The rarest of rashes

By the time he came to Stanford , Joe Carey had been sick for a decade. In 1993, in his mid-40s, he’d noticed a scaly red patch of skin on one thigh. Then other, similar patches had started to appear all over his body. His dermatologist told him to rub a mild cortisone cream on the spots, but they persisted, uncomfortably itchy eyesores that Carey was sure weren’t normal.

Yet tests for allergies, psoriasis and eczema came up empty handed. A full two years after he’d first noticed the patches on his skin, a doctor at the Mayo Clinic finally gave him a diagnosis: cutaneous T-cell lymphoma, a rare cancer. Over the next eight years, Carey underwent 200 sessions of UV light therapy and 36 radiation treatments, tried countless creams, and injected himself with medicine multiple times a week. But the cancer always came back.

“My symptoms were getting worse. I wasn’t happy with my life and where this was going, and I felt like I needed to bring in the heavy artillery,” Carey says. That’s when he scheduled an appointment at Stanford, a short plane flight away from his home in Arizona.

In the United States, only about 1,500 people a year are diagnosed with cutaneous T-cell lymphoma, mostly older adults, like Carey, who’s now in his late 60s. It’s a cancer of T lymphocytes, immune cells that normally circulate in the bloodstream to help the body fight invading pathogens. But when a person has cutaneous T-cell lymphoma, the lymphocytes grow uncontrollably in a place they’re not supposed to: inside the skin. Most cases of the condition, including Carey’s, begin as mycosis fungoides — which loosely means “mushroom-like fungal disease.” And although it can look like a fungus, there’s no microorganism involved. The rash associated with mycosis fungoides is a mix of infiltrating cancer cells and the skin’s reaction to the cancer cells.

While the mycosis fungoides form of cutaneous T-cell lymphoma can be slow-growing at first, lasting anywhere from months to years, if cancer cells escape the skin and begin flowing through the bloodstream or lymphatics, the disease becomes exponentially more serious — and harder to treat.

“Currently, we lack curative treatments,” says dermatologist Youn Kim, MD, the Joanne and Peter Haas, Jr. Professor for Cutaneous Lymphoma Research, who directs the Stanford multidisciplinary cutaneous lymphoma group. “Patients with advanced disease with adverse factors have a median life expectancy of less than five years.” Over the past decade, however, scientists have developed new treatments. Also, international collaborations, for the first time allowing large sample sizes of cutaneous T-cell lymphoma patients, are yielding results on how to manage the disease.

“What we have now is a larger armamentarium of new medicines which are somewhat more effective and less toxic,” says Steven Horwitz, MD, an oncologist at Memorial Sloan-Kettering Cancer Center who specialized in lymphomas. But there’s still work to be done. “We haven’t yet turned the corner in terms of fundamentally changing our approach to the disease,” Horowitz adds. “We’re still mostly treating to minimize symptoms, not to cure.” But researchers around the world, including Kim and her team at Stanford, and Horwitz’s group at Memorial Sloan-Kettering, are working to change that.

The dream team

Most lymphomas — a type of blood cancer — respond well to chemotherapy. Cocktails of drugs halt rapidly dividing cancer cells to keep the lymphoma at bay. But with cutaneous T-cell lymphoma, chemotherapy rarely works.

“We don’t know why yet,” says assistant professor of blood and marrow transplantation Wen-Kai Weng, MD, PhD, a Stanford oncologist and member of the cutaneous T-cell lymphoma group. “Maybe the drugs just can’t reach the skin.”

It’s just one of the things that makes treating the lymphoma so frustrating and complicated, and one of the reasons that Stanford’s group has turned to a team approach to fighting the disease. When patients with advanced cases of the condition visit Stanford for the first time, they’re not evaluated by just one physician. Instead, they walk into a room that’s full of representatives from diverse specialties: oncologists, pathologists, hematologists, dermatologists, radiation specialists and transplant doctors. Together, the team reviews and discusses the patient’s case, considering what each might offer. It’s a more focused version of the “tumor boards” that meet to discuss a broad array of cancer cases at most medical centers.

“I was very impressed with the team approach,” says Carey. “It’s almost a little bit intimidating because you’re sitting there in a gown in an exam room and a dozen people descend on you. But it also makes you confident they’re working together to do everything they can for you.” Of course, different parts of the exam are performed by different, individual doctors — one at a time — and each specialist has different questions, but the idea is that the clinicians collaborate on each patient.

To combat the skin symptoms of mycosis fungoides, the team often first turns to a special form of radiation. Aiming a beam of ionizing radiation at a small site, as is typical for breast or lung cancer, usually won’t work because mycosis fungoides occurs on many areas of the body at once.

In the 1950s, though, a group of Stanford doctors came up with an approach that could be used for this disease: They developed a technique to scatter electrons across a broader area. In the years since, researchers have further perfected what’s known as the “Stanford technique,” and today Stanford and many other institutions use total skin electron radiation.

A patient with cutaneous T-cell lymphoma being treated by the updated “Stanford technique” stands about 10 meters from a radiation source, with a large acrylic sheet in between to scatter the electrons. Then the patient carefully assumes six different positions.

“They even hold their arms in different positions so every bit of their body is hit. In the end, the entire circumference of the patient can be treated,” explains professor of radiation oncology Richard Hoppe, MD, the Henry S. Kaplan-Harry Lebeson Professor in Cancer Biology and co-director of the Cutaneous Lymphoma Clinic.

Hoppe and his colleagues are still optimizing the treatment; recently, they’ve discovered that when it comes to radiation for this illness, less can be more.

“What we’ve actually done recently is reduce the standard dose, which minimizes side effects,” says Hoppe. The reduced dose, they found, is just as effective at killing off cancerous T cells, but can be used more often throughout the course of a disease. And often, it’s incredibly effective at treating the skin tumors associated with the disease.

“One of the most rewarding things about working with this disease is that when a treatment works it benefits the patient so immensely,” Hoppe says. “They’re often very symptomatic and have horrible-looking, horrible-feeling skin. The treatment benefits their quality of life immensely.”

Now, Hoppe and his team are researching whether combining certain drugs with the radiation therapy might make the disease even more responsive to the therapy.

Of course, radiation doesn’t always work. Then it’s back to the drawing board, and back to the interdisciplinary cutaneous lymphoma group to discuss the case.

Stem cells offer new hope

Like Carey, Paul Raffer’s disease began with a rash. A rash that covered his entire torso and arms. A rash so itchy he couldn’t sleep and his skin started flaking and peeling off from the scratching. A doctor himself — a neurologist in San Diego — Raffer was used to looking for the most common diagnosis to fit a set of symptoms. “When you hear hoofbeats, think of horses not zebras,” doctors are taught. But Raffer had a gut feeling that his rash was something serious. And indeed, after visiting multiple specialists, he was diagnosed with cutaneous T-cell lymphoma, a zebra.

When cutaneous T-cell lymphoma spreads from the skin to the blood, it gains a new moniker: Sezary syndrome. And by the time both Carey and Raffer visited Kim’s group at Stanford, their diseases had progressed to Sezary syndrome, and stage 4 of the cancer.

“As a doctor, I did all the reading, and the reading was not very positive. I had an incurable disease,” says Raffer. “In my experience, stage-4 disease means the curtains are closing.”

But the team at Stanford had a new option for both of them: a blood stem cell transplant. Stem cells nestled inside a person’s bones act as constant factories of blood and immune cells, including the T cells affected by lymphoma. By taking the blood stem cells from a healthy person and giving them to a cutaneous T-cell lymphoma patient, doctors hope to take over their bloodstream with non-cancerous donor T cells.

Typically, stem cell transplants for lymphomas are tried after heavy doses of chemotherapy — with the aim to destroy a patient’s own blood cells before giving them new ones. But recently, Stanford doctors have started trying a new approach with the cutaneous disease.

“People have been doing transplants to treat lymphomas for a long time, but it’s never been successful with this particular lymphoma,” says Weng. “We’ve changed that over the last five years.”

Since chemotherapy is so rarely successful in minimizing cutaneous T-cell lymphoma’s growth, Weng decided to skip the chemotherapy that’s been considered a prerequisite to stem cell transplants. Instead, patients are prepared for the transplant with whatever combination of drugs and radiation the Stanford team deems most applicable to their disease — and that varies by person. The goal, Weng says, is to curb the spread of their disease as much as possible, and eliminate skin tumors, before sending in the new stem cells to finish the job.

For Joe Carey, it meant trying something new, after the constant itching from new tumors all over his body seemed like too much to handle. “I was at my wits’ end and things were moving in a bad direction,” says Carey. “I pleaded with Dr. Kim that I needed something to give me relief right away.” She suggested a clinical trial — for a new drug called mogamulizumab, produced by a Japanese pharmaceutical company. Within weeks of beginning the drug, Carey’s symptoms — which by then had lasted more than 15 years — began to wane. Tests showed his skin lesion clearing, lymph nodes shrinking and the number of cancerous cells in his blood dropping. In May 2011, stem cells were harvested from a donor in Europe (who had been identified as a match with Carey through an international database), flown across the Atlantic, and infused into Carey’s blood.

For Paul Raffer, preparing for his stem cell transplant took a different course. To lower the number of cancerous cells circulating through his body, Stanford doctors removed some of his blood, exposed it to ultraviolet radiation, and put it back in his body. Then, he was given a series of drugs — some of which worked, many of which didn’t — as well as Hoppe’s total skin electron beam radiation. Finally, in February 2011, Raffer received his stem cell transplant. Coincidentally, his cells also came from a European donor, who Raffer’s family has stayed in touch with to this day.

For both patients, preparing for the stem cell transplants presented a whole new host of challenges, including temporarily moving to Palo Alto for the course of the treatment. “I got really anxious that something would go wrong with the donor,” Carey adds. “If they got into a car accident or got sick, I wouldn’t be able to get the transplant.” But the cells destined for both Carey and Raffer made it across the Atlantic, and in 2011 they became two of the first handful of cutaneous T-cell lymphoma patients to receive a stem cell transplant using the new, non-chemotherapy regimen that Weng developed. Today, 32 patients have undergone the procedure at Stanford.

An international community

Despite its reputation as a hot spot for cutaneous T-cell lymphoma research and treatment, Stanford still sees a relatively small number of patients with the cancer — less than a hundred new cases per year. After all, only 1,500 people a year are diagnosed with the disease in the United States, and there are only about 16,000 patients total in the country. With those kinds of numbers, it can be hard to conduct research.

“When people publish single-center data, it can be interesting anecdotally,” Kim says. “But a small sample size doesn’t give you interpretable results.” To prove that a new radiation approach, drug or stem cell therapy is working, researchers need large numbers of patients to undergo the treatment. Not only does that let them have the statistical power to show whether it’s effective, Kim says, but it gives them the ability to find trends — to see which subgroups of patients it does or doesn’t work for.

That idea of statistical power is why Kim and the rest of the group at Stanford are leading the launch of an international consortium for cutaneous T-cell lymphoma research. In December 2014, representatives from 51 clinical research centers around the world convened at Stanford to discuss the disease and team up.

“Collaborations like this are absolutely essential for an orphan disease like cutaneous lymphoma, and Youn Kim has really been a leader at organizing this,” says Horwitz, who’s on the consortium’s board of directors. “In this field, more than any other I’ve worked in, people are much less competitive and more collaborative. We have to pull together to make things better.”

One of the first projects that Kim is spearheading through the consortium is the search for biomarkers — tests that can clump patients into groups predicting who will respond best to which treatment. By combining all their data sets, members of the consortium hope they can find genes, blood tests or immunological markers that can tell them whether, for instance, someone is likely to have a worse case of the disease and should be funneled toward a transplant earlier than other patients.

For cutaneous T-cell lymphoma, this kind of research is especially important, Kim says. “We don’t have any home-run mutations that explain a high number of cases like many other cancers do. There’s no mutation that’s present in 40 or 50 percent of our patients. This is an example of personalized medicine where in each person we have a different, relevant finding.” Rather than taking the trial-and-error approach largely used now to find the right treatment for each patient, Kim hopes the consortium can make it a more rational process.

The international group is also sharing approaches that have already worked for them. At a meeting in Paris, Weng presented his non-chemotherapy transplant approach and the detailed data he’s kept on just how well it’s worked for his patients.

“Already a large group in the U.K. has switched from using heavy doses of chemotherapy to adopting our protocol,” Weng says. In addition, a doctor at the University of Iowa just completed the first cutaneous T-cell lymphoma stem cell transplant there using the Stanford approach, and a large health-care system in Italy is considering making the switch.

Weng admits, though, that the approach might not work for every patient. That’s part of why he wants more centers to start trying it out.

“Transplant has a certain art to it. Why one thing works and not another is not always explained by science,” he says. “We want other people to generate more experience with our approach, so that if they have different results we can figure out why.”

It’s that kind of collaboration that’s moving the field forward, says Horwitz. “Five years ago, it was hard to see how we would ever be doing fundamentally better with this disease,” he says. “Now, we can at least see how we might get there.”

As for Raffer and Carey, both are still disease-free. Within a few months after each received his fresh donor stem cells, tests revealed that the donor cells had taken over the blood and eliminated the cancer. Four years later, they’re both pushing the limits on what can be expected after a cutaneous T-cell lymphoma diagnosis.

“We just saw Paul [Raffer] back in our clinic yesterday,” Kim said in late February. “He’s now four years out and still has no evidence of cancer cells. He would not be alive today if he didn’t go through the transplant. His life expectancy was less than a year. Paul is living evidence that finally we can cure this cancer. We are making transformative advances that give hope for our patients, their families and the physicians.” Today, Raffer is once again a practicing neurologist, has written a novel based loosely on his experiences with lymphoma, and enjoys spending time with his grandchildren. Carey, too, is enjoying his new lease on life, and credits his wife and a positive attitude for getting him through the ordeal. “I have no symptoms and I feel great,” he says. “I started this process when I was diagnosed at 45 years old and finally at 63 I got my life back.”