LIVING ON OPPOSITE SIDES of the country, Larry Saltzman and George Leder have never met, but have a lot in common: both received their cancer diagnoses in January 2010, both were diagnosed with more than one cancer, and both have hopped from one treatment to another to stay one step ahead of their cancers. They have adapted to living with a chronic blood cancer that will likely be with them for the rest of their lives. Neither feels guilty about surviving — although both have had plenty of reminders that they’re dealing with cancer &mdash; and both have found ways to continue enjoying life. “There were points in my journey over the past seven years where it came into my head every 30 seconds, ‘You have cancer,’ and now, it’s less for sure,” says LARRY SALTZMAN, diagnosed with CML in 2010, managed to run three halfmarathons in 2016.

Saltzman, M.D., a 63-yearold former family physician from Sacramento, California, who has atypical chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma. He responded initially with shock, sadness and feeling a bit sorry for himself, followed immediately by wanting to know his timeline. And now? “Lately, I guess I’m feeling so good about things that on rare occasions, I forget to take the pills out of the medicine cabinet first thing in the morning.”

But it’s a give-and-take, he adds. “My quality of life is good. I work, work out, see my family and we travel,” he says. “I don’t have the worst, and I don’t have the best.” He feels lucky, having lost friends to pancreatic cancer and his sister to breast cancer, and he knows he’s fortunate to have a health insurance plan that adequately covers his expensive treatments. He’s been able to visit the Grand Canyon, but still yearns to visit India, which his doctors have nixed because the risk of encountering life-threatening germs is too great. A former marathon runner, he managed to run three half-marathons in 2016. However, he has had to give up his medical practice. “Just like going to India or eating sushi, a family medical practice is not the most germ-free environment,” says Saltzman. “I had to give up something I was very good at and enjoyed very much.”

Leder, Ph.D., a 72-year-old former organic chemistry professor also has CLL, but it has remained dormant while his body fights multiple myeloma. He also takes occasional hormone shots to keep his prostate cancer under control. All in all, he’s managed to avoid side effects from his treatments. “I haven’t been very good at avoiding these cancers, but I have been pretty good at being treated for them,” he says. “My tolerance seems to be pretty good, which I’m grateful for. I feel absolutely terrific.”

Leder tries to be as active as he can, successfully dodging depression to focus on living life. “Because I generally feel so good, there’s a bit of a disconnect between the way I feel and what I have,” Leder says, so he doesn’t dwell on what he has. “At some point, I imagine, these things will catch up to me, but no one can tell me when.”

He therefore treats cancer as any other chronic illness, like the heart disease he also contends with.

“Don’t get bummed out by the word ‘cancer,’” he says. “Ultimately, it’s just another disease you can be treated for, and you can still wind up having a normal life.” Both he and Saltzman have benefited from new treatments that came out while they were living with their cancers. Saltzman advises others to get plugged into an academic medical center early on so that “if things go south,” they’re already working with people with access to the most current research and clinical trials.

Articles

Side Note

"Neither feels guilty about surviving &mdash; although both have had plenty of reminders that they’re dealing with cancer &mdash; and both have found ways to continue enjoying life." 

Waiting for the Next Breakthrough: Living With a Chronic Blood Cancer

A CANCER DIAGNOSIS COMES in all shapes and sizes, and so do the patients it affects. In fact, we know that certain cancer types affect a specific race or gender more greatly. Yet, as a whole, there is still a lack of diversity in clinical trials.

Physicians are not presenting the opportunity to patients, and patients are not asking their physicians. Numbers show that less than 5 percent of all adult patients with cancer enter clinical trials, and the recruitment challenge is even greater among African-Americans and other ethnic groups. So, how can the diversity gap be closed?

At the recent annual meeting of the American Society of Hematology in San Diego, California, a forum focused on potentially beneficial strategies — specifically in the multiple myeloma setting.

®, one feature focuses on what was presented at that forum. This included strategies such as building relationships with people who are known and trusted in the community, communicating with patients to help them understand how they could benefit and bringing more national awareness to the issue.

One of our feature stories explores the journey of patients given tyrosine kinase inhibitors or TKIs, which have been remarkably effective in halting chronic myeloid leukemia (CML). For many patients, these drugs can be the difference between life and death. Unfortunately, that means some may need to be on them for their entire lives — something that can take its toll on a person’s body and wallet.

You will meet a patient with CML, who stopped taking the TKI Sprycel, and did so safely and effectively. But stopping these drugs may not be best, and safe, for everyone. We dig deeper into the advantages and disadvantages of coming off TKIs from both the patient and physician standpoint.

Also in this issue are conference highlights, updates in research and a spotlight on an advocacy group that is working to delete blood cancer. DKMS, an international nonprofit organization, works to connect potential donors with patients who need bone marrow transplants. To date, it has registered more than 7 million potential donors.

We hope you find this special issue helpful in your quest to understand what lies ahead when it comes to treatment for blood cancers. As always, thank you for reading.

From the Chairman

A CANCER DIAGNOSIS COMES in all shapes and sizes, and so do the patients it affects. In fact, we know that certain cancer types affect a specific race or gender more greatly. Yet, as a whole, there is still a lack of diversity in clinical trials.
 

Breaking Down Barriers: The Drive for Diversity in Clinical Trials Goes Full Speed

WITH EVERY POTENTIAL NEW treatment for cancer, there are known and unknown risks. The balance of these have to be determined for all medical decisions, and that is best accomplished by an informed and shared decision between the patients, their medical team and any other input that is helpful. There are few situations where the stakes are higher than in the use of the sophisticated new approaches involving engineered T cells to treat refractory hematologic malignancies with no curative options.

For years, oncologists have been treating patients with cancer with surgery, chemotherapy and radiation therapy. These have been the “pillars” of cancer treatment. Now, immunotherapy, the so-called fifth pillar, is picking up steam and excitement along the way.

One area of immunotherapy that is showing great promise in early trials is chimeric antigen receptor T-cell therapy or CAR T-cell therapy. Still being studied and refined by researchers, this process involves “engineering,” or genetically modifying, a patient’s own immune T cells to specifically recognize and attack cancer cells. Some groundbreaking studies have shown durable complete remissions in patients with therapy-refractory lymphoma and leukemia, which otherwise would be rapidly fatal.

These results have prompted the Food and Drug Administration to grant it breakthrough status for B-cell malignancies like acute lymphoblastic leukemia, chronic lymphocytic leukemia, as well as in B-cell lymphoma and non-Hodgkin lymphoma.

However, there are still many obstacles to overcome. In particular, with side effects which can sometimes be fatal. There are major toxicities involved with CAR T-cell treatment. The hyperactive T cells can spiral so out of control, like an immunologic wrecking ball inside the body, that very sudden side effects can occur related to autoimmune effects. These may include unexpected organ damage, neurologic toxicities like speech impairment, seizures, hallucinations and facial nerve palsy. Some trials have even been shut down due to patient deaths.

®, we hear the story of one little girl who experienced a “cytokine storm”— caused by CAR T-cells &mdash; so severe, that she was put into an induced coma for two weeks.

This situation occurs when the immune cell activation results in the release of too many cytokines, which can result in labored breathing, rapid pulse, high fevers and decreased blood flow to internal organs. She survived that “storm” and has now been cancer-free for five years. This may be due, in part, to her team being prepared. Some institutions have specialized teams to handle CAR T-cell therapy side effects, such as the “cytokine storm” team that is on call at MD Anderson and has unique expertise and special biologic drugs to reverse these effects. But, at this time, this kind of team isn’t usually found at the community hospital level.

These serious toxicities speak to the need for careful deliberation for each case, support systems in place and, importantly, a dedication to ongoing research to perfect both the effectiveness and management of side effects of this exciting type of immunotherapy.

Chair, Department of Breast Medical Oncology 

The University of Texas MD Anderson Cancer Center 

Editor's Page

Weighing the Benefits and Risks of CAR T-Cell Therapy: The Stakes Are High

DKMS HAS A CLEAR MISSION: delete blood cancer. Founded just over 25 years ago, in Germany, the organization was created by Peter Harf, Ph.D., in an effort to save his wife, Mechtild, who had been diagnosed with leukemia. At the time, there were only about 3,000 potential stem cell donors in Germany. None of Mechtild’s siblings was a match, so she needed an unrelated donor. Unfortunately, that did not happen in time for her. But her death was not in vain. DKMS has registered more than 7 million potential donors and provided more than 60,000 transplants worldwide. The organization has expanded with offices in the United States, the United Kingdom, Poland and India.

® spoke with James Kirkland, content strategist for DKMS (and registered donor himself), about donor myths and what the process entails.

Kirkland: The registry is a list of people who are simply saying that they are ready, able and willing, if ever needed. I think that’s one of the major misconceptions that people have about the registry. They think when you sign up, you are donating then and there, or you have to schedule the donation. I’ve had people actually ask, “Do you take the bones here?” Which is wrong on so many levels.

The registry is a community effort to empower individuals who have no necessary connection to the medical community. Also, to connect them to patients in need, based on the unique qualities of human leukocyte antigen typing, which can be looked at as genetic factors that are specific to you.

What are some of the biggest myths that you will find?

Mainly, we dispel myths, while also raising awareness about this great cause by actively asking people to register at physical drives across the country. Then, we help to facilitate those transplants and are available, so that when a patient finds a match, they contact us and we work with that donor individually.

The biggest obstacle we have is that people don’t know that you can even do this, that it’s voluntary, that you can sign up and, potentially, save a life. But the people who do know, they usually have a very skewed understanding of it, something that tends to be much more suited for Hollywood productions. We’ve seen on TV where someone is getting bone marrow extracted, without anesthesia, for a person that they know. That’s not how this works.

People think it’s a very laborious process. But, 75 to 80 percent of all donations are made through a method called peripheral blood stem cell (PBSC), which is similar to blood platelet or plasma donation.

People equate it to blood donation, so they think there’s somebody else out there who can do this. It’s not something someone else can do.

Aside from PBSC, there is another method. How does that work?

You are, potentially, the only match for this person. I think there’s no greater way to highlight your uniqueness, biologically, and your uniqueness as a person, than to be able to say, “I matched this person and when the time came, when that call came down, I said ‘yes.’ I made the difference in their life.”

 Bone marrow donation is far, far less intensive than people think. The extraction from the pelvic bone is an outpatient procedure, so you go in for an hour or so, you’re under anesthesia and you’ll leave the hospital. However, there is usually pain or soreness in the iliac bone for days, maybe even weeks.

There is a cost to register. What if a donor can't afford that?

I’ve seen stories of people running a 5K two weeks after the procedure. We’re not encouraging you to do that — we think you should take your proper rest &mdash; but the idea of what it does to your body and the effect it has on you physically has been dispelled just by the number of examples that pop up.

That’s one of the things that we always kept as key to our organization: there should never be a moment when we have someone who is ready and willing to donate and is a match, but can’t go on because they don’t have the $65 to cover the cost. We do the fundraisers, the events and we solicit private donations.

We cover the cost of everything, the insurance of the patient covers the transplant itself. This process doesn’t cost you anything.

The amount of stories that are out there can be used as a powerful way to explain to people why this is such an incredible thing to do. Each story is unique — you hear the story of the donor and you hear the story of the patient. You are saving a person, an individual, an entire life with a connection to family and friends and community. It’s one of the most powerful, straightforward ways to explain why you should donate.

The Advocate

Just one person can make a difference for patients with blood cancer.

Debunking the Myths of Stem Cell Donation

At first, Kelly Starling just felt numb. When the 46-year-old heard on August 23, 2012, that she had chronic myeloid leukemia (CML), her biggest concern was that her three adolescent children would have to watch her go through the trials of chemotherapy, lose her hair and suffer the awful side effects. But then, like so many other patients diagnosed with CML, she was told, “If you’re going to have leukemia, this is the very best kind to have.”

This isn’t always the most comforting follow-up to a cancer diagnosis, but it refers to the fact that CML is a very treatable leukemia that rarely causes death — that wasn’t always the case.

Chronic myeloid leukemia develops when certain bone marrow cells acquire a mutation that causes white blood cells to grow out of control. Until 2001, scientists had no way to stop the cells with mutations from taking over. Interferon could extend a patient’s life up to five or 10 years, but the only cure was and remains a stem cell transplant. This involves high doses of chemotherapy to kill the leukemia cells, but this also damages normal bone marrow cells. A stem cell transplant can then take place. The most common is an allogeneic transplant, where the stem cells come from a donor.

However, when the new drug Gleevec (imatinib) was approved in May 2001 by the Food and Drug Administration (FDA), it exceeded everyone’s expectations and permanently changed the landscape of CML treatment. Gleevec converted an almost certain death sentence into a normal life span, usually with a reasonably good quality of life. But there was a catch: Those living with CML would need to take an increasingly expensive medication daily for the rest of their lives. Now, new evidence suggests that edict is changing.

Gleevec is a tyrosine kinase inhibitor (TKI), a drug that targets the protein in CML that directs white cells to multiply uncontrollably, and thereby, prevent other bone marrow cells from properly developing. This protein, which produces the enzyme tyrosine kinase, is itself produced by the fusion of two genes, the ABL gene on chromosome 9 and the BCR gene on chromosome 22. Their fusion, which is due to a chromosomal breakage and reconnection known as a translocation, creates the “Philadelphia chromosome” that characterizes CML.

Five FDA-approved TKIs inhibit this errant protein’s signal: Gleevec, Sprycel (dasatinib), Tasigna (nilotinib), Bosulif (bosutinib) and Iclusig (ponatinib). Gleevec was the first TKI, but second-generation drugs Sprycel and Tasigna have joined it as first-line treatments and may induce a stronger response than Gleevec. Bosulif and Iclusig are currently only used in patients who develop resistance or intolerance to the three first-line TKIs or develop a mutation, such as the T315I mutation.

Starling had become one of the more than 8,000 people newly diagnosed with CML in the United States each year. Soon she would become one of more than 70,000 people in the U.S. who live with it daily. And just over three years later, she would be among a few thousand or so to experience treatment-free remission.

 “As a mom, I can go through a lot, as long as my kids don’t have to witness it, so it was a relief that my family wasn’t going to have to watch me get chemo and all those side effects,” says Starling. But she wasn’t anticipating how the side effects of Sprycel would knock her almost as flat as chemotherapy might have. The TKI that patients start taking first depends on their age, lifestyle, other health conditions, insurance coverage and, sometimes, personal preference. If they cannot tolerate the side effects of that TKI after a reasonable trial, they may switch to another. Starling’s doctor had given her the choice of Sprycel or Tasigna; she chose Sprycel to avoid dietary changes required for Tasigna.

“The first four months, I had every side effect there was and ended up in the hospital for eight days while they tried to figure out what was going on,” she says. Starling had a fever for nearly a month, developed a rash, always felt exhausted, and ended up with almost a liter of fluid in her left lung, a condition called pleural effusion, which is a known side effect of Sprycel. Some of these symptoms likely came from the Lyme disease she didn’t know she had until her immune system became weakened enough for symptoms to appear.

After the standard course of antibiotics, the Lyme disease cleared up, but she still felt exhausted and had developed rheumatoid arthritis for what her doctor believes is as a result of the Sprycel. “I tried to pretend like this was not going to be a big deal because they told me ‘life’s not going to change, and you’ll be fine, just take the pill,’ but I was tired all the time,” Starling says.

Her experience was not unique. TKIs are remarkably effective in halting CML — Gleevec caused 10-year survival rates to jump from less than 20 percent to more than 80 percent &mdash; but anywhere from a third to more than half of those taking a TKI experiences side effects ranging from mildly uncomfortable to utterly unbearable. In fact, due to side effects and possibly other reasons, compliance with treatment, even though life-saving, is far from ideal.

Common side effects with Gleevec include nausea, fluid retention, swelling around the eyes, fatigue, diarrhea and muscle cramps. In addition to pleural effusion, rash and fatigue, Sprycel can cause nausea, diarrhea and headache. Less commonly, it can cause anemia, a low white blood cell count (neutropenia), a low platelet count (thrombocytopenia) and high blood pressure in the lungs (pulmonary hypertension). Tasigna can come with low blood counts, pleural effusion, rash, headache, nausea, diarrhea and itching. Rare, but more serious concerns with Tasigna include high blood sugar (hyperglycemia), pulmonary hypertension or swelling of the liver or pancreas, and both Sprycel and Tasigna carry cardiac risks.

When Starling’s doctor asked if she wanted to switch to another TKI, she declined. The side effects were awful, but Starling had responded to Sprycel faster than anyone else her doctor had ever seen. The primary goal of CML treatment is a thousand-fold reduction in leukemia cells, called major molecular response (MMR), ideally within 12-24 months. MMR follows a first-level hematologic response (a tenfold reduction, ideally achieved within three months) and a cytogenetic response (absence of Philadelphia chromosome in marrow cells). Starling had reached MMR — just 0.4 percent of her cells had the Philadelphia chromosome &mdash; in less than four months. Yet she was only taking 100 mg of Sprycel, the dose most people start with before titrating up to 140 mg.

 “It was magical. It worked so fast that I said I don’t want to leave this one,” says Starling. But she wanted a lower dose. “I talked to my oncologist and said if it worked that well, I’d like to try 70 mg,” she adds. She figured the awful side effects occurred partly because the dose was high for her, even if it was low for most people. Dropping to 70 mg goes against the recommendations for Sprycel, but her oncologist agreed, and she continued to improve. Within a year, she reached complete molecular response (CMR), with less than 0.003 percent of her blood cells containing the Philadelphia chromosome. She dropped down to 50 mg.

“My husband and I talked about it and decided if I could maintain CMR on any dosage, then we would ask for the next lower one,” Starling says. She knew what she was doing was completely contrary to Sprycel protocol, but three years and three months after starting therapy, Starling became a “CML outlier,” as one of her oncologists called her.

She enrolled in the LAST trial — Life After Stopping Tyrosine Kinase Inhibitors study, which is ongoing &mdash; and joined a small, intermediate number of other people in the world who had been able to safely stop taking TKIs without the CML roaring back.

STOPPING TKIS TO ACHIEVE TREATMENT-FREE REMISSION

In the French STIM trial, the first to explore ending TKI treatment, the 100 participants had maintained a deep response for at least two years before discontinuing Gleevec; 39 percent maintained a deep molecular response 24 months after stopping and none who relapsed saw their disease progress. In another small, early study, TWISTER, 47 percent of patients maintained treatment-free remission at 24 months. In trials that followed, stopping Sprycel and Tasigna showed slightly higher success rates, and larger trials in Europe such as EURO-SKI, have now established that somewhere between 50 and 60 percent of ideal patients safely and successfully stop TKI therapy.

“I think it’s clear that some patients can safely stop therapy,” says Jorge Cortes, M.D., chief of the CML and AML sections and deputy chair of the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas. “But I think there is still concern because, number one, I don’t think everybody understands in what patients it is safe to stop.”

The other major concern is whether potential candidates receive frequent and sensitive enough monitoring to be sure their values are accurate. “Not everyone has a polymerase chain reaction (PCR) that’s that sensitive or even know the sensitivity of the assay they’re using,” Cortes adds.

Until very recently, a debate among researchers questioned whether patients should have to be in clinical trials to attempt stopping TKI treatment or whether any appropriate candidates could do so with their oncologist’s supervision. “Does everyone know who can stop, and can they be monitored correctly?” asks Ehab Atallah, M.D., an associate professor of hematology and oncology at Medical College of Wisconsin and Froedtert Hospital in Milwaukee and a lead investigator of the LAST trial. “If both of those are satisfied, there should be no problem in discontinuation.”

 The ideal patient has taken a first-line TKI (not Bosulif or Iclusig) for at least three years and has sustained an MMR (identified as a percentage or a log reduction) for at least two years, assessed every six months with adequately sensitive PCR testing. Atallah requires a PCR value of less than 4 logs, and Cortes requires patients to have a 5-log reduction in their cancer cells. Most studies have required at least a 4.5-log reduction.

“The duration of the deep response is very important,” Cortes says. “In our experience, that seems to be more important than the duration of treatment itself, and it’s very difficult to differentiate the duration of deep response from the duration of treatment.” In the EURO-SKI study, for example, each additional year of treatment increased patients’ odds of maintaining MMR by 16 percent six months later.

Ideal candidates for stopping therapy should also have always remained in the disease’s chronic phase — never advancing to accelerated or blast phase. Most CML patients receive their diagnosis in chronic phase, when less than 10 percent of their blood or bone marrow samples contain immature cells called blasts. Patients with 10 to 20 percent blasts who are not improving are in accelerated phase, and more than 20 percent blasts in the patients’ marrow or blood cells indicates blast phase.

Proper monitoring after stopping TKIs ensures oncologists don’t miss any early signs of a relapse, says Aref Al-Kali, M.D., assistant professor of medicine and the program director for leukemia fellowship at Mayo Clinic in Rochester, Minnesota.

“It is critical that it is done in the right setting, in the right patients, with the right understanding, with the right monitoring,” Al-Kali says. “You don’t want to create a problem for patients who are, by definition, doing well.”

After stopping TKIs, people should undergo testing monthly for the first six months, then every two months for the next 18 months and every three months thereafter for life, though some slight variation in this schedule exists.

Patients who have switched from one first-line TKI to another because of side effects to achieve an even deeper response have shown similar chances of successfully stopping treatment. Patients who develop resistance to one of the TKIs, however — those who have a relapse or don’t initially respond optimally &mdash; have a lower likelihood of successfully stopping treatment, estimated at 30 percent success based on one small, unpublished trial, Atallah says. But no other factors &mdash; age, sex, other health conditions &mdash; appear to affect whether patients do or don’t relapse.

“We have no idea why some people relapse and some don’t,” he says. “That’s one of the big areas of research.”

SHOULD YOU STOP TKIS? THE ADVANTAGES AND DISADVANTAGES

The three main physical risks of stopping TKI treatment, according to Al-Kali, are withdrawal symptoms, relapse of the disease and, very rarely, progression of the disease. Most people who stop TKIs and relapse, then return to a deep response when they start the medication again, but 1 to 2 percent of people in the trials have seen their disease progress.

“It’s really about making the patient know the pros and cons of being on the drug versus being off the drug,” he says. “Make that decision in a dialogue that’s patient driven.”

Relapse, for example, can be both psychologically and physically painful. The side effects a patient experienced with the TKI initially may return, which can lead to anxiety and depression for a short period of time.

In addition, about 30 percent of patients, who stop TKIs, experience joint, bone and muscle pain during withdrawal. When Starling took her last Sprycel on November 18, 2015, it wasn’t smooth sailing.

“The first day without Sprycel was one of the most excruciating days I’ve ever had,” Starling says. “My long bones and my hips — I hurt all over. I remember crying and thinking, ‘Man, 20 mg of Sprycel and I don’t have to go through this, but I wanted to do my part to help write the next book on CML.’ ” She persisted, and the intense pain eventually passed. But for some, the bone and joint pain is so painful that they return to TKI treatment.

Of course, the side effects of taking TKIs is one of the major reasons many people want to stop. Further, patients who have diabetes or have experienced a stroke or heart attack may want to stop treatment to reduce any additional cardiac risks or to more easily manage their diabetes, Cortes notes.

“Lastly, is long-term toxicity, which we don’t know about at all,” Atallah adds. “Up until now, there has been no signal that there is long-term toxicity, but we don’t have data for 30 and 40 years out.”

Another reason a patient may want to stop TKIs is to conceive. Cortes says he sees younger women who want to become pregnant. Most research on TKIs during pregnancy comes from animal studies, which show significant negative effects on the fetus, such as severe neurologic problems or deformities.

Perhaps the biggest reason to stop treatment is financial: TKIs carry a hefty price tag. Gleevec cost $26,000 to $30,000 a year in 2001, but has since tripled. As of 2013, TKIs cost patients $92,000 to $138,000 annually, with no sign of dropping even though pharmaceutical companies had long since recouped development costs for drugs no one expected to become lifelong therapies.

 However, Al-Kali points out, that may change this year: In February 2016, the first generic imatinib (Gleevec) became available. In 2017, more generic imatinib may become available, so the price of Gleevec may drop to compete, possibly putting market pressure on the other first-line TKIs to drop in price as well.

Despite the advantages, people who choose to stop TKIs should not necessarily expect massive changes in their lives. “Interestingly enough, a few studies looked at the quality of life of patients, and, on average, it doesn’t change much,” Cortes says. “That is important to manage expectations.”

For Starling, stopping seemed like the next logical step. But now, in addition to the withdrawal pains, she’s contending with guilt she didn’t anticipate since many friends she made in the CML community are still dealing with what she’s largely left behind.

“It’s been a blessing, even feeling a little lost and not knowing where I stand in the CML community — that’s OK,” says Starling. “It’s even more fulfilling knowing that this data is actually going to benefit someone.” Her participation in the LAST trial may help guide decisions for current and future CML patients.

“Taking a disease that 20 years ago was a death sentence and it’s now turned into something that I haven’t had to take anything for in 14 months, that’s amazing.”

Features

Hope is growing for patients who are living with CML. 

A New Chapter Begins With CML

By January 2016, Jami Cameron of Fort Myers, Florida, had really been through the wringer: Beginning in 1994, she’d had lymphoma in her breast and in one eye, breast cancer, a mastectomy, multiple lashings of chemotherapy and radiation, a third recurrence of lymphoma and a bone marrow transplant. Now her lymphoma was back for the fourth time, chemo-resistant and so big she could see the tumor in her pelvis as it pushed on her nerves and caused excruciating pain. Her medical team gave her just months to live.

“There was no treatment,” says Cameron, now 53. “I didn’t qualify for anymore chemo or radiation. My bone marrow was so depressed from the previous treatments that I couldn’t tolerate a chemotherapy regimen.”

Then, a treatment counselor at the Leukemia and Lymphoma Society suggested a clinical trial of chimeric antigen receptor T-cell (CAR T) therapy, a new technique in which doctors extract some of a patient’s immune cells, alter them, and then re-infuse them into the bloodstream to jump-start the patient’s own immune system to fight their cancer. Cameron, a retired nurse practitioner, emailed the researchers immediately. Within a week, she was in Boston at Massachusetts General, signing consent forms for the study Three days after receiving her CAR-T infusion, Cameron could no longer see the tumor that had been bulging out of her pelvis. She left the hospital six weeks later, and remains in remission today.

“I thought I would not be able to see my daughter’s wedding,” Cameron says. “Now, I will be able to see it. I’m well. I’m not just existing, I’m really living.”

For decades, the pillars of cancer treatment have been surgery, chemotherapy and radiation.

Then, beginning in the 1980s, monoclonal antibodies have been able to target specific molecular changes or markers in cancer cells. Now, despite a few false starts over the last 20 years, the oncology community is beginning to get excited about immunotherapy, training patients’ immune systems to fight their own cancer. Some are even saying this could be the “fifth pillar” of cancer treatment.

Research teams are going at immunotherapy from many different directions, but some of the best early results have been with CARs in which certain immune cells, called T cells, are genetically engineered to zero in on particular markers found on the surface of cancer cells. In small, early studies, as many as 80 to 100 percent of patients responded to CAR-T treatment, prompting the U.S. Food and Drug Administration (FDA) to award breakthrough status to CAR-T treatments for B-cell malignancies such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), as well as in B-cell lymphoma and non-Hodgkin lymphoma. Beginning in 2013 and continuing today, these early results have led to a flurry of academic-business partnerships and hundreds of new research studies seeking to refine the treatment, and to see if it might be useful in more common blood cancers and solid malignancies.

 “We are at a watershed moment,” explains Renier Brentjens, M.D., of Memorial Sloan Kettering Cancer Center, the institution that published the first CAR-T study. “There is massive enthusiasm for CAR T, but also massive expectation. I think we can get there, but there are still many obstacles to overcome.”

Brentjens was part of a team that nearly 20 years ago showed that T cells with an added receptor for an antigen called CD19 could kill cancer cells in a Petri dish. That was followed by studies in mice showing that the CAR-T cells could stamp out cancer 50 to 100 percent of the time. But in the early 2000s, the researchers ran into challenges. It was difficult to find a “vector” that could insert the edited DNA into the T cell. It turned out that tumor cells could evade and suppress the edited T cells, and that it couldn’t be taken for granted that the changed T cells would multiply and thus persist in the patient’s bloodstream.

Today — thanks to advances in “gene editing” technology, as well as better understanding of the biology of both the T cells and the cancer &mdash; CAR T has begun to overcome these hurdles and show dramatic results in some blood cancers. In some leukemia patients who have relapsed, the still experimental treatment has helped 80 percent achieve complete response, whereas only 10 percent might respond using more traditional treatments.

In the studies done to date, CAR T primarily has been used in patients who have not responded to several lines of treatment. Many are just months, even weeks, from death. “How is CAR T better?” That’s an easy one,” says Ira Braunschweig, M.D., clinical program director, Hematologic Malignancies at the Montefiore Einstein Center for Cancer Care in the Bronx. “In patients with relapsed, refractory leukemia — both sexes, adults and children &mdash; who went into complete remission with CAR-T cells, there’s no other therapy that can offer that [kind of prognosis] to that kind of patient.”

Researchers often call CAR T “a living therapy.” That’s because the technique uses 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.

First, the doctors take a sample of the patient’s blood and isolate the T cell. In the lab, they insert a new gene that makes the patient’s T cells very sensitive to CD19, a particular marker on the surface of B cells, also expressed malignant B cells. Then, they enlist the help of a disabled version of the virus that causes HIV, which is efficient at getting the modified gene back into the T cells.

Meanwhile, the patient usually goes through some chemo to make room for the new cells. Then, the edited T cells are dripped back into the patient’s circulatory system. If all goes well, then 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 therapy is cell therapy, gene therapy and immunotherapy all rolled into one. Experts say it represents a radical departure from all medicines to date.

“A cell, as a drug, is a whole lot more complicated than an antibody or a vaccine,” explains Bruce Levine, Ph.D., who directs the lab for the University of Pennsylvania CAR-T team. “It’s all very labor intensive.”

Taking place in the context of academic studies, this complex process has proved quite expensive. The procedure may be similar in cost to a stem cell transplant. Estimates for CAR-T therapy vary, but could run anywhere from $300,000 to $750,000. Experts say that as the process becomes more efficient, and available to more patients, those costs will come down. But because all of these techniques are waiting for FDA approval, the costs haven’t dropped as of yet.

Not only this, but severe side effects from CAR-T therapy can emerge suddenly, requiring teams of specialists to keep patients alive while their immune system ratchets up to fight their cancer. Adding juiced up T cells to the immune system can make things go haywire.

Douglas Olson, 70, a retired biochemist in Pipersville, Pennsylvania, was the third patient to receive CAR-T therapy at the University of Pennsylvania. His CLL had gone into remission twice, but then the cancer mutated, making it more difficult to treat. About two weeks after his CAR-T infusion in 2010, Olson began to feel very sick.

“I got all excited that I felt terrible, I felt that it had to be working,” Olson says. “I was in the hospital for three days. Then a week after that, my doctor told me they couldn’t find a cancer cell anywhere.”

Olson experienced one of the dangerous side effects of CAR-T treatment, tumor lysis syndrome, in which the T cells destroy so many cancer cells that the massive release of all those cell fragments into the bloodstream causes a variety of metabolic problems, straining the kidneys, causing heart rhythm problems and seizures.

In various studies, patients receiving CAR-T treatment have developed neurotoxicities that caused problems speaking, delirium and hallucinations.

CAR-T patients may also suffer a “cytokine storm,” when the immune system ramps up so much, that it releases too many cytokines, such as interleukin (IL), the proteins that signal the immune system to react.

This can result in labored breathing, rapid pulse, high fevers and decreased blood flow to internal organs. It can be treated with supportive care like hydration and respiratory support, as well as specialized medical therapies such as corticosteroids or through targeting IL-6, a cytokine that drives some of the major toxicities, by using the IL-6 receptor antagonist Actemra (tocilizumab).

 Just after she became the first pediatric patient to receive CAR-T therapy, Emily Whitehead, now 11, had a cytokine storm so severe that her medical team put her into an induced coma for 14 days.

“When Emily got her treatment, things went out of control,” says Tom Whitehead, Emily’s father.

“One night, the head of the ICU said, ‘She’s not going to be here tomorrow.’ I said, ‘She will.’” She’ll be five years’ cancer-free in May 2017.

“Now parents call us from all over the world. We tell them, ‘We can’t tell you that it will definitely work, but when it does, it’s amazing.’”

It may still be a year or two before any of these treatments becomes widely available. At the front of the race is Kite Pharma, which has already submitted the agent KTE-C19 to the FDA. In an interim analysis of the ZUMA-1 trial, KTE-C19 demonstrated positive results for patients with chemorefractory aggressive non-Hodgkin lymphoma. In December, the Swiss pharma company Novartis reported that 82 percent of the patients in its worldwide, phase 2 CTL019 study (41 of 50) achieved remission, and said that based on those results it would apply for FDA approval in early 2017.

Hundreds of CAR-T clinical trials are ongoing, or recruiting patients. Large pharma companies are partnering with academic teams or startups: Novartis with University of Pennsylvania, Celgene with Baylor College of Medicine, Amgen with Kite Pharma, Intrexon with MD Anderson. They are trying to make the process of culturing CARs more efficient, to manage side effects, and make the treatment applicable to more kinds of cancer. They are also looking for new antigen targets, particularly ones that occur only on tumor cells, not on healthy ones.

All CARs include a piece that recognizes the tumor marker and a piece that signals the immune system to act. Juno Therapeutics and others are working on a second generation of so-called armored CARs that incorporate an additional signaling protein that puts out an even stronger all-points bulletin for T cells to activate and recruit each other. Others are trying to optimize accuracy by incorporating genes that urge the cell to look for two targets on the surface of malignant cells, not just one. Or the CARs may require the presence of both an antigen target and a drug in order to activate the immune response. The hope is that one or more of these strategies will make CARs more accurate: targeting only cancer cells and not healthy ones.

A third generation of CARs may include three immune-stimulating factors. Meanwhile, Bellicum Pharmaceuticals in Houston, Texas, is splitting the antigen-recognition piece from the stimulating piece, creating a molecular suicide switch that can modulate T-cell activity, in case of bad side effects. Ziopharm Oncology, a Boston startup, is exploring ways to mute the T cells without killing them.

 Other researchers are exploring using non-viral methods of getting the edited DNA into the T cells in the first place. And some teams are trying CAR T-cell therapy with other immunotherapies such as checkpoint inhibitors that could act as “on-off” switches for T-cells.

At least one company is exploring if they can develop off-the-shelf CARs, agents that would not have to be isolated from a patient’s cells, but could be a ready-made template that could be altered to order, even if a patient doesn’t have enough healthy B cells to culture.

“In our early studies, we find that these off-the-shelf CARs are very potent,” says André Choulika, Ph.D., chairman and CEO of Cellectis, the company exploring this approach. “We think that may be because we start with healthy cells, not ones battered by chemo.”

Many experts hope that the CAR approach may someday be used against new targets in solid cancers, such as EGFR in glioblastoma or CMET in other solid tumors. Various current studies are exploring CARs to fight sarcoma, a cancer of soft tissue, advanced prostate cancers, multiple myeloma, tumors of the chest cavity, mesothelioma, lung, breast and ovarian cancer. In a December 2016 case study, a report of just one patient, a patient close to death because of glioblastoma, a brain cancer, had CARs transfused into both his tumor cavity and his cerebrospinal fluid. The patient, a urologist with a busy practice, made such a full recovery that he was able to return to work.

“Really applying CARs in solid tumors is our next frontier, our next challenge,” says Christine Brown, Ph.D., associate director of the T Cell Therapeutics Research Laboratory at City of Hope, in Los Angeles, and the scientist who oversaw the glioblastoma case. "Our goal is to show that this therapy can have promise against many other tumors not just those that have the CD19 antigen.”

The application to solid tumors remains challenging, experts say. Blood cancers are essentially the excessive 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 the immune response. And then there’s the question of delivery: tumors may occur deep within healthy tissues. “We have really opened the door to use the human immune system to cure cancer in the last two or three years,” says Andrew Pecora, M.D., vice president of Cancer Services at John Theurer Cancer Center in New Jersey. “We’re in the first room of this house, so to speak. It’s so exciting and profound. There are lots of reasons to be hopeful. That’s not hype. That’s real.”

CAR T-cell therapy is drastically changing the landscape of cancer treatment.

Zeroing In on CAR T-Cell Therapy

When it comes to clinical trials, many patients are skeptical that joining one will offer them the best treatment for their cancer. Others worry that even just getting to the trial site is one hurdle too many, or they believe that the process of enrollment and repeated follow-up visits is too cumbersome and will pose yet one more hardship on their already overburdened family caregivers.

Clinical trials can result in major cancer treatment breakthroughs and many patients benefit from participating in them. Today, such research has become even more critical with the many personalized therapeutic approaches that are now available based on an individual’s tumor characteristics, allowing treatments to be tailored to a patient’s specific genetic profile. Nonetheless, cancer clinical trials attract less than 5 percent of all adult patients with the disease, and the recruitment challenge is even greater among African-Americans and other ethnic groups who, the research shows, are underrepresented in these studies.

Against this backdrop, Takeda Oncology convened a special industry/advocacy forum at the recent annual meeting of the American Society of Hematology in San Diego, California, focused on strategies aimed at closing the clinical trial diversity gap, overall — and specifically, in the multiple myeloma setting. The panel, moderated by Fatima Scipione, senior director of patient advocacy for Takeda, featured perspectives from the survivor, health care provider and research community &mdash; all sharing the goal of increasing minority participation in clinical trials.

“In some ways, myeloma has been the ‘poster child’ for demonstrating this disparity,” explained panelist Daniel Auclair, Ph.D., senior vice president of research at the Multiple Myeloma Research Foundation. He noted that the rate of this disease is about two to three times higher among African-Americans, yet their genetic abnormalities are less aggressive. “In theory, if [African-Americans] received equal access to treatment, they should do as well, or even better.”

One of the biggest obstacles to clinical trial participation, these stakeholders agreed, involves proximity and access to the trial. While many cancer clinical trials are designed and led by investigators, at large, academic cancer centers, many patients with cancer — and especially those minority groups currently underrepresented &mdash; receive their cancer care in the community setting.

It can be very difficult to enlist and identify people for clinical trials if they’re not part of the larger networks and the systems everyone typically uses to share information and recruit patients, explained multiple myeloma survivor and patient ambassador Cheryl Boyce. She called for “bridging those community doctors with people who are at the comprehensive cancer centers to have a dialogue and ensure that, at least once a year, those patients get into a comprehensive cancer center to be seen.”

Leveraging technology represents one way to facilitate the interface between clinical trials being run out of larger cancer centers and patients who find transportation to these centers an obstacle. Web-based technology can help, said panelist Tricia Mangan, R.N., M.S.N., who serves as lead nurse for hematologic malignancies and bone marrow transplant at the University of Pennsylvania’s Abramson Cancer Center. “It is hard to go on a clinical trial. There are many more visits to the office, more blood drawing, more bone marrow biopsies.”

Given that, part of trial participation involves assessing for toxicities and blood abnormalities, Mangan suggested that patients be enabled to go to their local oncologist and click onto a computer to speak with the principal investigator on the study to discuss their treatment and side effects in real time — “that’s an untapped resource.”

Granted, some patients may not be up-to-speed on the technology, she acknowledged, but, “if we can build the infrastructure within our health care systems, that could be really helpful to drive a more diverse population to a trial.”

Given the controversy surrounding the early study of untreated syphilis in black men in Alabama, dating back to 1932, people may be surprised to learn that it holds useful lessons for those hoping to enroll a more diverse pool of patients in clinical trials today.

Although leaders of this Public Health Service trial, known as the “Tuskegee Study of Untreated Syphilis in the Negro Male,” did not follow what are now considered standard and essential study protocols, such as informed patient consent and offering the men who had syphilis the antibiotic penicillin when it became the accepted treatment in 1945, organizers were nonetheless successful in their messaging to drive enrollment in the study.

“Most people would be appalled by Tuskegee,” explained Boyce, yet some of their "low-tech” recruitment strategies still make sense. For example, the research team sent out reading material to local stores, churches, schools and barber shops to help recruit patients for the study.

“We can put all of the information out on the Internet, and even though that may help improve awareness and increase education, the computer is not going to build the trust that’s necessary for people to enter and stay in a clinical trial,” she said.

Boyce added that another secret to the study’s success was the personal touch, which, in this case, took the form of nurse Eunice Rivers, who had grown up in that region of Alabama. “Everybody knew her and trusted her,” said Boyce. “Their trust was in her, not the U.S. government … people believed her.”

Those looking to boost clinical trial recruitment in today’s health care environment should keep in mind that the effort is “a marathon and not a sprint,” said Boyce. “It means building those relationships with people who are known in the community and trusted and respected,” and making sure that those trusted messengers not only fully understand the trial information they are sharing with potential recruits, but also believe that what they’re sharing with the community will benefit patients.

“That’s where the legitimization will come.”

The impact and sway of a trusted health care provider in explaining the benefits of clinical trial participation cannot be overestimated, Auclair said. He pointed to a study exploring the reasons why more African American patients don’t participate in clinical trials. That study found that only 14 percent of the patients recalled a trial opportunity being presented favorably to them.

Other reasons cited, among those who declined to participate in a therapeutic clinical trial, included misunderstanding the trial information, fear of side effects and worry over burdening their family members.

Even explaining clinical trials to patients and family members is time-consuming, explained Mangan. As a result, streamlining — and sensitively targeting &mdash; explanations in a way that they can understand is key. Clinical trial consent forms can run as long as 15 to 20 pages, and merely telling patients and families to, “take this home and let me know if you’re interested,” doesn’t provide them with much of an incentive to enroll.

“We need to make sure that patients understand the issues: why they are being considered for the trial, how they may benefit, that they may be randomized to the other arm and why we think the trial is in their best interest,” said Mangan. And, if English is not their native language, ideally, a translator would be present for the discussion.

Unfortunately, the old paradigm of patients in trials believing that they are “human subjects” persists, said Auclair, who advocates a way of thinking about these trials that is rooted in the notion of patients being “active participants in the research.” Sharing their side effect experiences is a good example. Given that clinicians often underreport drug side effects, these patient-reported outcomes offer considerable value to researchers.

A more diverse clinical trial pool also means better science and “smarter trials,” Auclair said, because in some cases, varied ethnic or age groups — even women versus men &mdash; will respond differently to a particular therapy. “You need meaningful numbers of patients in these groups to pick up on that kind of nuance,” he explained.

Boyce recommended a national awareness campaign involving the many stakeholders, such as the oncology professional societies and cancer advocacy groups. The goal of such an effort would be to “raise the bar” to help patients understand precisely what it means to be part of a clinical trial, and that enrolling means, “much more than just putting someone in one group where they get the medication and another group where they don’t get it.”

This patient-as-research-partner model underscores the benefits when clinical trial enthusiasts come from a larger sphere than just health care providers. As Auclair explained, “I’ve seen very interesting initiatives where patients who have been on clinical trials themselves serve as patient educators and ambassadors,” encouraging fellow patients to learn more about their disease and enroll in trials that are right for them.

Boyce wholeheartedly agreed: “I would love to see inclusion of diverse populations in clinical trials to become truly a priority for this country.” This, she said, will require a Cancer Moonshot type of effort that clearly identifies payment mechanisms and support services to help break down barriers to participation.

“This is hard to do, it will take time,” concluded Mangan, who stressed that community oncology practices, primary care physicians and patient advocates, especially those in underserved areas, are all crucial to the effort to overcome the barriers and recognize the biases. These are themes that should be emphasized early on in medical and nursing school programs.

“It’s about working together to build that trusting relationship.”

Diagnosis Cancer

It is vital to have diverse groups of patients register for clinical trials so that treatment advances can continue to be made.

Hematology Special Issue (March) | CURE