Spring/Summer 2001
  Current Issue
  Top Story
  Campus News
  Medical Updates
  Sparrow's Point
  Post Op
  Past Issues
  Talk To Us
  Site Index
  Search HMN
  Front Door

On the Trail of a Cure

By Mat Edelson | Photographs by Bruce Weller

(Related Stories: For Transplantation, the Implications Could Be Staggering, Telling It Like It Is)

In 1996, Rob Brodsky began using a new drug regimen to treat patients with fatal autoimmune diseases. One by one, he watched their immune systems return to a state of complete health.

Rob Brodsky

Over time, Robert Brodsky has come to understand that stunning advances in medicine can sometimes take place almost accidentally. Brodsky is a hematologist. In 1987, in his second year in medical school, he became fascinated by the fact that the blood is at the center of the body's action, and like the catcher on a baseball team, there isn't a play in the game in which it's not involved. After that, Brodsky never wavered in his choice of a specialty. He sped through a two-year internal medicine residency at Vanderbilt, spent three years working in the National Institutes of Health's hematology lab and came seven years ago to Johns Hopkins as an oncology fellow. Since then, he's become something of an expert on one particular blood disease, a rare and often fatal autoimmune condition called severe aplastic anemia.

Like other autoimmune diseases, severe aplastic anemia, or SAA, occurs when the body's immune system inexplicably goes haywire, suddenly sees normal healthy body proteins as the enemy and attacks. For the stricken person, the result is as devastating as walking into combat and being fired on by your own commanders. In SAA, what the immune system attacks—unmercifully—are the stem cells, the progenitors of all blood cells produced in the bone marrow. It renders them incapable of making new oxygen-carrying red blood cells, infection- fighting white cells and clot-inducing platelet cells.

Brodsky with his colleague Galina Mukhina in the lab looking at long-term bone marrow cultures.
Brodsky with his colleague Galina Mukhina in the lab looking at long-term bone marrow cultures.

SAA is what's known in medical parlance as an orphan disease. It strikes so rarely—in only four out of one million people—that it's not something researchers spend a lot of time studying. It's also not a condition that funding agencies and pharmaceutical firms usually want to sink money into. Still, for the second time in Brodsky's lifetime, a new approach to treating SAA looks as if it could evolve into a significant advance in treating diseases that do strike millions of people, conditions like lupus or rheumatoid arthritis. For that reason, Brodsky is convinced that orphan diseases deserve more attention.

The first time a treatment for SAA turned out to have this kind of broad application was in the early '70s, when hematologists began transplanting bone marrow to cut the death rates in these patients. Bone marrow transplantation did help some people live through SAA, but only a small subset of those with the disease turned out to be eligible for it. Patients needed to be young enough to tolerate the harsh procedure and lucky enough to come up with a bone marrow match in a brother or sister. Even the 10 to 20 percent who managed to receive a transplant faced potentially fatal complications afterward like graft-versus-host disease.

Ironically, bone marrow transplant proved more successful in fighting diseases like leukemias because the procedure allows physicians to give higher doses of chemotherapy. Still, it was as a treatment for SAA that bone marrow transplant first came into use. Now, that sequence has occurred again. A new way of using the drug cyclophosphamide to treat SAA has been found to produce astonishing turnarounds in patients with common autoimmune disorders like lupus. And this time Rob Brodsky himself has been in the vanguard of the medical breakthrough.

After Brodsky came to Johns Hopkins in 1994, it didn't take him long to realize he'd had his fill of the standard of care for SAA. Like most autoimmune diseases, the affliction couldn't be cured, only controlled through bone marrow transplant or drugs that suppress the diseased immune system but leave patients wide open to dangerous side effects like infection, hormonal imbalance, sterility and osteoporosis. More than half the SAA patients who responded to the immunosuppressive antithymocyte globulin (ATG), the gold standard treatment, in fact, either relapsed or developed some type of malignant blood disease and eventually died. Brodsky was desperate for a better treatment.

In the fall of 1994, Rick Jones, director of Hopkins' Bone Marrow Transplant Program, suggested that Brodsky might want to look up some 20-year-old research by a former Hopkins oncologist, Lyle Sensenbrenner, involving the drug cyclophosphamide. Cyclophosphamide, often known by its commercial name, Cytoxan, is well-known in medical circles today as an immunosuppressant that's given long term in small oral doses to fight autoimmune conditions. Back in the '70s, though, Sensenbrenner hadn't been interested in the low-dose approach: He had been looking for a hammer.

Bone marrow transplants were just coming of age then, and a major stumbling block to their success was the need to suppress the patient's immune system to the point where it would accept foreign marrow. George Santos, founder of the Hopkins Bone Marrow Transplant Program (see obituary on page 41), had mastered the technique of using the immunosuppressive drug cyclophosphamide to make this happen. Meanwhile, Sensenbrenner, an oncologist in the BMT clinic, began noticing that several of the patients Santos treated with cyclophosphamide were recovering some of their own marrow instead of the donor's. Theorizing that the drug might have some ability to build marrow, Sensenbrenner decided to try it in a last-ditch effort to save 10 young SAA patients who were not candidates for a transplant and for whom all other options had run out. He administered a massive short- term dose of cyclophosphamide to each.

Then, in 1987, Sensenbrenner left Hopkins to join the faculty at Wayne State University in Michigan, and no one ever kept track of how his cyclophosphamide-treated patients fared long term—until Rob Brodsky came along.

Brodsky figured that by all rights, Sensenbrenner's patients were long dead, They had been given no new marrow to replace the marrow destroyed by the cyclophosphamide, and without transfusions they would have had no way to produce blood cells. Still, he wanted to make sure. To his amazement, Brodsky found seven of the 10 original SAA patients not only alive but completely disease-free. No relapses. No secondary diseases. He had never seen such a response to an immunosuppressive drug. Always before, this kind of medication had left some aplastic anemia in the patient's system. Cyclophosphamide had behaved as a cure.

Brodsky published his findings in the January 1996 issue of Blood. But he remained cautious. "Ten patients is just 10 patients," he says. "Diagnoses were different 20 years ago. It could have been some other subtle drug difference. We had to make sure the treatment worked."

And so, in the fall of 1996, Brodsky opened a new high-dose cyclophosphamide study to SAA patients, following Sensenbrenner's original protocol. One of the first to sign on was Vikki Goffredo. Twenty- three-year-old Goffredo, who'd grown up in a family of South New Jersey railroad workers, had awakened one morning to find she'd lost most of the vision in her left eye. At a Philadelphia-area emergency room, doctors found she'd had a retinal hemorrhage and discovered her red cell count was practically non-existent. "Your blood counts," one of them told her, "are so low that you should be in a coma."

A cured Vikki Goffredo with Brodsky.
A cured Vikki Goffredo with Brodsky.
Within days, Goffredo's disorder had a name: severe aplastic anemia. And though physicians refused to speculate on her prognosis, Vikki's mother, who turned immediately to the Internet, came to a horrible realization: people with this disease and these symptoms have a life expectancy of about six months. A bone marrow transplant was out because Goffredo couldn't find a donor whose marrow matched hers. So she began receiving massive transfusions to fortify her decimated red blood count and taking a cocktail of the immunosuppressive drugs ATG and cyclosporine and the steroid prednisone. Within a month, she was hit by the predictable side effects. She gained 70 pounds and developed diabetes and arthritis. Her behavior also became erratic from the drugs, as minor details began controlling her life. Later, Goffredo remembered, "I wouldn't go to bed unless every stuffed animal I had was in a certain position. If one fell that was it. I had to rearrange them all again." For three months, fear of infection turned her into a shut-in, and still her blood counts remained dangerously low. By the middle of 1997, both Goffredo and her physicians were out of options. One of the doctors, who was vaguely familiar with Robert Brodsky's emerging work, suggested she go to Hopkins.

Rob Brodsky minced no words with Vikki Goffredo in explaining the intensive regimen she would need to endure to try to rid her body of SAA. Four straight days of inpatient I.V. cyclophosphamide would wipe out her white blood cells, compromising her diseased immune system while temporarily stunning her bone marrow and sending her already low blood counts to zero. She would then become an outpatient and require daily checks for infections as transfusions bolstered her bone marrow. If all went well, at this point Goffredo's stem cells would begin to produce red blood cells, and her immune system would return to what Brodsky described as a healthy virgin state, like that of a newborn child. Once that happened, her chances of redeveloping SAA would be remote.

With help from a hometown Conrail fund-raiser, Vikki and her mother put together enough money to rent an apartment in the Inner Harbor and moved to Baltimore for the duration of the treatment. The 12-hour days of cyclophosphamide infusion passed quickly—the side effects began two weeks later. Brodsky had alerted his patient that some nausea would follow treatment, but the symptoms she experienced were brutal. First, she vomited uncontrollably, then a fungal infection near her brain threatened her life. It took 83 days for Goffredo's white blood cell counts to reach an acceptable range for discharge from the hospital. Her red cell count remained far below normal. Early in 1998, she returned to New Jersey to continue weekly transfusions—and wait.

As goffredo waited, Brodsky was using the high-dose cyclophosphamide regime on dozens of other fatally ill SAA patients and, just as with Sensenbrenner's original patients, watching their immune systems return to a state of complete health. Astounded at the drug's capabilities, he began thinking: if cyclophosphamide can effect this change in SAA, why not other autoimmune disorders?

The names of autoimmune diseases may vary—lupus, multiple sclerosis, Crohn's disease and rheumatoid arthritis are some of the better known—but their effects are usually the same: chronic, often painful debilitation and occasionally death as the immune system destroys healthy cells, tissues and organs. The more than 80 autoimmune disorders cross nearly every medical specialty, showing themselves in everything from permanent full-body hair loss (alopecia universalist) to the destruction of the body's nerves (chronic inflammatory demyelinating polyneuropathy).

Brodsky first used cyclophosphamide to treat a non-SAA patient on a woman dying from a massive hemolytic anemia, an autoimmune disease in which red blood cells, which normally live 90 to 120 days, are destroyed so soon and so fast they can't be replaced by the marrow. "I'll never forget the note that came with her when she was transferred to Hopkins," he remembers: "Do not expect to live through the weekend." After cyclophosphamide, the woman recovered completely. For Brodsky, it was the first clue that the treatment could go beyond aplastic anemia.

By then, Hopkins scientists had uncovered why cyclophosphamide works and why bone marrow responded to this drug by bouncing back when other chemotherapies that obliterate a diseased immune system also destroy bone marrow. The reason was a fluke of nature. Whenever the naturally occurring enzyme aldohyde dehydrogenase is present in cells, the enzyme prevents cyclophosphamide from attacking those cells. The components of the immune system that run amuck in autoimmune disease—the white blood cells, lymphocytes, and B- and T-cells—contain very little aldohyde dehydrogenase, so cyclophosphamide destroys them easily. In stem cells, however, the body's most primitive building block of red blood cells located in the marrow, an abundance of the aldohyde dehydrogenase enzyme is present, so these cells remain unaffected by cyclophosphamide.

"There is no dose of cyclophosphamide that can kill a stem cell," Brodsky says. "The cyclophosphamide does kill existing mature blood cells, but the marrow retains the ability to create new ones. That means patients who receive cyclophosphamide have no need for transplants. The rebuilt immune system functions properly and eliminates the need for any immunosuppressive drugs." For Brodsky, the implications were clear: the cyclophosphamide regime was radical, but in the long run, it was far safer than the existing standard of care.

Armed with this knowledge, he and Rick Jones began approaching Hopkins colleagues who treat other autoimmune diseases to describe what cyclophosphamide was achieving. They met first with rheumatologist Michelle Petri, one of the nation's leading authorities on lupus, a disease 10 times more prevalent than SAA.

"I asked questions because it sounded so drastic to do this to patients," Petri recalls. "I wanted to know. 'Do people die from it?' They said no." Petri knew, on the other hand, that the standard treatment for lupus was slowly killing her patients. "As much as treating lupus today, I treat the complications of high-dose steroids," she says. "Prednisone is giving patients compression fractures, they're developing extreme osteoporosis and breaking their hips, they're developing severe atherosclerosis, becoming morbidly obese, getting fungal infections."

Out of her more than 1,000 lupus patients, Petri chose 20 to test the cyclophosphamide regime. They were the sickest of the sick, the ones who hadn't responded to anything. Many were covered with sores. One woman had an open infection down to the bone. "You could look at these people and cry," Petri says.

The protocol started in June 1997. The patients were taken off all immunosuppressive drugs and each given four days of central line cyclophosphamide, 50 milligrams per kilogram of body weight per day. It was more than 10 times the usual monthly dose that lupus patients receive. Today, three years after that initial study, 45 percent are in remission. Petri considers that remarkable, though she tempers her optimism. "We don't want to use the word cure. With three years of follow-up, two patients who were in a long-term remission came out of it." Nonetheless, she has opened a new cyclophosphamide protocol that will monitor 100 additional lupus patients.

That the intense cyclophosphamide regime was a significant breakthrough in treating automimmune disorders was no longer in doubt. In the December 15, 1998, issue of Annals of Internal Medicine, Brodsky reported on 10 debilitated patients who had suffered from a variety of autoimmune diseases including rheumatoid arthritis, one type of lupus, and chronic inflammatory demyelinating polyneuropathy, an inflammation that destroys the myelin sheaths that protect the nerves. All had been treated with high-dose cyclophosphamide; six were still alive; four were disease-free. Meanwhile, neurologist Dan Drachman had been using cyclophosphamide on patients with severe cases of the muscle-weakening autoimmune disease myasthenia gravis and was witnessing incredible improvements.

Vikki Goffredo was not faring well. Her counts had slowly improved, but not enough for her to be weaned from transfusions. Eighteen months after her initial treatment, she returned to Hopkins for yet one more visit with Brodsky. By then, she and her mother had moved to Columbia, Md., to be close to him. One more time, the hematologist checked her blood counts, and found no change. Brodsky finally admitted to himself that he'd given up hope. When Goffredo's SAA had first been diagnosed, her hemoglobin, the measure of the oxygen-carrying component of red blood cells in her body, had stood at only five grams per deciliter (g/dl) out of a normal 13 g/dl. Regular transfusions would temporarily buck up that count, but inevitably it would slip back toward the danger level.

BEFORE: Bone marrow of a patient with severe aplastic anemia prior to taking cyclophosphamide. There are virtually no blood cells. AFTER: The same patient's bone marrow more than a year after taking cyclophosphamide. The blue dots are blood cells.
Before: Bone marrow of a patient with severe aplastic anemia prior to taking cyclophosphamide. There are virtually no blood cells. After: The same patient's bone marrow more than a year after taking cyclophosphamide. The blue dots are blood cells.

Early in September 1999, nearly two years after receiving cyclophosphamide, Goffredo entered Hopkins for a hip replacement—yet another complication of the steroids she had taken when her disease was first diagnosed. After that, with no visible explanation, her hemoglobin counts slowly but steadily began to rise: 8.0 g/dl...8.6...8.9. Week by week, without assistance from transfusions, the hemoglobin numbers climbed above 10 g/dl. Goffredo's platelet count, which had been only 1 percent of normal at diagnosis, followed suit.

In the year and a half since, those numbers have only gotten better. Today Goffredo is off all medication; her hemoglobin is an everyday 12.6 g/dl, and her platelet counts, though not textbook perfect, are close enough. At 26, Vikki Goffredo has her life back. Rob Brodsky's theory—backed up by anecdotal evidence—is that SAA patients who are treated with ATG/cyclosporine prior to the cyclophosphamide treatment take longer to recover.

For Brodsky, the message in Goffredo's spectacular turnaround and that of dozens of other desperately ill patients who are now disease- free thanks to cyclophosphamide goes far beyond the miracle of the drug itself. "What's been reinforced for me," he says, "is that diseases like severe aplastic anemia—these orphan diseases—can't be ignored. They need to be studied, and the researchers who do the work deserve funding. If George Santos hadn't begun working with cyclophosphamide in the laboratory 30 years ago, we'd never be seeing these amazing results today in patients with automimmune diseases."

Brodsky pauses. Then he says one more thing: "What's especially touching to me is that this particular adventure has been a Johns Hopkins story from the very beginning."