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Promise and Progress - The Legacy of an Orphan Disease

A Cancer Revolution

The Legacy of an Orphan Disease

Date: December 1, 2004

Severe aplastic anemia (SAA) is one of those horrible diseases that people like to tell stories about. So unusual, it’s interesting, and so rare that we can take comfort that the odds are in our favor. We couldn’t possibly be one of the few who unexpectedly and inexplicably finds his own immune system turning on his body, attacking the bone marrow stem cells and halting the production of red blood cells, infection-fighting white blood cells, and clot forming platelet cells and leaving him at the brink of death. That’s the catch with statistics, though. We want to celebrate the low numbers as an accomplishment, a good thing. We make them insignificant, until we are smacked with the realization that they represent real people with real lives interrupted by a horrible twist of fate. This is the story of those people and the investigators who have fought for them.

There is a name people in the medical arena give to diseases like severe aplastic anemia (SAA), so uncommon that it strikes just four in a million adults and two out of every million children. They call them “orphan” diseases, and as the name implies, they are diseases that few in the research community or pharmaceutical industry choose to pursue.

With so few patients, clinical studies can become mercilessly bogged down, and as a result, research grants are hard to come by. For drug companies, profits from drug sales are sparse, so they invest elsewhere to make reasonable returns on their investment.

Still, there are a few that aren’t afraid to go against the odds, and take on these “orphan” diseases. They see it differently. “Maybe instead of orphans they are diamonds in the rough,” says Robert Brodsky, who took a 30-year-old observation from a former Cancer Center SAA expert and turned it into a potential cure. “Sometimes they get us to think harder and to look in new and unusual places for answers,” he says.

For Brodsky, this meant looking 30 years back in time, back to the early 1970s and the files of Lyle Sensenbrenner, who was leading the Center’s aplastic anemia program at the time. Sensenbrenner was among the first to study bone marrow transplantation, a therapy in which the diseased bone marrow is destroyed with high doses of the drug cylcophosphamide and then replaced with marrow from a healthy donor, as treatment for SAA. For patients that could find donors whose immune system matched their own, and were healthy enough to undergo this rigorous therapy, bone marrow transplant offered hope for a cure and became the treatment of choice for SAA. But, Sensenbrenner found—and documented in his files—that some of the patients seemed to recover some of their own marrow function, instead of their donors’. In a last-ditch effort to save the lives of 10 young patients who were not candidates for bone marrow transplant and had exhausted all other treatment options, Sensenbrenner, following a gut instinct, treated them with a single massively high dose of cyclophosphamide.

Then, in 1987, Sensenbrenner left Hopkins, and as the sole member of the SAA team, no one kept track of his 10 patients until Brodsky came to town in 1996. On the recommendation of Richard Jones,  the Center’s Bone Marrow Transplant Program director, Brodsky began to look through Sensenbrenner’s old notes and patient files. He figured the 10 patients were surely dead. Like a good scientist, however, he followed the lead, and to his amazement learned that seven of the patients were not only alive, but completely disease-free. The high dose of cyclophosphamide had cured them. Brodsky wondered how that could be. Immunosuppressant drugs like cyclophosphamide had been used to treat SAA for years, and while they worked for a while they had never been successful in curing patients. Sooner or later, the disease always came back. Something must have been lost in the translation between 1970 and now, he thought. “Maybe diagnoses were different then. Or, there was a subtle drug difference. I had to make sure the treatment really worked,” says Brodsky.

Following Sensenbrenner’s original protocol to the “T”, Brodsky opened up a new study of high-dose cyclophosphamide and began seeing similar results. His next step was to figure out why.

The key, Brodsky found, was in the high dose. The doses of cyclophosphamide were high enough to wipe out the abnormal bone marrow cells. But, the stem cells, the factory of all types of blood cells, were resistant to the therapy. “There is no dose high enough to kill a stem cell,” says Brodsky. Within their basic biology is an enzyme that makes them untouchable by cyclophosphamide. “The treatment re-programmed the immune system, wiping out the abnormal cells and allowing the stem cells to rebuild a new, disease-free immune system,” explains Brodsky.

As treatments for orphan diseases often do, Sensenbrenner and Brodsky’s high-dose cyclophosphamide has turned out to work in other, more common diseases of the immune system, including severe, treatment-resistant Myasthenia Gravis and Scleroderma. “This, to me, is part of the intrigue of so-called ‘orphan’ diseases like SAA. The impact they have on medicine is often overlooked. Efforts to fight SAA in the 1970s with the development of bone marrow transplantation led to major advances in the treatment of cancers like leukemia and lymphoma,” says Brodsky. “Now,” he says, “high dose cyclophosphamide may have a similar legacy.”