine release syndrome, or a “cytokine storm.”

The therapy can produce brain changes that cause confusion, seizures and severe headaches. In some cases, patients develop serious infections, low blood cell counts and a weakened immune system. As scientists actively explore and develop new ways to control CAR-T cells after infusion, doctors are learning how to manage these risks.

The greatest likelihood of dangerous side effects seems to be in people with the highest disease burden. “So, the question is, when is it best to use CAR-T cells?” LaCasce says. “When patients have minimal residual disease? Are there ways to combine CAR-T cells with other therapies to make them more effective for the 50 to 60 percent who don’t respond? This is an area under very active investigation.”

Although the prognosis for people with non-Hodgkin lymphoma continues to improve, the critical need is for increasingly personalized treatments. That means answering questions, such as when to treat indolent disease, when to use CAR-T cell therapy, who will respond to standard treatments and who is most likely to relapse.

“Hopefully, over time, we’ll better understand the biology, mutations and pathways in a patient’s disease so that we’ll know which patients will benefit from which therapies,” LaCasce says.

Targeted therapies, immunotherapies and combinations add new weapons to fight against non-Hodgkin lymphoma.

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