Immunotherapy, which uses the body’s own immune system to fight cancer, has shown great promise in helping patients with cancer live longer, with fewer of the side effects that may accompany other treatments, such as chemo&shy;therapy. Much of the excitement revolves around one type in particular: chimeric antigen receptor (CAR)-T cell therapy.

CAR-T cell therapy involves removing a patient’s T cells, re-engineering them in a lab and then putting them back into the person’s body to fight their cancer. Two of these treat&shy;ments have been approved by the Food and Drug Administration (FDA): Kymriah (tisagenle&shy;cleucel) and Yescarta (axicabtagene ciloleucel), for some adults and children with certain types of blood cancers.

, Jill O’Donnell- Tormey, Ph.D., chief executive officer and director of Scientific Affairs of the Cancer Research Institute, discussed the state of CAR-T cell therapy and what lies ahead.

: Where does the science stand for CAR-T cell therapy in patients with blood cancer?

 I think we are still in early days. We have two drugs that have FDA approval for either a pediatric population with acute lymphocytic leukemia or an adult population with relapsed/refractory non-Hodgkin B-cell lymphoma. We’ve seen initial results that the response rates have been extremely high in these hard-to-treat patient populations that have failed available treatments. People are now looking to see if these responses are long-lasting. Recent results indicate that not every patient who initially responds will continue to respond at two years, though a good number are (doing so). We need more research to understand both who will respond to CAR-T cells, as well as why some patients relapse after initially responding. We also need to determine how best to treat those patients who relapse.

It’s cautionary, and patients should try to keep this all in perspective. Many may feel like this is “the cure,” and in some patients, it has been. But it’s not a cure for everyone. The hope is that, with research, we’ll get there.

The CAR-T cell therapies available now are mostly for the same target, which is the CD19 molecule found on B-cell lymphomas and B-cell leukemias. Right there, that boxes in who is eligible for these treatments. And in most cases, at least for the approved treatments, a person has to have failed multiple treatments. CAR-T cell therapy is not yet a front-line treatment, but I think that’s where the research is going.

Do you see more approved CAR-T cell therapies on the horizon? 

Absolutely. There are other agents being tested — in a year, there has been an increase of about 113 percent in the number of cell therapies in the (research and development) pipeline, according to a global landscape report from the Cancer Research Institute published earlier this year. Chronic lymphocytic leukemia may be where we see the next approval. In multiple myeloma, several CAR-T cell therapies are aimed at BCMA (B-cell maturation antigen), which seems to be the target in this disease. There is also a lot of research going on to see if CAR-T cell therapy can be effec&shy;tive in treating solid tumors.

How do you envision the future of CAR-T cell therapy? 

We’ve proved that certain patients can have amazing responses. Emily Whitehead is the poster child — she was the first pediatric patient to be treated with CAR-T cell therapy &mdash; and she is still in total remission, now more than six years out. So there is great potential for CAR-T cells, but we have to figure out why not every patient responds the way Emily did.

CAR-T cells will be one of the options for patients with hematological malignancies and, potentially, solid tumors going forward. In most of these cases, the patient gets one treatment — one infusion &mdash; and this yields some remark&shy;able results, so that makes this treatment very appealing. If we could figure out how to get more people to respond to this and move it to the front line, that could have an amazing effect on patients’ lives. The results to date show just how powerful immunotherapy can be, and now we must figure out how to harness it for more patients.

, is chief executive officer and director of scientific affairs of the Cancer Research Institute (CRI), a nonprofit organization founded in 1953 that is today the global leader in supporting and coordinating research aimed at harnessing the immune system’s power to conquer all cancers. Prior to joining CRI, she served as a research associate in the department of medicine at Cornell University Medical College and as a postdoctoral fellow in the laboratory of cellular physiology and immunology at The Rockefeller University.

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An expert describes how far the field has come, with two treatments approved and more in the works.

The State of CAR-T Cell Therapy

In 2010, while finishing up his sophomore year at St. John’s University in Queens, New York, Jordan Segal signed up to be a bone marrow donor to help a friend who was running a drive. Segal now admits he had no idea what placing his name on that list truly meant.

Fast-forward a year to when Segal, then 21, received a life-changing phone call: He was a potential match. “That’s kind of when reality sunk in,” Segal said in an interview with 

. “Because I made the decision and didn’t think much of it, suddenly it became a much bigger choice.”

He asked for time to think it over. “I started doing research and got a little nervous because I saw stuff about bone marrow and I had misconceptions,” he said. “I thought it would be super painful.”

Hours after Jordan Segal donated his stem cells on Christmas Eve 2011, the recipient received his transplant.

With some advice from his mom, a nurse manager of an oncology unit in Rhode Island, Segal chose to donate his stem cells. Before he could undergo the procedure, Segal had blood drawn to make sure he was healthy and the best match. Four days before the stem cell retrieval, Segal was injected with a synthetic protein to help boost the amount of stem cells in his blood. On Christmas Eve 2011, with his mother and grandmother by his side, he donated his stem cells, an outpatient process that lasted eight hours. “I felt like I had to step up,” Segal says. “It was an experience that humbled me and made me focus on how I can contribute to my community.”

That experience changed the course of his life. Segal now works for DKMS, an international nonprofit organization dedicated to fighting blood cancer and blood disorders. As a recruiter, he feels he is making a difference and creating hope for people in need of a lifesaving transplant. Founded nearly 30 years ago by Peter Harf, Ph.D., when he lost his wife to leukemia, DKMS has registered more than 8 million potential donors worldwide. The organization focuses on quality over quantity when recruiting potential donors. “We try to educate people and help them understand what they are signing up for,” he said.

Segal along with members of DKMS College Ambassadors attend a conference in Orlando, Florida.

Segal is also part of the patient engagement team that determines where the organization can support patients with their particular needs. For example, he worked on a project that created Sunny the Bear to visit sick children and help them better understand what they were about to go through.

“Finding a match at one particular drive is rare, but it’s about the collective whole,” Segal said. “While one drive is happening, so are others all over, and a potential match may be found there.”

Although he has never met the man whose life he saved, Segal received a letter from him two years after the donation. He learned that the man was a fit 50-something retiree who had been traveling and working with charities when he received a leukemia diagnosis. Hours after Segal donated his stem cells, they were transferred to the recipient, who experienced infections for about six months after the transplant. He was now doing well, he wrote, and planned to resume his travel plans.

“He thanked me for giving him his life back,” Segal recalled. “At the end of the day, I didn’t do it for recognition or gratitude — I did it for the sake of humanity.”

The Advocate

Following a stem cell donation through an international organization, one man works to recruit others to help save lives.

Stem Cell Donation: The Circle of Life

 of child and adolescent patients with advanced-stage Hodgkin lymphoma are vulnerable to productiv&shy;ity loss at work, according to phase 3 trial findings.

Researchers defined productivity loss as “a measure of work engagement; spe&shy;cifically, missed time and/or altered per&shy;formance, experienced by parent caregiv&shy;ers of children with cancer.”

The participating caregivers, who were an average age of 43.8 and mostly women, were asked to complete the Caregiver Work Limitations Questionnaire and the Child Health Ratings Inventories- Global Health measure before the start of their children’s therapy.

Researchers explained that the ques&shy;tionnaire quantifies the percentage of time respondents had difficulty perform&shy;ing four key aspects of work because of caregiving: physical, mental-interperson&shy;al and output tasks and time manage&shy;ment. The 10-item inventory measures the child’s health-related quality of life (HRQL), based on the parent’s responses.

Nearly 300 parents completed the two sets of questions; of those, 159 reported working at a paying job and thus were eligible to complete the remainder of the study. All patients were newly diagnosed; most were boys with an average age of 15. The mean HRQL score was 65.2.

Based on the participants’ self-report&shy;ing, researchers determined that care&shy;giving disrupted work tasks at least 31.4 percent of the time. The average amount of disrupted time for mental-interper&shy;sonal tasks, output tasks and time man&shy;agement, as well as productivity loss, was higher in caregivers of children with HRQL scores in the lowest quartile com&shy;pared with caregivers of children with higher scores.

“High productivity losses noted at initial diagnosis indicate that financial hardship begins prior to the start of cancer treat&shy;ment,” the researchers wrote.

Productivity loss among parent caregivers associated with poor health-related quality of life in pediatric advanced stage Hodgkin lymphoma. 

Parent Caregivers Face Decreased Job Productivity

Treating younger patients with low-risk diffuse large B-cell lymphoma (DLBCL) with two fewer front-line cycles of standard treatment greatly reduced toxicity without sacrificing effi&shy;cacy, according to findings from the FLYER trial.

Patients with DLBCL typically receive Rituxan (rituximab), cyclophosphamide, doxorubicin (hydroxydaunomycin), Oncovin (vincris&shy;tine) and prednisolone, a regimen known as R-CHOP. Researchers randomly divided nearly 600 patients aged 18 to 60 to receive either six cycles of R-CHOP or four cycles of R-CHOP followed by two cycles of Rituxan. Of those patients, 588 were evaluable for the efficacy analysis. The patients were enrolled at sites in Germany, Denmark, Norway, Italy and Israel and had similar demographics, according to the researchers.

At a median follow-up of 66 months, the three-year progression-free survival (PFS) rate—how long patients lived without disease worsening&mdash;was 94 percent for patients who received R-CHOP for all six cycles compared with 96 per&shy;cent in those who received R-CHOP followed by Rituxan. The three-year overall survival rates &mdash; length of life after diagnosis or start of treatment &mdash; at a median follow-up of 67 months were 98 percent and 99 percent, respectively.

The patients who received six cycles of R-CHOP experienced more total side effects than those who got four cycles — 1,295 versus 835, respectively. This included 70 versus 46 severe (grade 3 or 4) nonhema&shy;tologic side effects. Severe hemato&shy;logic side effects included low white blood cell and blood platelet counts and anemia.

“With a shorter duration of che&shy;motherapy, patients are back to daily life with their families and back to work more quickly,” said lead study author Viola Poeschel, M.D., of Saarland University Medical School in Homburg/Saar, Germany. “Our study shows you can spare two cycles of chemotherapy and it is equally effec&shy;tive. We think this will be the new standard treatment for this patient population.”

Conference Coverage

Treating younger patients with low-risk diffuse large B-cell lymphoma (DLBCL) with two fewer front-line cycles of standard treatment greatly reduced toxicity without sacrificing effi&shy;cacy.

Reduced Treatment Proves Safer and Just as Effective in Younger Patients With Diffuse Large B-Cell Lymphoma

When Linda Tedone sought medical advice for pain in her back, knees and shoulders, her primary care physician attributed her discomfort to the typical aches and pains of aging. Tedone’s condition worsened significantly over the course of a year, however — at one appointment in 2015, she screamed in pain during an exam. Her doctor ordered an MRI, which revealed three lesions on her spine. Biopsies confirmed Tedone’s worst fear: She had multiple myeloma, a type of blood cancer that cannot be cured.

“I was terrified,” says Tedone, 63, of Belchertown, Massachusetts. “When I heard the word ‘cancer,’ I thought I was going to die.” After her husband and children searched online to learn more about the disease, it quickly became clear that the field of multiple myeloma research was burgeoning with innovative biotechnology and new treatments. Her oncologist at Baystate Medical Center in Springfield, Massachusetts, suggested that she enroll in a clinical trial that would allow her to start treatment with Kyprolis (carfilzomib), a drug that had been approved by the Food and Drug Administration (FDA) only for relapsed patients who had tried other therapies. Kyprolis, a proteasome inhibitor, stops enzyme complexes in cancer cells from breaking down excessive proteins generated by cell division, thereby choking cellular function.

Tedone started taking Kyprolis in combination with Revlimid (lenalidomide), an immunomodulatory agent, and dexamethasone, a corticosteroid. “I responded well and had no side effects,” Tedone says. “But the cancer was aggressive, and the treatment stopped working after six months.” She underwent a stem cell transplant, and the disease was in remission for almost a year. When it returned, she started a combination that included a different proteasome inhibitor and immunomodulatory agent, but after eight months, her body started aching and a lesion on top of her head grew to the size of a baseball.

Tedone was losing hope in fall 2018, when her doctor recommended she see an oncologist at Dana-Farber Cancer Institute in Boston. Nikhil Munshi, M.D., director of basic and correlative science at the Jerome Lipper Multiple Myeloma Center, introduced an option that was showing promise in clinical trials: chimeric antigen receptor (CAR)-T cell therapy. The treatment involved engineering Tedone’s T cells to target a protein on the myeloma cells called B-cell maturation antigen (BCMA). A week after treatment, the tumor on her head had shrunk to the size of a raisin and a tumor in her jaw was gone. “They saw no cancer in my blood or bone marrow,” she says. “It really was a miracle.”

In the past, patients with aggressive multiple myeloma — like Tedone &mdash; would have quickly run out of treatment options, but that has changed in recent years. “I’ve actually been amazed by the number of advances we’ve had,” says Jeffrey Zonder, M.D., a myeloma specialist at the Barbara Ann Karmanos Cancer Institute at Wayne State University in Detroit. “It’s easy to argue that there are no areas of cancer that have seen more progress than multiple myeloma in the last 10 years.”

Adding Monocolonal Antibodies to the Combination

Vicki Watkins received a multiple myeloma diagnosis in 2014 after a urine test showed high levels of protein.

Multiple myeloma is relatively uncommon, with a lifetime risk of 0.76 percent and about 30,000 new cases diagnosed each year in the United States. This form of cancer, which is usually found in people over 65, starts in the plasma cells in the bone marrow. When these cells grow out of control, people with the disease may experience weakness from anemia and pain related to fractures in the bones as myeloma cells release substances that lead to the breakdown of bone and crowd out other substances that form new bone. Symptoms may also include acute and worsening kidney function, which can result in fatigue, discomfort or swelling of the legs.

To diagnose the disease, a physician may order a complete blood count to measure levels of red cells, white cells and platelets. Low levels of these blood cells can be a sign that myeloma cells are growing out of control. Blood chemistry labs test for creatinine, calcium and albumin to find other indicators of myeloma. A physician may also order blood or urine tests to look for excess production of certain antibodies produced by malignant cells. The cancer is then assigned a stage using the Revised International Staging System, which is based on four factors: the amount of albumin, beta-2-microglobulin and lactate dehydrogenase in the blood, as well as the specific gene abnormalities of the cancer.

After staging, the physician addresses the possibility of a stem cell transplant. Factors such as age and heart and lung function help determine a patient’s eligibility for the procedure, says Kenneth Shain, M.D., Ph.D., a myeloma specialist in the departments of malignant hematology and tumor biology at Moffitt Cancer Center in Florida. Before undergoing a transplant, patients in the U.S. typically receive a combination known as VRd — the proteasome inhibitor Velcade (bortezomib), Revlimid and dexamethasone &mdash; in four to six cycles, according to Shain. “VRd and other induction therapies for myeloma are much more effective and less toxic than the chemotherapies we used in the past,” he says. “It is the combination of these drugs that makes them so successful.”

Most patients experience minimal side effects, but physicians and patients still need to be aware of potential issues. Velcade can cause peripheral neuropathy and injection site reactions; it can also increase the risk of shingles, which might be avoided by taking antiviral medications prophylactically, Shain says. Revlimid can sometimes cause fatigue, rash and gastrointestinal side effects, and dexamethasone can cause symptoms such as insomnia, agitation, weight gain and gastritis.

More recently, studies have shown the benefits of adding monoclonal antibody drugs to these combination treatments. Darzalex (daratumumab), for example, targets the CD38 protein in myeloma cells, flagging them for destruction by the immune system. In May 2018, the FDA approved Darzalex in combination with Velcade; prednisone, a corticosteroid; and melphalan, a type of chemotherapy, for patients who recently received a diagnosis of multiple myeloma and are ineligible for a stem cell transplant. The approval was based on findings that showed that adding Darzalex to the combination reduced the risk of progression or death by 50 percent. A recent study also showed that combining Darzalex with Revlimid and dexamethasone reduced the risk of disease progression or death by 45 percent compared with Revlimid and dexamethasone in patients with new diagnoses and who are not eligible for a stem cell transplant.

Monoclonal antibodies often have fewer side effects compared with conventional chemotherapy drugs because they target proteins on myeloma cells that are not expressed extensively on other tissues of the body, which is one reason researchers are testing whether adding these medications to existing three-drug combinations can benefit patients, says Peter Voorhees, M.D., a myeloma specialist at Levine Cancer Institute-Morehead in North Carolina. In December 2018, Voorhees presented findings of a safety study that tested a combination of Darzalex, Velcade, Revlimid and dexamethasone in patients with new diagnoses who are eligible for stem cell transplants. Researchers found that all the patients achieved a very good partial response — a 90 percent reduction of the disease burden (measuring myelomasecreted proteins in the blood or urine) &mdash; to the fourmedication therapy. Fifteen of 16 patients achieved a complete response, meaning there is no evidence of disease, as their best response, and the side effects were manageable.

Selinexor, an oral drug not yet approved by the FDA, is also generating excitement: Study findings show that it can extend life for patients who cannot tolerate or have progressed after five other FDA-approved medications, which is known as penta-refractory multiple myeloma. One way cancer cells proliferate is by escaping mechanisms that normally control cell growth, and this drug traps tumor suppressor proteins within the nucleus of cancer cells, forcing them to stop growing or die. Recent study results showed that the drug had an overall response rate of 26.2 percent in penta-refractory patients, and the median response time was 3.7 months. The results led the FDA to expedite the approval process for the drug, which is now under review.

Venclexta (venetoclax) also shows promise for patients with relapsed/refractory multiple myeloma. Researchers discovered that patients with the disease who test positive for a particular chromosomal rearrangement often respond well to Venclexta, which works by inhibiting the BCL-2 protein in myeloma cells. “Cancer cells take advantage of a mechanism that signals the cells to keep them from dying, but this drug blocks that signal,” says Andrew Kin, M.D., an assistant professor of oncology at Karmanos Cancer Institute. Clinical trials are underway to test the potential benefits of combining Venclexta or Selinexor with other approved therapies.

Patients are also increasingly taking advantage of clinical trials that are testing other monoclonal antibody-based approaches for the treatment of multiple myeloma, such as antibody-drug conjugates. “These monoclonal antibodies have a warhead, or chemotherapy, attached to them,” Voorhees says. “When they bind to myeloma cells, not only do they engage the immune system to go after the cancer, but (also) the antibody is taken up by the myeloma cell. This allows the chemotherapy drug to be directly released inside the cell, maximizing tumor cell kill and minimizing side effects. It is like a Trojan horse-based approach to therapy.”

Clinicians and patients have also been impressed with the success of CAR-T cell therapy in recent clinical trials. “I’ve been an oncologist for 30 years, and I have never seen something that works so well, so quickly,” says Munshi, who is involved in a clinical trial for this therapy. “Patients are having an amazing response rate within weeks, and these are people who had no hope.”

In this form of therapy, patients’ T cells are separated from their blood and sent to a lab, where they are genetically modified and multiplied. The altered cells, which can better recognize and kill cancer cells, are then re-infused into the patient’s bloodstream.

“One potential benefit of this therapy is that we don’t have to keep redosing patients like other treatments,” Zonder says. “In some cases, the cells can persist in the patient’s system for an extended period of time.” However, he cautions, the cell therapy is associated with inflammatory reactions, such as potentially lifethreatening cytokine release syndrome and neurological complications.

Vicki Watkins, 62, experienced severe side effects from CAR-T cell therapy, but she says the benefit of a longer life has outweighed the disadvantages. Watkins, of Orlando, Florida, discovered she had multiple myeloma in 2014 after a urine test during a routine physical exam showed high levels of protein. At the time, she was working as a bus driver for Walt Disney World and felt no symptoms, but her primary care physician referred her to a specialist. Results from blood tests and a bone marrow biopsy made it clear that she had multiple myeloma.

Under the care of Shain, she tried four drug combinations but relapsed after six to eight months on each regimen. “My biggest prayer during that time was that I would not have nausea and could work,” she says. “The only symptom I experienced was fatigue, and I learned to listen to my body and get more rest.”

In early 2018, Shain told her that a slot was available in a clinical trial for CAR-T cell therapy. Watkins was aware of the potential side effects and benefits, and in February 2018 she started the treatment process. Watkins recalls that three days after the infusion of engineered T cells, she heard the medical team explain that she was cancer-free, but soon after that, she started losing her balance and her thyroid stimulating hormone levels skyrocketed. She went into a coma for two months, and when she woke up in April 2018, her muscles had atrophied to the point that she could not walk, and she struggled to vocalize her thoughts.

After months of physical therapy, Watkins relearned how to walk and her speech improved; recently, she felt strong enough to walk through Disney World with her husband and friends for the first time in months. Although she still struggles to maintain her balance and speak as quickly as before, Watkins has no regrets about her decision to enroll in the clinical trial. “I was in the right place at the right time,” she says. “I would not be here without CAR-T therapy. It saved my life.”

Patients with multiple myeloma find relief from side effects, thanks to newer drug combinations.

Power in Numbers

Kevin Richards with his wife, Dale, is living with IgM multiple myeloma, a rare subtype of the disease.

After Kevin Richards received a diagnosis of IgM multiple myeloma, a rare subtype of the disease, in August 2009, he was treated successfully with a standard chemotherapy regimen, followed by a bone marrow transplant. Then, to reduce the risk of relapse, his oncologist put him on a low dose of Revlimid (lenalidomide), an immunomodulatory drug, monitoring him monthly the first year, and bi-monthly the second year with blood or bone marrow tests that can find minuscule amounts of cancer long before they would show up in any other routine test. Testing for traces of cancer, or minimal residual disease (MRD), is becoming part of the standard of care in multiple myeloma, and it’s starting to catch on in the treatment of several other blood cancers, too. MRD tests give oncologists the opportunity to detect cancer cells hiding out in the body and try to eliminate those cells before they explode into a full-blown relapse.

Richards’ MRD test came up clear in 2012, prompting his oncologist to take him off Revlimid for good. Every MRD scan since has been clean — a huge relief to Richards, 65, who works as an estate planner in Paso Robles, California. Richards used to call “relapse” a four-letter word, he says. “That’s what’s hanging over a patient’s head. With MRD testing, I know my doctors will find out early enough to make the next set of treatments more effective and easier for me,” Richards says. “For a myeloma survivor, that is a huge relief. It allows me not to just exist, but to get involved with my regular activities, pursuits and passions.” MRD can be measured using a variety of technologies. A cell-counting tool called flow cytometry can find one tumor cell in 10,000 cells in bone marrow samples. A more advanced technology, polymerase chain reaction testing, can pick out one cancer cell in 100,000 cells. “Now we are entertaining multiple MRD technologies that might even be able to measure one cancer cell out of one million cancer cells,” says Luhua “Michael” Wang, M.D., a professor of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center in Houston.

What’s more, advanced MRD tests can reveal details about the remaining cancer cells that point oncologists to personalized treatments, Wang says. “This is a huge advantage, not only to detect when the disease is starting to come back, but also to track its evolution,” he says. “We’ll know which mutations are in the cells. That means we’ll know at a very early stage whether the relapse will be sensitive to (targeted) treatments.”

In October 2018, the Food and Drug Administration (FDA) approved the first test that can do just that: clonoSEQ, for monitoring patients with multiple myeloma or acute lymphoblastic leukemia (ALL). What makes it different from other technologies for monitoring MRD is that it identifies specific gene sequences in T and B cells — immune cells in the blood that have become cancerous. That lowers the amount of MRD that the test can detect to the coveted one-in-a-million level, in addition to revealing changes in cancerous mutations over time.

The FDA approved the test based on data from 273 patients with ALL and more than 1,000 with multiple myeloma. Patients who were MRD negative when tested with clonoSEQ had longer event-free, progression-free and disease-free survival rates than those with measurable MRD.

Several trials are examining whether clonoSEQ can improve the monitoring of patients with other types of blood cancer. For example, Memorial Sloan Kettering (MSK) Cancer Center in New York City is leading a trial of the technology in predicting relapses in aggressive B-cell non-Hodgkin lymphoma. The study, which will enroll 500 patients who have already undergone treatment, will assess whether clonoSEQ better detects MRD than traditional methods like CT scans, physical exams and symptoms reported by patients.

When monitoring patients with blood cancers for MRD that can’t be detected by clonoSEQ, oncologists select the technology that’s best suited to the patient’s diagnosis. In acute myeloid leukemia (AML), for example, a technology called multi-parameter flow cytometry is gaining ground, says Mary-Elizabeth Percival, M.D., assistant professor at the University of Washington and assistant member at Fred Hutchinson Cancer Research Center in Seattle. It uses fluorescent antibodies to label and count cells based on specific immunophenotypes, or abnormalities in patients’ cancers, before treatment. “Once (abnormalities) are characterized, they can be measured post-treatment,” Percival says. “It’s an extremely sensitive test.” It’s also a major improvement over older tests that merely count cancerous blood cells in bone marrow, she adds.

The increasing ability to personalize MRD testing helps oncologists better predict which patients are most likely to relapse. A 2016 study of patients with AML who underwent bone marrow transplants between 1988 and 2013 examined a commonly used polymerase chain reaction test for detecting MRD based on a single gene that’s overly active in most patients. That test was just 14 percent effective at predicting relapses. But in patients whose MRD was measured based on several genetic abnormalities that were detected using multi-gene panels, those who were MRD negative after transplant had no relapses in the first year. By contrast, there was an 83 percent relapse rate among patients who were MRD positive after transplant, as determined by the more sensitive MRD test.

MRD tracking is becoming more prevalent in clinical trials, and the results can provide valuable information for oncologists treating blood cancers. For example, one trial tracked patients with multiple myeloma who were treated with either two drugs or three drugs to prevent relapses after achieving MRD negativity. The three-drug regimen was superior. But after the primary endpoint of the study was reached, researchers noticed that some patients who got the less aggressive treatment had outcomes — namely MRD negativity &mdash; similar to those who received three drugs. And all patients who were MRD clear had similar progression-free survival regardless of which treatment they received.

That’s important insight, particularly for treating patients who may not be able to tolerate the more aggressive three-drug therapy, says Ola Landgren, M.D., Ph.D., chief of the myeloma service at MSK. “MRD negativity appears to be more important than what therapy that was given to reach MRD negativity,” he says. “Genomically, multiple myeloma is a very heterogenous disease, so it is not unexpected that some patients with (less aggressive) disease could achieve negative MRD with less active therapy. We are seeing the exact same patterns in newly diagnosed patients with multiple myeloma; modern combination therapy can deliver high rates of MRD negativity in the absence of bone marrow transplant and data suggest that MRD negative patients — with or without transplant &mdash; have the same progression-free survival and overall survival. The multiple myeloma treatment field is changing very fast.”

The idea of monitoring and treating MRD has been slow to catch in the realm of some blood cancers — most notably, Hodgkin lymphoma. But several clinical trials underway could help change that, says Alex Herrera, M.D., an assistant professor of hematology at City of Hope in Los Angeles. Most patients can be cured, but when Hodgkin lymphoma does recur, positron emission tomography (PET) scans often fail to detect it, he says. “There are very few malignant cells in a (Hodgkin lymphoma) tumor, so it’s been difficult for many years to figure out how to test for MRD,” Herrera says. “Now sequencing-based technology looks like it could be a powerful tool.”

One emerging technology that Herrera is watching closely is cancer personalized profiling by deep sequencing (CAPP-Seq), which tests the blood for tiny bits of genetic material that cancer cells release as tumors grow. Developed at Stanford University, the tool can detect multiple genetic mutations in a tumor and track them over time. In a study published in 2017, CAPP-Seq detected relapses in the most common type of non-Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), more than six months earlier than PET/CT scans could.

In another study — this one involving patients with Hodgkin lymphoma &mdash; a group of scientists led by the Institute of Oncology Research in Switzerland demonstrated that CAPP-Seq could not only detect MRD early but also be used throughout therapy to track how tumors were evolving over time.

Such precise MRD testing could help fine-tune treatment strategies, Herrera says. “CAPP-Seq can investigate hundreds of mutations at the same time, which allows us to track a patient’s disease,” he says. For example, some patients with B-cell lymphomas are treated with the targeted drug Imbruvica (ibrutinib), which inhibits an enzyme that causes B cells to grow out of control. CAPP-Seq can detect the formation of genetic mutations that cause patients to become resistant to the drug. “That could be used to guide decision-making about how to treat the disease going forward,” Herrera says.

With MRD testing, oncology researchers have turned to a pressing question: Once MRD has been detected, what is the best way to clear the remaining cancer cells and lessen the probability of a relapse? Several therapies are being explored in clinical trials aimed at clearing MRD, including targeted drugs and engineered cell treatments that are intended to boost the immune system’s ability to recognize and defeat cancer.

Percival is leading a trial of Mylotarg (gemtuzumab ozogamicin), an antibody attached to a cancer-fighting compound. The drug was initially approved to treat some patients with AML but was removed from the market due to safety concerns. It was re-approved in 2017 with different dosing recommendations for patients with new diagnoses or who had relapsed, and now Percival hopes to learn if it might also prevent relapses in patients with AML who also are MRD positive. Trial participants are receiving the drug intravenously three times a month, after which they will be followed for six months.

Rituxan (rituximab) is also in clinical trials for treating MRD in several types of lymphoma, including mantle cell and follicular lymphoma. In one study, the drug was shown to clear MRD in patients with mantle cell lymphoma who relapsed after undergoing drug treatments and bone marrow transplants.

In March 2018, the FDA approved Blincyto (blinatumomab) to treat patients with B-cell precursor ALL who are in remission but are MRD positive, marking the agency’s first approval of an ALL drug based on MRD status. In a clinical trial, 70 of 86 patients returned to MRD-free status after being treated with the drug. More than half of the participants were still in remission nearly two years later. Ongoing trials are investigating whether Blincyto is equally effective at clearing MRD in patients with other blood cancers, including DLBCL.

As MRD testing evolves, many oncologists hope it will point to treatments that can prevent relapses and at the same time allow patients to maintain a good quality of life. MSK recently opened a clinical trial that is recruiting patients with multiple myeloma who achieved MRD-negative status and were put on Revlimid but later converted back to MRD-positive status. Participants will stay on Revlimid and receive an additional six months of another multiple myeloma drug, Darzalex (daratumumab), to see if very early and short-term treatment can return them to MRD-free status.

Several trials are examining personalized cell therapies for treating MRD in different blood cancers. Fred Hutchinson is recruiting for one such trial, designed for patients with high-risk AML, many of whom have MRD and are not currently candidates for bone marrow transplant. The trial involves removing the immune system’s T cells from patients’ blood, then engineering them so they can recognize WT1, a molecule produced by leukemia cells. T cell receptor (TCR) therapy is similar to chimeric antigen receptor (CAR)-T cell treatment used in some blood cancers. But instead of targeting protein markers on the surface of cancer cells, like CAR-T therapy does, TCRs are engineered to recognize telltale markers inside of the cells. The Fred Hutch investigators hope to find that when the TCRs are put back into the body, they will home in on leukemia cells and kill them.

Deborah Sims with her children, Cameron, 14, Natasha, 9, and Marlowe, 12, who were only 7, 2 and 5, respectively, when she received her diagnosis and was given five years to live. She says every year is a blessing.

Advances in MRD testing are benefiting patients like Deborah Sims, who received a diagnosis of chronic lymphocytic leukemia (CLL) in 2011 and was found to be MRD positive after undergoing a standard chemotherapy regimen. In 2015, Sims enrolled in a clinical trial of Venclexta (venetoclax), which inhibits BCL-2, a protein associated with cancer cell survival and chemotherapy resistance. Sims traveled to London from her home in Melbourne, Australia, to get the drug. A little over a year after she started the trial, her MRD test showed she was clear of her disease, and she has been on Venclexta ever since — an easy regimen of four pills a day that have not caused her any side effects, she says.

In September 2018, the FDA updated Venclexta’s label to include MRD data. More than half of patients treated with a combination of the drug and Rituxan were MRD negative after nine months compared with 12 percent of patients taking a standard treatment of Rituxan with the chemotherapy drug bendamustine.

MRD results can help physicians and patients work together to figure out the best time to stop treatment altogether. Sims has been MRD negative for three years and continues to have her blood checked every two months for signs of the disease. Even though some research suggests that patients with CLL can stop treatment after testing negative for MRD, Sims opted to continue taking Venclexta. “I hope this is a cure. It’s looking good,” says Sims, 45, a mother of three who works for a public policy think tank. “But I like taking my four tablets a day. It’s a safety net.”

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