In 1996, a Johns Hopkins investigator uncovered and reopened a 30-year-old clinical protocol that offered the promise of a cure for patients with the rare and deadly immune disorder known as severe aplastic anemia (SAA).

The new treatment was based on one developed three decades earlier by one of the first Cancer Center investigators, Lyle Sensenbrenner.

In the early 1970s, Sensenbrenner gave 10 SAA patients with no other treatment options very high doses of the immune-suppressing drug cyclophosphamide.

Then, in 1987, Sensenbrenner left Johns Hopkins. Since Sensenbrenner was the sole member of the SAA team, no one kept track of his 10 patients until hematologist Robert Brodsky came to town in 1996. On the recommendation of Richard Jones, the Center’s bone marrow transplant program director and his mentor, Brodsky looked back to see what happened to those 10 patients.

For Brodsky, this meant looking 30 years back in 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 cyclophosphamide and then replaced with marrow from a healthy donor, as treatment for SAA. For patients who 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.

However, Sensenbrenner found — and documented in his files — that some of the patients seemed to recover some of their own marrow function, not that 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 followed his gut instinct and treated them with the same high dose of cyclophosphamide used for transplant but without the transplant.

When following up on these early studies, Brodsky learned that seven of the patients had been cured of their aplastic anemia by the high dose of cyclophosphamide, and six were still alive up to two decades later.

Brodsky wondered how that could be. Immunosuppressant drugs like cyclophosphamide had been used to treat SAA for years, and although they worked for a time, 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.

Brodsky returned to his laboratory to figure out how the drug worked against the disease. He learned that high doses were strong enough to wipe out diseased blood and immune cells, but did not affect bone marrow stem cells, immature cells that differentiate or change to form all new blood cells — red cells, white cells and platelets. The high doses of cyclophosphamide were enough to kill off abnormal cells, giving the stem cells a second chance to repopulate the bone marrow with healthy, normal blood cells. Now, it was time for Brodsky to test his theory on a new set of patients diagnosed with SAA.

SAA is a characterized by complete failure of the bone marrow factory, which stops producing blood cells. It is a rare disease, striking about 4 in 1 million adults and 2 in 1 million children each year.

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

The key was the high dose, he found. The doses of cyclophosphamide were high enough to wipe out the abnormal bone marrow cells, but the stem cells — the factory for 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 reprogrammed the immune system, wiping out the abnormal cells and allowing the stem cells to rebuild a new, disease-free immune system,” he explains.

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.

“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, high-dose cyclophosphamide has a similar legacy.”