NEVER IN THEIR WILDEST dreams would immunologists from the last generation have imagined chimeric antigen receptor (CAR)-T cell therapy coming to light. The very notion of genetically engineering a T cell to recognize a tumor antigen would have been viewed almost as a pipe dream.

But, in 2018, this is an exciting, new cancer treatment reality that brings much hope to patients who may have felt their options had ran out. With two Food and Drug Administration approvals for CAR-T cell therapy at the end of 2017, the way in which certain pediatric and adult patients with relapsed or refractory blood cancers are treated has changed. Moreover, the cancer-fighting T cells stay around and multiply if they encounter wayward and recurrent tumor cells over time. Although CAR-T cell therapy shows great promise, it also comes with concerns.

First, it requires new technology in gene splicing, which involves cutting the DNA of a patient’s T cell and inserting a gene. It is crucial to make sure that the gene is not accidentally inserted in the wrong place and, in turn, induces a malignant transformation, something that set back the field of oncology in the past with gene transfer studies.

Then there are the side effects associated with CAR-T cells. The most serious is cytokine release syndrome — a “cytokine storm” &mdash; that can be life-threatening. Signs of this include fever, nausea, headache and rash. Other serious side effects range from changes in the brain that cause confusion or seizures to low blood cell counts. And although these side effects can be managed, will the future hold better ways to monitor and treat them? It’s also key to note that researchers are still studying the long-term effects.

Another drawback is that CAR-T cell therapy is the new poster child for runaway drug costs. Kymriah (tisagenlecleucel), the pediatric regimen, runs $475,000, and Yescarta (axicabtagene ciloleucel), approved for adults, is priced at $373,000.

Will society be able to cover the bill if this therapy is expanded into more common solid tumors? There is some hope that, rather than using the patients’ T cells and the laborious process of modifying them, off-the-shelf CAR-T cells not derived from the host will succeed the current generation. Only time will tell. For now, let’s revel in the revolutionary idea that was brought to life. A big success often generates a string of follow-up innovations that make it more feasible and accessible to all.

Chair, Department of Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

Articles

Editor's Page

Never in their wildest dreams dreams would immunologists from the last generation have imagined chimeric antigen receptor (CAR)-T cell therapy coming to light. The very notion of genetically engineering a T cell to recognize a tumor antigen would have been viewed almost as a pipe dream.

CAR-T Cell Therapy: What We Never Dreamed Of

DIET AND SUPPLEMENT USE can help alleviate some of the symptom burden experienced by patients with myeloproliferative neoplasms (MPNs), according to a study conducted by Mayo Clinic researchers.

Patients with MPNs have increased inflammatory cytokines, which contribute to symptoms such as fatigue, night sweats and bone pain, as well as low cholesterol and weight loss related to nutritional deficiencies.

To examine the habits, needs and preferences among this population, researchers used an internet-based survey through the Mayo Clinic Survey Research Center and promoted it on many MPN-focused websites and communities in February 2017. The survey included data on demographics, disease characteristics, nutritional habits, supplement use and symptom burden using the Myeloproliferative Neoplasm Symptom Assessment Form and Total Symptom Score.

The 1,329 patients who responded to the survey represented 37 countries and had the following types of disease: myelofibrosis, 24 percent; polycythemia vera, 37 percent; and essential thrombocythemia, 38 percent. Of those patients, 1,131 consented to taking the survey. The average total symptom score was 31.

Survey results showed that 34 percent of patients endorsed using diet to help control their symptoms or disease, 23 percent had food allergies or intolerances and 31 percent followed a specific or restricted diet.

Nearly all patients who responded (96 percent) said they would be willing to eat only certain foods if it helped to control symptom burden, stabilize their disease or reduce the risk of it worsening (98 percent). Over-the-counter supplements were used by 72 percent of patients, more often by women (74 percent) than men (66 percent).

Supplement users also were more likely to be older, have lower self-reported body mass index and engage in at least 30 minutes of physical activity.

Lower symptom score was associated with alcohol intake, baked foods, dairy and pasta; higher score, with fast food, premade snacks, soda and refined sugar. Symptom burden was significantly lower among patients using amino acid supplements and N-acetylcysteine, but significantly higher in those taking Bach flower remedies. 

Editor’s Note: This article originally reported on study results from the American Society of Hematology Annual Meeting. After it was posted, it was brought to CURE’s attention, the conclusions were to be amended, and reflective upon the survey results presented. While nutritional change may be a potential strategy to improve symptom burden and inflammation in this patient population, no causal relationship has been confirmed through this study. The researchers are currently undertaking efforts to look at the role of prospective dietary change in symptom burden.

Features

Nutritional change may be a potential strategy to improve symptom burden and inflammation in patients with MPNs, whohave increased inflammatory cytokines, which contribute to symptoms such as fatigue, night sweats and bone pain, as well as low cholesterol and weight loss related to nutritional deficiencies.

Patients with MPNs Willing to Alter Diet, Supplement Use to Alleviate Symptoms

LAST YEAR, A DEAR friend received a cancer diagnosis and gave me a call. “Do you think I should put it on Facebook?” she asked. Her sister had suggested that by sharing updates about her planned surgery, she could efficiently keep people — friends, neighbors, cousins and selected colleagues &mdash; in the loop about her condition.

“Think before posting,” I advised. Social media does have its advantages for patients. “But once you post about your medical condition, you can’t take it back.” Besides, there’s a lot of misinformation out there. People will offer all kinds of advice.

Since I became a journalist in 2009, online resources for health have proliferated. Dozens of websites sponsored by government agencies, like the National Institutes of Health and Centers for Disease Control and Prevention, or run by disease-oriented nonprofit organizations, offer vetted facts and definitions, research updates, statistics and news of clinical trials.

Through disease-specific Facebook pages and Twitter hashtags, it’s easier than ever to connect with peer patients and caregivers. In Facebook groups, members trade tips for coping with hematological conditions including sickle cell disease, multiple myeloma and low platelets.

Social media facilitates ties between patients that tend to grow over time and may even be life-saving.

For people living alone or in rural areas, web ties represent more than a source of health information; these connections foster camaraderie and, surprisingly often, true friendships emerge. In recent years, I’ve seen patients and advocates gather at medical conferences; as online acquaintances meet in real life and spend occasional days together, the sense of caring and trust — between patients and within their virtual communities &mdash; becomes genuine and stronger.

Some patients choose to follow expert physicians on Twitter; a trusted doctor or hospital may indeed be one of the more reliable sources of online information about health. Yet sometimes it’s patients who take the lead in distributing careful updates. Social media posts, such as about a new blood thinner or lymphoma drug, may prompt patients to ask better questions of their providers and, in that way, lead to better care.

Web connections do carry risks, however. On the internet, anecdotes abound. Individuals’ stories may disproportionately affect others’ treatment choices. When a patient reports doing well on a new drug or in a clinical trial or enters remission, their improvement can spark a feel-good moment in their network. Conversely, news of someone entering hospice or dying can reverberate with unexpected depth, stirring sadness.

Fake news about health spreads on social media, just as it does for other topics. Doctors disagree; what one clinician calls a terrific new drug might be deemed dangerous by a colleague. Yet by following conversations among physicians, ordinary people may gain a better sense of legitimate medical debates that previously took place behind closed doors. Now, those discussions about data and evidence are exposed for all to read. This kind of information can be both confusing and illuminating.

Consider the loss of privacy. A man with chronic leukemia, for instance, might post enthusiastically about finding a doctor he likes and responding to medication. A few years later, perhaps when looking for a new job or partner, he may regret his prior openness.

Telling “the world” of your illness can yield sympathy and connections, but it cannot be undone. Joanna Fawzy Morales is a Los Angeles attorney who co-founded the nonprofit patient advocacy organization Triage Cancer with her sister, Monica Fawzy Bryant. The siblings aim to raise awareness of patients’ legal rights, including privacy and workplace concerns. Last June, I heard Morales speak before hundreds of cancer survivors at a Cancer and Careers meeting in New York City.

“What you post online can affect others besides you,” Morales said. She shared the cautionary tale of a woman who posted on Facebook that her daughter had breast cancer. The daughter, in her 30s, wasn’t keen on publicizing her diagnosis. Other, less obvious sources of lost privacy include having your name listed in disease-related charity events or being tagged in fundraising photos.

In the end, my friend elected not to share her diagnosis on social media. “I’m glad I held back,” she told me later. “I value my privacy too much. If I want to tell people, I can let them know by phone or email.” It’s each patient’s decision. As with almost any medical intervention, there are benefits and risks to consider.

Speaking Out

A retired oncologist and survivor talks cancer in a digital world.

For Patients, Social Media Provides Perks and Perils

PATIENTS WITH CHRONIC LYMPHOCYTIC leukemia (CLL) are willing to accept a shorter duration of progression-free survival (PFS) if it means avoiding serious side effects from treatment, according to the results of a study published online in 

, a journal of the American Society of Hematology.

Researchers from across the country also found that out-of-pocket costs played a deciding factor, too.

“People have preferences based on what they value the most,” Carol Mansfield, Ph.D., senior research economist at RTI Health Solutions, said in an interview with 

®. “As medicine moves toward a more patient-involved paradigm, we are learning that people have different preferences and circumstances, so there may not be a ‘one size fits all’ medicine choice.”

The Leukemia & Lymphoma Society sent an email survey to more than 4,000 patients with CLL, 384 of whom consented to and completed it. Patients were, on average, aged 65 years; approximately half were men, and most were white.

The participants were asked to choose between hypothetical treatment options, each defined by five variable attributes — PFS, mode of administration, typical severity of diarrhea, chance of serious infection and chance of organ damage.

Although patients placed the highest importance on longer PFS, reductions in the risk of side effects also appeared to be important. For example, patients said they would need, on average, an additional 36 months of PFS in order to accept an increased risk of serious infection. In turn, that amount of added efficacy would offset a change in side effects — in this case, patients going from having no risk to a 30 percent chance of an adverse event, according to the study authors. “Patients value both efficacy and quality of life during treatment, and they are often willing to make trade-offs,” Mansfield said.

In addition, cost of care plays a significant role in treatment decision making. When cost was not a factor, 91 percent of respondents said they would choose the medicine with the longest PFS. But when the choice involved two medicines with out-of-pocket costs, patients opted for the cheaper medicine despite the lower PFS.

In a scenario with a $400 difference between out-of-pocket costs, 75 percent of patients chose the cheaper medicine. In the case with a $75 difference per month, half (50 percent) chose the lower-cost medicine.

“Cost is complicated. It varies from patient to patient, based on insurance and access to other sources of financial aid,” Mansfield said. “The reality is that the costs we presented in the survey were high enough that some patients couldn’t afford them.”

The study authors hope that these findings will encourage health care providers to have frank and open discussions with patients about how different treatments will affect their lives, Mansfield said.

Having providers help manage side effects can make a big difference and may even convince patients to stay on drugs that have higher efficacy and worse side effects, she added. “Choosing a treatment is more than a go or no-go decision,” Mansfield said. “Patients don’t always understand the trade-offs involved with different treatment plans. Once they understand the impact of their choices, they can make decisions based on what they are willing to tolerate and what they are willing to risk.”

Survey finds quality of life and cost affect treatment decisions.

Patients With CLL Are Willing to Trade Efficacy for Less Severe Side Effects

FOR THE FIRST TIME in more than 40 years, patients with acute myeloid leukemia (AML) have 

. After years of little to no improvement, four new agents were approved in the same year bringing huge advancements to the field. 

Leading experts agree that there is a lot to be excited about in the developments of these new agents, but there are also many questions to still ask such as how they work with one another and what they mean for survival rates. 

, we feature an article on the new therapies available — Rydapt (midostaurin), Vyxeos (CPX-351), Mylotarg (gemtuzumab ozogamicin) and Idhifa (enasidenib) &mdash; and what other agents are in the pipeline as researchers try to determine the best ways to personalize care for patients with AML. 

Another feature examines how frontline therapy for 

may be changing in favor of a less toxic approach. Bleomycin, a chemotherapy drug often used in combination to treat Hodgkin lymphoma, has many side effects including lung toxicity. Therefore, researchers replaced it with a newer agent, Adcetris (brentuximab vedotin), in a clinical trial to test differences. This feature highlights the results of that trial and introduces two patients whose lives have been extended through the use of Adcetris. 

 that would improve your progression-free survival if it meant that you would save money, or avoid more serious side effects? This is a decision faced by some patients. A study found surprising results: The majority of patients with chronic lymphocytic leukemia are willing to accept shorter progression-free survival. The study’s senior researcher shares her insight on why she believes these patients are willing to make tradeoffs when it comes to their health. 

, which can be a powerful tool for patients, survivors and caregivers, especially to gain informational resources, seek support groups or keep family and friends informed on diagnosis and treatment. However, there are risks involved, too. An oncologist and cancer survivor weighs the perks and perils of these online platforms specifically for individuals in the blood cancer community. 

chimeric antigen receptor T cell therapies

, stress reduction after stem cell transplant and how to improve symptom burden and inflammation in patients with myeloproliferative neoplasms through nutrition. 

From the Chairman

FOR THE FIRST TIME in more than 40 years, patients with acute myeloid leukemia (AML) have reason to hope. After years of little to no improvement, four new agents were approved in the same year bringing huge advancements to the field. 

After 40 Years, Acute Myeloid Leukemia Gets 4 New Treatments

GENETIC ABNORMALITIES PLAY A role in multiple myeloma — and better understanding of them will improve outcomes, particularly for high-risk patients, said Shaji K. Kumar, M.D., a professor of medicine and chair of the Myeloma, Amyloidosis, Dysproteinema Group at Mayo Clinic in Rochester, Minn., during his talk at the 35th Annual CFS®.

“Over the years, as we have understood the biology of this disease better, it has become more clear that myeloma is not just one disease, and as multiple myeloma has become richer, so to speak, the divide between the rich and the poor has become even wider,” he said in reference to subgroups of patients for whom there are and are not effective treatment strategies.

“We still have over a quarter of these patients who are dying within the first three years,” even though median overall survival for patients with multiple myeloma is now eight to 10 years and improving, Kumar said. Targeting translocations, trisomies and chromosomal deletions is the key to superior outcomes, he added: “What is clear is that when patients have one or more of these abnormalities, their outcome is much poorer compared with the remaining patients.”

Fluorescence in situ hybridization (FISH) — a technique researchers use to visualize and map the genetic material in an individual’s cells &mdash; continues to be useful for diagnosing underlying causes of tumor growth, but there is a need for greater clarity in characterization of disease drivers for an appropriate therapeutic response, Kumar said.

“Unfortunately, FISH isn’t the answer to everything. It’s the most easily accessible test that we have,” he said. “The problem with the FISH testing is we all have patients now in our practice who may have del(17p) (a chromosomal deletion) or the t(4;14) translocation (a chromosomal translocation) who do much better than what we would have expected them to, and the reverse is also true.”

This has created huge interest in developing techniques that may be more specific in identifying patients with highrisk myeloma. These are necessary to tailor therapy according to intensity of duration and specific agents, which cannot be so easily accomplished on FISH alone, Kumar said.

FISH can effectively be used in conjunction with the International Staging System and other tests, such as gene expression-based classifications, which include a 70-gene prognostic signature, developed by the University of Arkansas for Medical Science, and a 92-gene signature test from SkylineDX, a Dutch molecular diagnostics company, he said.

Recent efforts to sequence the genome of relapsed multiple myeloma helped identify the most common mutations, such as KRAS and NRAS, some of which also have prognostic value. Involvement of del(17p) and mutated DNA repair genes can portend outcomes, but sequencing also holds the promise of “being able to develop therapies that are specifically targeted toward the underlying mutations,” Kumar said.

Such initiatives could also help high-risk populations, such as patients with plasma cell leukemia, “although this is a very small proportion of patients with myeloma, their outcomes are extremely poor, and — even though they have improved a bit &mdash; we’re still looking at median or overall survival of less than two years,” he said.

Ten years ago, the resources for such disease was limited to alkylating agents, anthracyclines and corticosteroids. Today’s tool kit holds significantly more — and more effective &mdash; options. Proteasome inhibitors, immunomodulatory agents, histone deacetylase inhibitors and monoclonal antibodies are now at a physician’s disposal.

“We have a whole host of new therapies, so we have a choice. We need to find out what is the best combination of these different choices that could make a difference to these patients with high-risk multiple myeloma,” Kumar said.

Tailoring such therapies to fit the patient and disease state could involve using specific drugs or drug classes, combining drugs, varying therapy duration and targeting a particular level of response, such as complete response or minimal residual disease negativity.

Kumar provided a few examples of new approaches that are working, such as use of the proteasome inhibitor Velcade (bortezomib) in cases of t(4;14) translocation. “Both in the newly diagnosed and the relapsed setting, what has become clear is that when you treat patients with bortezomib for a long period of time, there seems to be a significantly improved outcome compared with what we have historically seen in these patients,” he said.

Tandem autologous stem cell transplants (ASCTs) in cases of del(17p) with or without t(4;14) also are promising, Kumar noted. At 48 months, 76 percent of patients were alive following tandem ASCT, as opposed to 33 percent for a single ASCT, following Velcade-based induction regimens, according to trial results published in 2013.

“These data also seem to be borne out by some of the more recent trials, which looked at tandem versus single transplants. There is some suggestion that patients with high-risk abnormalities do benefit from tandem ASCTs,” Kumar said.

Experts focus on genetic abnormalities to advance cancer care.

Better Outcomes in High-Risk Multiple Myeloma

JOE PLEASANT was selected to participate in the ECHELON-1 clinical trial where he was treated with Adcetris. - PHOTO BY Eder Escamilla

Joe Pleasant was at a high school football game in 2012 when he first noticed a pain in his back. It was a little thing, and he let it go. A few months later he visited his doctor after the lymph nodes in his neck swelled up, but that was a false alarm. Then came odd neurological symptoms, panic-stricken Googling, a visit to a specialist and more back pain. “I knew I was sick,” he says. “I just didn’t know what it was.”

After more back pain, surgery, and a second look at a chest X-ray, Pleasant was summoned back to the hospital. He was stunned when a scan revealed a baseball-sized tumor in his chest. “My whole midsection was covered with cancer,” he says, stage 4 Hodgkin lymphoma. “I was just a walking cancer stick.”

Pleasant shared the news with his boss. After the initial shock wore off, a light bulb went on. “You’re sure it’s Hodgkin lymphoma?” he asked. Pleasant was sure, and before long he was on a conference call with a friend of his boss at Seattle Genetics, which had been developing Adcetris (brentuximab vedotin) for the treatment of Hodgkin lymphoma. Adcetris targets CD30, which is found on the surface of most classical Hodgkin lymphoma cells.

Pleasant liked what he heard: promising results with minimal side effects. The catch? Adcetris for Pleasant’s diagnosis was only available via a phase 3 clinical trial, ECHELON-1, that was barely just underway.

Pleasant met his oncologist and learned about the standard treatment: Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine (ABVD). “I was pretty scared. I thought the chemotherapy would be horrible,” he admits.

He then asked about Adcetris, and was pleased to discover his oncologist had a colleague at the University of California, San Diego who would be administering the trial locally. “I really wanted this new drug,” Pleasant says. With a willing patient and some administrative elbow grease they managed to open the trial early.

ECHELON-1 replaced the bleomycin in ABVD with Adcetris. Because it’s a randomized trial, Pleasant still had to win the coin toss. Would he receive the experimental Adcetris plus Adriamycin, vinblastine, dacarbazine (A+AVD) or the control arm ABVD? When a phone call revealed he would receive Adcetris, he and his wife highfived each other over the couch. Their enthusiasm was soon matched with dramatic results: Two months into the 6-month treatment, a PET scan showed no visible disease. “Nothing lit up,” Pleasant says. “In two months’ time, I went from stage 4 to they can’t even see it anymore.”

Pleasant’s response was better than most, but in the ECHELON-1 trial overall Adcetris outperformed the ABVD regimen. Based on the findings, in January the Food and Drug Administration (FDA) granted a priority review for Adcetris as a frontline treatment for advanced classical Hodgkin lymphoma. In December 2017, at the annual meeting for the American Society for Hematology, ECHELON-1 study lead author Joseph Connors, M.D., clinical director of the British Columbia Cancer Agency Centre for Lymphoid Cancer in Vancouver, Canada, presented the highly anticipated results: a 23 percent risk reduction in progression, death or need for additional therapy with A+AVD versus ABVD. A supplemental new drug application has been filed with the FDA and is likely to be approved sometime this spring.

Adcetris has been available since 2011, when it was approved for patients whose Hodgkin lymphoma had returned after autologous stem cell transplant or at least two prior multiagent chemotherapy regimens. “We have a lot of experience in this relapsed setting, where it’s done wonders for patients,” says Lauren Maeda, M.D., a hematologist at Stanford Cancer Center in Stanford, California. In 2016 when a supply chain issue led to shortages of bleomycin, Stanford often replaced it with Adcetris for patients with advanced stage disease, similar to ECHELON-1.

“It has a lower risk of significant side effects than any other comparable chemotherapy used in that phase of the game,” Maeda says. Bleomycin can cause shortterm side effects such as nausea, vomiting, weight loss and mouth sores. A more serious, long-lasting side effect related to bleomycin is lung toxicity, which may require frequent testing of lung functioning. But despite these positive returns, when she polled her colleagues she found that the ECHELON-1 trial may not yet be practice changing.

“It’s a very unique patient population,” she explains, with a high cure rate using a variety of treatments. “Because there is such good response even in the relapsed setting, some people would argue: do we really need to be as aggressive upfront?” The benefit of Adcetris and its significantly higher cost is harder to project given recent advances in treatment that are already minimizing the use of bleomycin.

Hodgkin lymphoma was one of the first cancers for which truly successful treatments were developed. Early innovations in radiation therapy and chemotherapy were further refined using clinical research. As a result, Hodgkin lymphoma became one of the first consistently curable cancers, and continuing refinements improved treatment options. This model for clinical success helped to inspire early generations of oncologists.

ABVD emerged in the 1970s and, as it was perfected, cure rates began to approach a remarkable 80 percent. With a success rate that high, some of the toxicities of the treatment — from bleomycin, in particular &mdash; were tolerated. “Standard treatment hasn’t changed for quite some time, but is starting to change,” explains Jane N. Winter, M.D., a hematologist at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago. “What we’re learning now is that the sins of the past, combined chemotherapy and radiotherapy, leaves many patients with very significant comorbidities.” Even now she has a patient in the cardiac care unit being evaluated for a heart transplant because of the intensity of radiation and chemotherapy used on a chest mass in the early days of Hodgkin treatment.

Thinking about long-term impacts is even more important in Hodgkin lymphoma because many patients are young, between 15 and 40 years old. “What we’re trying to do going forward is to balance upfront control with the risk of long-term complications from our therapy,” Winter says.

The ECHELON-1 trial is a part of that attempt to reduce long-term toxicity and improve upfront disease control. “We do have a long way to go,” she says. “There will be, and is, a lot of discussion about this trial.”

The major challenge is that the standard arm was not exactly conducted the way treatment unfolds today. That’s to be expected because lag time in clinical trials is an inherent problem as our understanding accelerates. When ECHELON-1 was designed, the standard was ABVD. But in the intervening few years oncologists began using PET scans to determine where treatment should go after the first couple of cycles. If ABVD was not working, treatment would be escalated to the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone regimen — used less in the United States because of higher toxicity. In other cases, bleomycin was removed, and treatment continued with AVD alone.

Another of Winter’s current patients is 55 years old and a longtime smoker. “That’s a patient for whom I would not consider bleomycin because of the lung toxicity. For those situations, this provides an excellent alternative,” Winter says. “Whether it will be or should be the standard of care I think will require a little more investigation of the data.”

TREATMENT TRADE-OFF As side effects go, the primary challenge with A+AVD is peripheral neuropathy, which causes pain, weakness and numbness in the hands and feet. It’s common to have mild neuropathy with ABVD, caused by the vinblastine. Adcetris compounds the peripheral neuropathy risk, making it significantly more common to have severe neuropathy, some of which may be permanent.

Peter Martin, M.D., chief of the Lymphoma Program at Weill Cornell Medicine and NewYork-Presbyterian in Manhattan, is concerned about that trade-off, especially for a younger population.

Martin breaks down the statistics this way: Imagine a room with 20 people who are about to be treated for Hodgkin lymphoma. First, they are told that there are two treatment options and that both will cure the same number of people. In the end, one person in the room will need more treatment, but if they choose the A+AVD over the ABVD the time before they need further treatment will be delayed.

Most people would probably take that trade-off, right? Would that same patient make that decision if it was going to double the chance of neuropathy? A less exciting choice, but they would probably still go for it.

But now everyone else in this room is told that they won’t receive any benefit, and a third of them are going to get neuropathy, too. “You’re giving a third of the people neuropathy without giving them any clinical benefit,” Martin says.

“I don’t want to give anybody the impression that ABVD is a bad idea,” Martin says. “You’re curing this huge number of people with pretty minimal short-term toxicity. The toxicities that are there take decades to show up. To replace ABVD you have to be really confident that your short-term efficacy is better and that your short-term toxicity isn’t a lot worse. You have to show that, long term, it’s not going to result in any other side effects.”

WALTER CZARNIK with his daughter EVELYN, and wife SARAH, credits the combination of Adcetris and Opdivo with jumpstarting his remission. - COURTESY WALTER CZARNIK

Adcetris available for frontline enhances the toolbox, and that’s the real benefit. “As more and more data comes in we’ll find more ways to use the tool,” he concludes.

Walter Czarnik was just 25 years old when a doctor at his IT job site pulled him aside in concern. Did he always look so pale? He had been tired lately, consuming four or five energy drinks a day, and his doctor had prescribed him iron for anemia. Czarnik figured his exhaustion was easily attributed to the stress of losing his mother, followed by the birth of his daughter, Evelyn.

But the doctor encouraged him to visit a hematologist, and it wasn’t long before Czarnik faced a stage 4 Hodgkin lymphoma diagnosis. A week before his 26th birthday he began standard ABVD treatment in Flint, Michigan, with no apparent results. He then went to Detroit, where he enrolled in a clinical trial combining Adcetris and the immunotherapy agent Opdivo (nivolumab).

Interim results of the phase 1/2 trial showed a 90 percent objective response rate and a 62 percent complete response rate from 29 response-evaluable patients.

Treatment from the trial cleared the disease from Czarnik’s bone marrow, but it was still active in his lymph nodes. By the end of his 18-month ordeal he had endured treatment with ifosfamide, carboplatin and etoposide followed by carmustine, etoposide, cytarabine, and melphalan, then finally an autologous stem cell transplant.

Czarnik credits the Adcetris/Opdivo combination with jumpstarting his remission, giving him time with his wife, Sarah, and their young daughter. “I got to watch her develop and spend all of that time with her,” he says. “Immunotherapy was the best. I can’t think of any side effects that I had.”

“We’re seeing across the board an increasing use of immunotherapy and Adcetris,” Winter says. “We certainly don’t know the best way to incorporate these new agents and I think we’ll have to be very scientific about it looking at both early and late effects.”

Martin agrees, noting that immunotherapy may lead to later autoimmune problems. “We have to be really cautious as we evaluate it not to jump full scale into some toxicities that might be life threatening or have some significant toxicity attached to them for long periods of time.”

“ECHELON-1 demonstrates that ABVD is still great. The fact that we have Adcetris hopefully approved in another scenario is even greater. And the fact that we have immunotherapy in clinical trials is even greater,” Martin says. “Every time I think it’s not going to get better, it gets better.”

Experts examine the use of Adcetris for patients with Hodgkin lymphoma.

The Future of Frontline Treatment in Hodgkin Lymphoma

KATHLEEN PACKARD and her daughter, AMY, took this picture on the seventh day of chemotherapy to show unity during her cancer battle. - PHOTO BY KIM SMITH

The biggest battle of Kathleen Packard’s life began in late 2016 with sudden severe pain in her abdomen. The 59-year-old resident of Amherst, New York, couldn’t remember the last time she had been sick, but this kind of stomachache warranted a trip to the hospital.

The doctors discovered that Packard had pancolitis, a severe form of ulcerative colitis that had spread throughout her large intestine, and ordered a blood test. From there, her life took an unexpected and tumultuous turn.

“My white blood cell count was 86,000, whereas normal is 4,500 to 11,000. They sent me to Roswell Park Comprehensive Cancer Center immediately, where I met the phenomenal Dr. Eunice Wang,” Packard recalls. “She made sense out of madness.”

Wang, M.D., chief of the Leukemia Service at Roswell Park in Buffalo, New York, diagnosed Packard with acute myeloid leukemia (AML) and started her on treatment the very next day. In patients with AML, the bone marrow makes abnormal malignant blood cells such as myeloblasts (a type of white blood cell), red blood cells or platelets. It is one of the four main types of leukemia.

The American Cancer Society estimates that in 2017, there were 21,380 new cases and 10,590 deaths from AML. Although AML can occur in children, adults aged 45 years and older are generally most susceptible. The disease is slightly more common in men than in women, but the average lifetime risk for both sexes is less than half of 1 percent.

A bone marrow sample at diagnosis confirmed that Packard had a subtype of AML characterized by a mutation in the FMS-like tyrosine kinase 3 (FLT3) gene, which plays an important role in blood-forming stem cell survival and proliferation. About 1 in 3 patients with AML has this mutation, which may be associated with a particularly poor prognosis. But Wang offered Packard hope through participation in a clinical trial for a new drug specifically targeting FLT3-mutated AML.

Patients with AML are typically treated with two phases of chemotherapy: induction and consolidation. Induction involves treatment with the chemotherapy drugs cytarabine and daunorubicin. Consolidation chemotherapy occurs after remission — clearance of malignant leukemia cells in the marrow followed by regeneration of normal marrow blood-forming cells &mdash; to help prevent a relapse and usually includes high doses of cytarabine, often followed by an allogeneic stem cell transplant.

At Roswell Park, Packard took the two induction drugs in combination with crenolanib, an experimental FLT3 tyrosine kinase inhibitor. “I was on heavy chemotherapy for 13 days, and I was very sick,” she says. “I had every side effect they had to offer. It was a horrific time.”

In January 2017, Packard had an allogeneic bone marrow transplant from an unrelated donor. Today, she remains in remission and recently restarted maintenance therapy with crenolanib as part of another clinical trial.

“My blood went from 99.9 percent filled with leukemia to 99.9 percent cancer-free. I got over that hump,” Packard says. “It was a horrible situation, but when you’re going through it, you learn very quickly that you’re a strong person.”

Packard represents one of countless patients who have benefited from a growing number of treatment options for AML. After 40 years of little to no improvement in higher remission or cure rates since the advent of cytarabine and daunorubicin, four new agents were approved for AML by the Food and Drug Administration (FDA) in 2017 alone: Rydapt (midostaurin), Vyxeos (CPX-351), Mylotarg (gemtuzumab ozogamacin) and Idhifa (enasidenib). Several other promising drugs, such as crenolanib, are still in the pipeline but expected to gain approval in the near future. More treatment options will translate into better outcomes for patients, because oncologists can figure out which of several agents will work best for a given individual. For instance, through a bone marrow sample, Wang found out at diagnosis about Packard’s FLT3 mutation and gave her a targeted drug.

“I think it will change the work that we do upfront to better stratify patients in order to offer the benefits of these targeted therapies,” Wang says. “We have an abundance of riches, and it’s up to physicians to understand that it will take a little time to identify the particular individuals who will benefit.”

The sudden bounty is the culmination of AML research and knowledge that built up for decades — patient genome sequencing, identifying new mutations and understanding their consequences, performing clinical trials, and so on. The discovery of mutations that characterize subtypes of AML led to more personalized treatment options that could outperform the standard regimen.

“We’re reaping the benefits of major innovations in basic science which are sometimes not immediately cancer related, like sequencing the human genome,” says Akil Merchant, M.D., assistant professor of medicine at the University of Southern California in Los Angeles. “These aren’t directly studies of cancer, but they ultimately lay the foundation for these kinds of rapid approvals.”

Typically, about a quarter of adults with AML can be expected to survive three or more years and may be cured. But a number of factors, such as advanced age, systemic infection at diagnosis, elevated white blood cell count, central nervous system involvement with leukemia and certain genetic mutations, lead to poorer outcomes.

Factors that increase a person’s risk of AML include advanced age, being male, previous cancer treatment with certain chemotherapy drugs, exposure to radiation, smoking, toxins (some solvents, for example), other blood disorders, genetic syndromes and family history. Signs and symptoms in the early stages of AML, such as fever, bone pain, fatigue, shortness of breath and pale skin, can mimic the flu or other common diseases.

Because it doesn’t usually form tumors, AML is not staged the same way other cancers are. Instead, lab tests determine subtypes and a patient’s outlook. The French- American-British classification divides AML into subtypes, M0 to M7, based on the type of cell from which the leukemia develops and how mature the cells are. An updated classification by the World Health Organization separates AML into several groups by considerations such as the presence of certain genetic abnormalities, disease related to previous chemotherapy or radiation, and disease related to blood disorders.

“AML is not one disease. What it will come down to one day is that if you have a disease like AML, it will be as unique as you are,” Merchant says. “That’s where we’re heading with precision medicine and really tailoring the therapy to that individual.”

To that end, two of the new agents target subtypes of AML characterized by specific genetic abnormalities. In April 2017, the FDA approved Rydapt for the treatment of adults with newly diagnosed FLT3-positive AML in combination with standard two-phase chemotherapy. The phase 3 RATIFY trial randomized 717 patients with AML who had the FLT3 mutation to standard induction and consolidation chemotherapy plus Rydapt (360 patients) or placebo (357 patients).

Median overall survival was 74.7 months with Rydapt versus 25.6 months with chemotherapy alone.

Four months later, Idhifa was approved for treating patients who have relapsed or refractory isocitrate dehydrogenase 2 (IDH2)-mutated AML based on the promising results of a phase 1/2 study.

The IDH2 gene encodes for metabolic enzymes found in mitochondria, the energy- producing centers within cells. The single- arm, multicenter clinical trial included 199 adults with relapsed or refractory AML who had an IDH2 mutation. They took the oral drug daily, and 19.3 percent experienced complete remission with a median duration of 8.2 months.

Both Rydapt and Idhifa were approved along with companion diagnostic tests, the LeukoStrat CDx FLT3 Mutation Assay and the RealTime IDH2 Assay, respectively. As a result, the diagnostic workup for patients will change to identify those who would benefit from the new drugs. “With these new agents in our arsenal, we’ll be able to translate the positive results in clinical trials to improving the outcome of patients with these mutations,” says Bruno Medeiros, M.D., associate professor of hematology at Stanford Cancer Center in California. “Information about the patient which used to be prognostic is now relevant and critical for treatment. It changes the potential outcome for patients, but it also changes how physicians and patients should expect the initial workup to take place.”

Common side effects of Rydapt include low levels of white blood cells with fever (febrile neutropenia), nausea, inflammation of the mucous membranes (mucositis), vomiting and headache. Idhifa’s side effects include nausea, vomiting, diarrhea, increased levels of bilirubin (a substance found in bile) and decreased appetite.

In August 2017, the FDA approved Vyxeos, a repackaged formulation of induction chemotherapy drugs cytarabine and daunorubicin, for two subtypes of AML with typically poor prognoses. Therapy-relatedAML occurs as a result of specific types of chemotherapy or radiation, and AML with myelodysplasia-related changes is characterized by a history of certain blood disorders and other mutations within cancer cells.

Vyxeos combines the two drugs into a single formulation encapsulated in liposomes. In a clinical trial, 309 patients newly diagnosed with one of the two AML subtypes received either Vyxeos or separately administered treatments of daunorubicin and cytarabine. Those who received Vyxeos had a median overall survival of 9.56 months versus 5.95 months for patients who received the two drugs separately. Side effects of Vyxeos include hemorrhage, febrile neutropenia, rash, swelling of tissues, nausea, mucositis and fatigue.

Lastly, anti-CD33 antibody drug conjugate Mylotarg received approval in September 2017 for adults with newly diagnosed AML whose tumors express the CD33 antigen. The drug combines an antibody with chemotherapy to attack tumor cells with CD33. It was originally approved in 2000 but voluntarily withdrawn from the market after several early deaths and lack of evidence of efficacy.

“Mylotarg was previously approved and now has been reapproved,” Wang says. “It was taken off the market for several years because of questions by the FDA that required additional analysis based on patients who developed liver issues. Liver problems with Mylotarg are still an issue, but the incidence has decreased.”

The agent has a new dosing regimen that has been shown to be more safe and efficient. A randomized phase 3 trial, ALFA-0701, compared daunorubicin and cytarabine with or without the addition of Mylotarg in 271 patients with CD33-positive AML. Those who received Mylotarg had a median event-free survival of 17.3 months compared with the control group’s 9.5 months. However, no significant improvement in overall survival was seen with Mylotarg.

Severe side effects of Mylotarg include low blood counts, infections, liver damage, blockage of veins in the liver, infusion-related reactions, and severe bleeding. In the clinical trial, patients who took Mylotarg were seven times more likely to experience side effects compared with those in the control group.

“These are exciting times, but with that excitement comes questions,” Medeiros says. “All of these agents were tested in isolation of one another, so it’s going to be a challenge for us to learn how to use and combine these agents.

But there are more opportunities for treatment, which will, hopefully, lead to improvements in the survival of a disease that is very hard to treat.”

Last year brought many new possibilities in the treatment of AML, and it appears 2018 does likewise. Specifically, Medeiros says ivosidenib, an IDH1 inhibitor that targets IDH1-mutated disease, has a good chance of hitting the market early this year. It was submitted to the FDA in December following phase 1 trial results that showed a complete response or complete response with partial hematologic recovery rate of 30.4 percent, which lasted for a median duration of 8.2 months.

Another potential target is B-cell lymphoma 2 (BCL-2), the protein that makes cancer cells resistant to therapy. BCL-2 inhibitors have shown promise for patients who aren’t good fits for induction chemotherapy, such as older adults. Venclexta (venetoclax), previously approved for patients with chronic lymphocytic leukemia, recently demonstrated a complete remission in up to 50 percent of patients aged 60 years or older with relapsed or refractory AML.

Although Rydapt is already on the market, Merchant expects other FLT3 inhibitors to follow suit: “Rydapt is the first but not the best FLT3 inhibitor. There is a whole crop of FLT3 inhibitors that are more targeted, more specific, and have fewer side effects and greater activity than Rydapt. I think the three or four agents on the horizon are even more exciting.”

In a recent study conducted by Wang, crenolanib combined with chemotherapy saw very high response rates of over 80 percent complete remission or complete remission with incomplete hematologic recovery. While most FLT3 inhibitors bind only to the receptor in its inactive configuration, crenolanib can bind for FLT3 in both active and inactive configurations.

Packard says she owes her survival to Wang and other members of her care team at Roswell Park who are willing to take a chance with new therapies. She takes crenolanib in pill form three times a day, every eight hours, which disrupts her sleep schedule and normal routine. But her main objective is survival, and although the treatment has been tough, she feels grateful to be alive.

“The most important thing to believe in is your doctor,” says Packard. “Have a strong bond with your doctor and realize that you matter. It’s your journey, and you have the right to have a bad day, but you need to get back up. You have to reach the top of that mountain and have a strong will to live.”

New drugs bring advancements to acute myeloid leukemia after 40 years.

Lab of Plenty: New Drugs Bring Hope for AML Treatment

CAROLINA HERNANDEZ and her mom, JULIA LEAL, took a chance by opting for the newly approved CAR-T cell therapy. - PHOTO BY: JARED REY

In fall 2016, Carolina Hernandez, then 10 years old, started complaining that her bones hurt. Her primary care doctor attributed the symptom to growing pains. But by February 2017, the pain had become so severe that Carolina, an enthusiastic soccer and basketball player, could barely walk. She was brought to the emergency department.

Soon after, her family received the devastating news: Carolina had B-cell precursor acute lymphoblastic leukemia (ALL). The next five months passed in a blur of chemotherapy treatments. But Carolina’s cancer did not respond — cancer cells stubbornly remained in her bone marrow.

By October 2017, Carolina’s medical team said she had two choices left: a bone marrow transplant or a newly approved treatment called a chimeric antigen receptor (CAR)-T cell procedure. The latter involved removing and genetically re-engineering some of Carolina’s immune cells — T cells &mdash; to find a specific marker on her cancer cells and then kill them.

Carolina’s family opted for CAR-T. And although Carolina did have a fever right after the procedure, she now is much stronger. “The doctors are amazed at how quickly it worked — and how well,” says Carolina’s mother, Julia Leal, 40, a housekeeper who quit work to take care of her daughter. “I’m very hopeful. It gave me my life back, as well as my daughter’s life back. I’m very glad that we did it.”

Carolina is one of the first patients to receive this treatment, Kymriah (tisagenlecleucel), outside of a clinical trial. Two Food and Drug Administration (FDA) approvals for CAR-T cell therapy came in late 2017, one for use in children and young adults with advanced leukemia, and another for use in adults with refractory lymphoma. Although available only to a very specific group of patients, CAR-T cell treatment is a real breakthrough.

Just after World War II, the approach to cancer treatment was basically “slash, poison, burn” — surgery, chemotherapy, radiation. Then, in the 1960s, monoclonal antibodies allowed oncologists to precisely target malignant cells by looking for molecular changes or markers.

CAR-T cells are a completely different animal — a “living drug.” The procedure adapts the immune system to fight a patient’s own cancer, part of a larger field called immunotherapy, which has taken the oncology world by storm.

Rather than dragging a patient through months or years of treatment, CAR-T cell treatment takes just a few weeks. It offers the possibility of a durable cure to patients who had no options before.

CAR-T cell treatments involve regimens rather than drugs. The technique enlists a patient’s own T cells, a type of white blood cell. These lymphocytes recognize and remember invading bacteria and viruses by analyzing various markers on the surface of infectious or malignant cells.

“This is a new way to treat leukemia that is different from anything we’ve used before,” says Ted Laetsch, M.D., Carolina’s doctor and an assistant professor of pediatrics at the University of Texas Southwestern Medical Center in Dallas.

First, Laetsch explains, doctors take a blood sample and isolate the white blood cells. In the lab, they use a highly modified form of the virus that causes HIV to insert a new gene that makes the patient’s T cells. This gene causes T cells to attack CD19, a particular marker on the surface of B cells, another type of white blood cell that turns malignant in leukemia.

Meanwhile, the patient usually goes through some chemotherapy to make room for the edited T cells, which are dripped back into the circulatory system. If all goes well, these chimeric T cells multiply into an advancing army that takes out all the cancerous B cells by bursting their cell membranes, putting the patient into remission.

In a sense, CAR-T cell treatment combines cell therapy, gene therapy and immunotherapy in one package. Experts say it represents a radical departure from all medicines to date. “This is revolutionizing how we treat patients,” says Julie-An Marie Talano, M.D., director of clinical research in Pediatric Bone Marrow Transplant and Cellular Therapy at the Medical College of Wisconsin in Milwaukee and clinical researcher in Pediatric Bone Marrow Transplantation at Children’s Hospital of Wisconsin. “The next decade is going to be really exciting.”

In small, early studies, as many as 80 to 100 percent of patients responded to CAR-T cell treatment, leading the FDA to award breakthrough status to CAR-T treatments for B cell malignancies such as ALL and chronic lymphocytic leukemia, as well as some types of lymphoma.

In August 2017, the FDA approved Kymriah for treating patients aged 25 years or younger who have B-cell precursor ALL that resists other treatments — what doctors call refractory &mdash; or relapsed at least twice after traditional treatments. The approval was based on phase 2 results from a single-arm, international trial of 63 patients who received a single dose of Kymriah. Overall remission rate was 82.5 percent in treated patients. Forty patients (63 percent) had complete remission (CR), and 12 (19 percent) had CR with incomplete hematologic recovery (CRi). All patients who had CR or CRi were associated with negative minimal residual disease status in the bone marrow, meaning the blood or bone marrow is clear of the abnormal cells.

Kymriah was granted priority review early this year from the FDA to be used to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma who either relapse or are not eligible for an autologous stem cell transplant.

Less than two months after approving Kymriah, the FDA cleared the second CAR-T cell therapy. The approval, announced in October 2017, covers the use of Yescarta (axicabtagene ciloleucel) for patients with large B-cell lymphomas whose cancer progressed following at least two prior treatment regimens. This type of cancer includes diffuse large B-cell lymphoma (the most common), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and transformed follicular lymphoma.

So far, just a handful of patients have received Yescarta in the U.S. due to holdups with insurance, Medicaid and Medicare for payment.

Both Kymriah and Yescarta target a marker called CD19 that occurs on the surface of B cells. Investigators conducting ongoing clinical trials with CAR-T cells hope to recognize two markers, as well as explore other good surface targets for amped-up immune cells.

CAR-T cell approaches were the darling of the annual American Society of Hematology (ASH) meeting held in December 2017. Clinicians are hopeful that the technique will extend to other blood cancers. For instance, just before the ASH meeting, the FDA approved a CAR-T cell regimen breakthrough status for treating multiple myeloma.

“This is one of very few therapies where it is intellectually honest to speak of a cure — that is a word that I use very rarely,” says James L. M. Ferrara, M.D., D.Sc., director of the Hematologic Malignancies Translational Research Center at Tisch Cancer Institute in New York City. “You know within four to six weeks if a person is likely to be cured. That in itself is a great advance.”

For now, this approach is approved only for patients who have not responded to several lines of treatment. And because the treatment is pricey, insurance companies are unlikely to approve its off-label use, doctors say. Still, many are trying to build the case that this might be effective earlier on, perhaps even at diagnosis.

“The next step is to move to upfront treatment in those B-cell leukemias that we already know are high risk,” says Dean Lee, M.D., Ph.D., director of the Cellular Therapy and Cancer Immunotherapy Program at Nationwide Children’s Hospital in Columbus, Ohio. “We will eventually make it to a point where we can deliver as a first-line therapy, even in more common leukemias.”

Because each treatment is custommade for every patient, requiring time, transit and complicated lab work, CAR-T cell regimens are expensive.

They cost substantially more than the bone marrow transplants that until now were the last resort in many blood cancers. The list price for Kymriah, the pediatric regimen developed by Novartis, is $475,000.

Kite Pharmaceuticals’ Yescarta is set at $373,000. Although some medical plans will get discounts and both companies have committed to helping patients who cannot pay, price will continue to be an issue, experts say.

Side effects of CAR-T cell treatment can be severe — essentially releasing weaponized immune cells into the body is bound to create some biological fallout. The most severe reaction is cytokine release syndrome (CRS), dubbed a “cytokine storm” to describe what happens when a feedback loop of immune responses causes inflammation, pain, fever and swelling that can spill over into life-threatening symptoms such as acute lung injury, sepsis and paralysis.

To treat severe or life-threatening CRS, the FDA expanded the approval of Actemra (tocilizumab) for use in patients two years of age or older. The approval is based on data demonstrating that in clinical trials of CAR-T cell therapy, patients who received Actemra had complete resolution of CRS within two weeks following one or two doses of the treatment.

CAR-T cell treatment can also be toxic to the nervous system, causing seizures or loss of speech, although these are usually temporary. In some patients, normal B cells don’t regrow, making transfusions of antibodies a long-term reality, Ferrara said.

That is also what complicates finding new targets to combine with this approach: A patient can live if the treatment kills every B cell, but that isn’t necessarily true of the immune cells of many other cancers. Some are crucial to life — it would be tough to survive without, say, brain or lung cells.

Despite the challenges, experts hope that the CAR approach may someday be used against new targets in solid cancers, such as epidermal growth factor receptor in glioblastoma — a rare but deadly type of brain cancer &mdash; or hepatocyte growth factor receptor, also called c-MET, in other solid tumors. Current studies are exploring CARs to fight sarcoma (a cancer of soft tissue), advanced prostate cancers, multiple myeloma, tumors of the chest cavity, and mesothelioma, as well as lung, breast and ovarian cancers.

The application to solid tumors remains challenging, experts say. Blood cancers are essentially the out-of-control multiplication of single cancerous cells. That’s a more straightforward target than a solid tumor, which is a bit like an organ gone rogue, with its own microenvironment and vascular system.

Solid tumors also create various cell messengers that can dampen or mute the immune response. Then there’s the question of delivery: How might CAR-T cells reach the middle of a solid tumor deep within healthy tissue? That’s not easy to figure out.

Several teams are exploring the development of off-the-shelf CARs, agents that would not be isolated from a patient’s cells but would instead involve a template that could be altered to order, even if a patient doesn’t have enough healthy T cells to culture.

Other centers are testing approaches where CARs are simultaneously targeting more than one tumor receptor. The Medical College of Wisconsin has developed a clinical trial with a CAR-T cell that recognizes two targets on B cells: CD19 and CD20. Although this is indeed a breakthrough, experts caution that there’s no guarantee of wide application. “It will be trickier in other blood cancers and solid tumors,” explains Nirav Shah, M.D., MSHP, assistant professor of medicine at the Medical College of Wisconsin, division of Hematology and Oncology, specializing in lymphoma and stem cell transplant at Froedtert Hospital, and a member of the Bone Marrow Transplantation and Cellular Therapy team.. “Right now, the success is really in the B-cell malignancy space.”

Newly approved CAR-T cell treatments inspire hope in patients with blood cancer.

Hematology Special Issue 2018 | CURE