Promising quest for cure

Fifteen months ago, the pain from Pamela Newton's sickle cell disease was excruciating. She spent more time in the hospital than in her Capitol Heights apartment. She was on 15 pain pills a day, all heavy narcotics. She was bleeding regularly and needed daily transfusions of platelets.

She had just months to live.

Today, doctors at Johns Hopkins Hospital say that Newton is one of the first adults in the world to be cured of sickle cell disease - and the first using an experimental bone marrow transplant that could cure thousands like her who have been told they will never get better.

Word of a breakthrough gives hope to the roughly 80,000 Americans - and millions around the world - who suffer from this debilitating and usually fatal disease, which is predominant among African-Americans and Hispanics.

"It could very much open things up," said Dr. John F. Tisdale, a senior investigator at the National Heart Lung and Blood Institute. "Everyone's cautiously optimistic."

What makes the Hopkins procedure different is that it allows patients to receive bone marrow from a donor who is not an exact match - a longtime obstacle to healing large numbers of people.

Sickle cell is an inherited blood disorder that affects red blood cells. Normally round, they become "C" shaped, like sickles, and pile up on one another, keeping them from properly supplying oxygen throughout the body. The patients, prone to infection and serious pain, typically live only into their 40s.

Until now, few have been cured - and there has been little progress in developing new treatments. Only one drug has been approved for treatment of sickle cell. Painkillers and antibiotics help patients live longer, but nothing has addressed the core problem of the genetic defect.

Newton's hematologist, Dr. Robert Brodsky, and his colleagues say they hope to change that. They are trying to enroll 25 patients in a clinical trial.

Still, the procedure is not without risk. When performed on patients with leukemia and other diseases, it has a mortality rate of 16 percent.

"We may shorten people's lives, but this is their only chance for a cure," Brodsky said. "Would you offer this to every sickle cell patient? Absolutely not. But the patient who is ending up in the emergency room three and four times a month and having organ-threatening and life-threatening complications from the disease ... should be able to make that decision."

Critics say the risk associated with Hopkins' procedure is too high, even for a small trial. They say most sickle cell patients aren't likely to die immediately without a bone marrow transplant.

"I don't think the time is right yet to go ahead with such transplants at full tilt," said Dr. Rainer Storb, an oncologist at the Fred Hutchinson Cancer Research Center in Seattle, which cured several children with sickle cell using bone marrow transplants during the 1990s.

Bone marrow transplants have been used to treat sickle cell disease for 20 years - but almost all of the 200 cured have been children. The treatments - high doses of chemicals that knock out the patient's own marrow before the transplant - are so toxic that adults with sickle cell-induced organ damage would be unlikely to survive them.

Brodsky said his team's procedure, developed by Dr. Ephraim Fuchs and Dr. Leo Luznik, is less toxic. They say they no longer believe they have to destroy as much of the patient's marrow as they once did - so they administer just enough chemotherapy to suppress the immune system. That dose keeps patients from rejecting the new marrow without harming their organs.

This change allows transplants for adults, as well as children. Because the procedure occurs later in life, it relieves parents of the burden of making the decision for their youngsters (even in children, the sickle-cell transplant mortality rate is 5 percent to 10 percent). Instead, it allows the adult patient to see how severe the disease is before deciding whether to have a transplant.

Another transplant obstacle has been finding a perfect bone marrow match - a full sibling's marrow provides the best chance. But there's only a 25 percent chance that even a full sibling will be a match. And since sickle cell is inherited, siblings may also have the disease. That leaves about a 10 percent chance that a patient will find a suitable donor.

Brodsky's procedure requires just a half-match - meaning that children and parents of the patient could be suitable donors.

Three days after the transplant, the patient is given a high dose of a drug called cyclophosphamide. Just as the bone marrow is taking root, the drug kills off the donor's lymphocytes - blood cells that are part of the immune system.

The cyclophosphamide spares the donor's stem cells and allows them to establish new blood cells and a new immune system. The nascent immune system is re-trained to see the patient's body as friend, not foe. This prevents the patient from rejecting the transplanted bone marrow - and prevents the newly developing immune system from attacking the patient.

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