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Hope is on the Horizon

Conquest - Fall 2007

By Eileen A. Ellig

Anas Younes, M.D., wants no patient left behind.

He’s determined to give all patients with Hodgkin’s lymphoma a fighting chance.

A professor in M. D. Anderson’s Department of Lymphoma/Myeloma, Younes says it often can be difficult to get pharmaceutical companies interested in developing new drugs for a disease that affects only about 7,800 people each year and that already has a high survival rate, upwards of 85% at five years.

View video: Anas Younes, M.D., talks about clinical trials available for Hodgkin’s lymphoma at M. D. Anderson.

“But it’s not impossible,” he says. “You just have to do a lot of preclinical testing, provide a solid scientific rationale and show the true human impact of the disease.”

He and his team have been doing just that, working tirelessly in the laboratory to bring new therapies for Hodgkin’s lymphoma to the clinic.

While viewed as more curable than other cancers, “hidden from cure rates are the long-term side effects and development of second cancers,” he explains. “Not to mention that Hodgkin’s lymphoma strikes young people who have their whole lives ahead of them, only for it to be cut short because of the limited drugs available to treat the disease.”

Hodgkin’s lymphoma arises in the body’s lymphatic tissues, primarily involving the lymph nodes, which manufacture and store the all-important immune cells needed to help fight infection and disease. It also can affect other organs responsible for regulating the immune system and the production of blood cells, such as the spleen, bone marrow and thymus.

“Also hidden from view is the fact that nearly a third of patients will require additional therapy at some point,” says Younes, director of the department’s Clinical Investigational and Translational Research Program.

Thousands of these folks, he notes, have been hanging in there for years with little or no hope of a curative treatment after all current available therapies have been exhausted.

Kelly Stewart, a mother of three, was one of them.

Fourth time is a charm

Extreme fatigue had plagued Stewart for years, but blood tests showed nothing abnormal.

Her doctor chalked it up to age, weight and chasing after her kids.

But all along, she knew this wasn’t a “normal tired,” plus a red rim resembling a necklace circled the bottom of her neck.

It took a move to northern California in 2002 and a friend’s prodding before the true reason behind her fatigue was uncovered. A routine X-ray revealed a lemon-sized tumor in her chest.

Stewart had Hodgkin’s lymphoma.

A concoction of four different chemotherapy drugs — the standard, frontline therapy for Hodgkin’s lymphoma — put her disease into remission, only to return four months later. She was then referred to an oncologist at Stanford University, a day’s drive from her home in Stockton.

There, Stewart underwent a transplant using her own stem cells to fight the disease — and for six months they did so valiantly before losing their strength. The next best thing to try, she was told, was a transplant using someone else’s stem cells. This meant finding a compatible donor.

“My brother and sister were fighting over who would donate,” Stewart laughs. “My brother’s cells matched so he won,” and so had she for the next year.

Then, the disease came back. “My doctor at Stanford said, ‘I can treat you, but I want you to be cured. That’s my goal. I want you to go to M. D. Anderson and see what they have,’” Stewart recounts.

She wondered, could the fourth time be the charm?

So far, it appears to be.

On borrowed time

Just two weeks later, Stewart boarded a plane headed to Houston, balancing hope in one hand and despair in the other.

After several standard treatments failed, Kelly Stewart began taking an investigational agent that quickly eliminated her tumors.

Hope would prevail, as she soon discovered she had many options. “Dr. Younes was so positive, and there were so many things available to me that it really renewed my spirits,” Stewart says.

Several years ago that wouldn’t have been the case, Younes notes. “But today, we can offer patients like Kelly the opportunity to participate in several clinical trials that may give them more hope.”

Stewart was faced with a tough decision — which clinical trial to try. After careful consideration, she decided on a protocol testing an investigational agent that inhibits proteins supporting cancer cell survival. These proteins are called histone deacetylases, or HDACs for short.

To date, 18 different HDACs have been identified in human cells. Many of them have been linked to cancer cell growth and survival. Targeting HDACs with a new class of drugs called HDAC inhibitors is a hot strategy in cancer therapy, Younes says.

One HDAC inhibitor called vorinostat already is approved for treatment of a rare type of T cell lymphoma involving the skin. At least five other HDAC inhibitors are currently being tested in clinical trials in several cancers.

In laboratory studies, Younes and his team showed that HDAC inhibition may be a good strategy for treating Hodgkin’s lymphoma. They quickly designed a clinical trial to test the activity of a novel HDAC inhibitor called MGCD0103 in patients with relapsed Hodgkin’s lymphoma.

Younes says early results of this Phase II clinical trial have been very encouraging. At the annual meeting of the American Society of Clinical Oncology in June, Younes and his team reported that 40 percent of patients had major clinical responses to the experimental drug. Stewart was among them.

Like Stewart, these patients have tried virtually every treatment available, from chemotherapy to radiation to stem cell transplants, only to have those therapies ultimately fail them, Younes says.

Shortly after taking MGCD0103 orally three times a week, her tumors had shrunk considerably and then completely disappeared. She’s been in remission for more than a year.

Now, Younes and his group plan to build on this success and combine MGCD0103 with other drugs to enhance its effectiveness. They’re also studying exactly how this agent works in Hodgkin’s lymphoma. One theory is that MGCD0103 not only kills the cancer cells directly, but also may boost the immune cells to make them more competent in fighting the tumor cells.

“Hodgkin’s lymphoma is a unique and intriguing cancer because the primary cancer cells are less than one percent of the mass,” Younes says. “These so-called Reed-Sternberg cells originate from premature B cells that fail to develop into normal, mature functioning immune cells. The rest of the tumor mass is made up of reactive inflammatory cells, which is a normal immune response to any injury, infection or disease.”

With such an overwhelming advantage, “you would expect these immune cells to kill the tumor. But they can’t,” he says. “What we find is they’re actually collaborating with the cancer cells, providing support by secreting factors that help the cancer to grow. It’s the ultimate immune betrayal.” 

He believes MGCD0103 is influencing the reactive immune cells either by turning them into killer cells, or simply by getting rid of them.

Whatever the case, Stewart is happy it’s working.

She has been through a lot over the years. “But I have come out on the other side really well. I’m hoping this drug will keep me in remission. If this nasty disease decides to come back, I know I still have lots of options. I just live with it as best I can and hang on until they come up with something better.”

Plenty more options

Younes believes the most rational treatment approach will be to combine these new active agents with current standard regimens, such as ABVD or ICE chemotherapy.

ABVD (Adriamycin®, bleomycin, vincristine and dacarbazine) is widely used in patients with newly diagnosed Hodgkin’s lymphoma, while ICE (ifosphomide, carboplatin and etoposide) is used in patients whose disease relapses after ABVD treatment.

Ultimately, Younes hopes that a combination of several new drugs will replace chemotherapy and provide a higher cure rate with reduced short- and long-term toxic effects.

Currently, there are several clinical trials evaluating novel agents, either singularly or in combination with standard therapy, for the treatment of Hodgkin’s lymphoma.

They include:

  • Pairing rituximab (Rituxan®) with ABVD chemotherapy 

Already approved to treat non-Hodgkin’s lymphoma, rituximab is a monoclonal antibody that targets CD20, a molecule expressed on the outside of a cell. While the Hodgkin’s lymphoma Reed-Sternberg cells typically aren’t CD20 positive, about 20% of these cells will express it, says Michelle Fanale, M.D., assistant professor in M. D. Anderson’s Department of Lymphoma/Myeloma.

An earlier study showed that when used alone, rituximab decreased the number of CD20 positive Hodgkin’s lymphoma cells, Fanale says. It also wiped out the surrounding non-cancerous B cells, which nearly universally express CD20 and support the Reed-Sternberg cells’ growth.

These findings led to a Phase II clinical trial, testing whether rituximab plus ABVD chemotherapy could actually increase the number of patients who can be treated successfully.

“In the majority of patients, we’re seeing that it can, even for patients who have very advanced disease with lung, spleen and bone marrow involvement,” Fanale says. “They’re going into complete remission with this regimen. Now, several years out, most are still disease-free.”

Fanale says a multi-center randomized Phase III clinical trial comparing rituximab plus ABVD to standard ABVD chemotherapy for patients with advanced-stage disease is the next step. If rituximab plus ABVD proves superior, “we hope to get this treatment approved as a new standard of care,” she says.

  • Combining bortezomib (Velcade®) with ICE for patients with relapsed Hodgkin's lymphoma

Bortezomib is used to treat multiple myeloma and mantle cell lymphoma. It works by blocking proteasomes (a cell’s equivalent to a garbage disposal), which are responsible for protein turnover. Inhibiting proteasomes leads to cancer cell death.

“Bortezomib plus ICE is producing early encouraging results that seem to be better than what we’re used to seeing with ICE alone,” says Fanale, who plans to confirm these results in a randomized study.

  • Examining the effects of SGN-35 as a single agent

SGN-35 is a monoclonal antibody similar to rituximab, except that it targets cancer cells expressing CD30 on their surface and has a toxin affixed to it. Hodgkin’s lymphoma cells express CD30 while normal cells don’t. Therefore, it’s believed that SGN-35 can potentially kill tumor cells while having little or no toxic effect on normal cells.

SGN-35 goes straight to the tumor cells, releases the toxin and then kills the cells. “It’s still early, but patients seem to be responding nicely,” Younes says.

Another anti-CD30 antibody, MDX-060, in combination with gemcitabine (Gemzar®) also is being examined in a Phase II clinical trial with promising responses thus far, Fanale says.

  • Evaluating the effects of 17-AAG as a single agent

17-AAG is a small molecule inhibitor of Heat Shock Protein 90, an essential protein required for maintaining the function of several survival proteins inside tumor cells, including those of Hodgkin’s lymphoma.

By inactivating this protein, investigators believe the function of the cells will be severely disrupted and as a result, they’ll eventually die. Laboratory experiments performed by Younes’ team showed that 17-AAG is effective in killing Hodgkin’s lymphoma cells. Based on these results, a Phase II clinical trial was initiated in patients with relapsed Hodgkin’s lymphoma.

So far, Younes says, “we’re seeing some positive responses in patients who have been heavily pretreated.”

Although it’s too early to know the long-term success of these studies, Younes feels they represent a major step forward in improving treatments for Hodgkin’s lymphoma after standing still for almost three decades.

“Not that long ago there wasn’t much hope for a lot of our patients,” he says, “but now there are several possibilities.”

Without a Cause

Hodgkin’s lymphoma is a rebel without a cause.

There are suspects to be had, but no definitive outlaw willing to take the rap.

However, like in any good investigation, there are speculations and leads to follow.

The Epstein-Barr virus, which causes infectious mononucleosis, is suspect. Although not a clear-cut cause, patients who have had “mono” are more likely to develop Hodgkin’s lymphoma in the future.

“It’s thought that when people are exposed to EBV and subsequently develop mono, their B cells (a type of immune cell) are activated in response to the infection, which is a good thing,” says Michelle Fanale, M.D., assistant professor in the Department of Lymphoma/Myeloma. “But instead of returning to their normal state after fighting the infection, these B cells remain activated, possibly making them more susceptible to developing mutations that can eventually lead to Hodgkin’s lymphoma.”

Michelle Fanale, M.D., and research nurse Gracy Zachariah are looking into the causes of Hodgkin’s lymphoma and investigating the potential of new drugs to treat the disease.

The role EBV plays in Hodgkin’s lymphoma, however, is still questionable since many patients have no prior history of EBV infection, Fanale says. The current thinking is that while EBV might be associated with Hodgkin’s lymphoma development, there are many other factors involved. The presence of EBV in Hodgkin’s lymphoma cells may also predict outcome, she says, but this is still under investigation.

People with impaired immune systems, such as organ transplant recipients and those who have HIV and hepatitis, also have a higher likelihood of developing Hodgkin’s lymphoma.

It’s not evident, however, whether it’s the disease itself that makes them more vulnerable, or the immunosuppressive drugs they take to control their illness, Fanale says.

As one can see, Hodgkin’s lymphoma is still somewhat of a mystery — one Fanale and others want to unravel.

Helping Patients Every Step of the Way

Often the first person a patient with Hodgkin’s lymphoma comes in contact with at M. D. Anderson is research nurse Amy Wedgwood. In her hands, she holds a list of clinical trials that may be their only hope for survival. Many of these patients have fallen in and out of remission one too many times, she says, and they think they have run out of options. But to their surprise, they learn there are now several new investigational agents available.

Wedgwood helps patients sort through the different protocols, determining which ones they qualify for. Once they’re officially enrolled in a study, she follows them throughout their treatment — checking vitals, going over lab results and PET scans, asking about side effects and answering a multitude of questions. She’s with them every step of the way.

While the best news Wedgwood and her patients can hear is that the drug is working, they know that it probably won’t cure everyone. “We hope it does,” she says. “But I always tell my patients that it’s trial and error. We’re learning as we go. And if one drug doesn’t work, we can try something else. Until they say ‘stop,’ we’re going to keep going.”

Marvin Hill Jr. - "I'm a Lucky Man"

“Dad, what’s wrong with your neck?”

That was the first thing Marvin Hill Jr.’s daughter said to him when she arrived home from college in the summer of 2000.

He knew then that the lump that had appeared on the side of his neck a little over a year before was something more than just the swollen gland his doctor originally suspected.

His daughter’s shock sent him straight back to the doctor.

“Come to find out, I had Hodgkin’s lymphoma,” says Hill, who also learned he had some growths in his chest.

Hodgkin’s lymphoma has taken Marvin Hill Jr. down many unexpected paths. But now in remission, he’s looking forward to taking long trips with his wife on his new Harley-Davidson motorcycle.

At a hospital close to his home in Katy, Texas, Hill underwent nine months of chemotherapy and a month of radiation. For a time, these treatments held his disease in check. But as is the case for many patients with Hodgkin’s lymphoma, the disease recurred.

“My 18-month tests showed it had come back,” he says.

He was told a stem cell transplant using his own cells would be his next best chance for beating the disease. He was referred to M. D. Anderson and underwent the transplant in 2003.

Hill enjoyed three, disease-free years, only for it to come back once again. He then asked his doctor, “What do I do next?”

Hill had two choices. One, to undergo another stem cell transplant, but this time using donor cells; or two, enroll in a clinical trial.

He opted for a clinical trial, and in October 2006, he began receiving an investigational agent that inhibits a protein responsible for keeping cancer cells alive.

“It’s been keeping my cancer at bay for about a year,” he says, noting the side effects of the agent are minimal.

As protocol dictates, Hill can only stay on this trial for one year, at which time he has to stop taking this agent. He confides that he’s a bit apprehensive, but knows there are other investigational agents available if the need arises.

And, he says, “there’s always the stem cell transplant to try. As it turns out, my daughter is a perfect, 10-for-10 match — the odds of that are less than a half percent.

“I’m a lucky man.”

Conquest - Fall 2007

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Hope is on the Horizon
View video: Anas Younes, M.D., talks about clinical trials available for Hodgkin’s lymphoma at MD Anderson
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© 2015 The University of Texas MD Anderson Cancer Center