|As the failures and deaths mounted, Protocol 126 was altered again and again, but new patients still weren't told the risks.
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Copyright © 2001 The Seattle Times Company
New theory on failures
By mid-1984, Martin and Hansen began to discuss their setbacks in seminars. An issue of the medical journal Blood includes an article in which they note the high graft failure in their experiment - 40 percent at that point - was "a highly unusual outcome."
But not, apparently, reason enough to end the trial.
The Blood article outlined their plan: While eight of 11 patients with the best prognoses had failed to engraft, only one of the other nine patients had failed. The authors theorized that the higher radiation given sicker patients had weakened the immune system enough to let the donor marrow take hold.
The IRB, still headed by Kaplan, instructed Martin to change the patient-consent form before Protocol 126 could proceed. "Specifically, the risk of loss of graft should be more clearly stated," the panel said.
|Fred Hutchinson Cancer Research Center
|Dr. Paul Martin (in tie) stands behind Dr. E. Donnall Thomas, a Hutch co-founder, in a photo taken in the mid-'80s, during Protocol 126.
The form being shown to patients said: "To the best of our knowledge, (Protocol 126) does not damage the cells necessary for engraftment."
A revised form conceded that the treatment "may damage cells necessary for engraftment," then continued with its previous assurance, "In this case, a second marrow transplant would be necessary."
Again, it didn't say that second transplants fail 95 percent of the time. It didn't say there was a higher risk of relapse, nor did it disclose the Storb alternative, nor the financial interests.
Pesando thought the IRB, under duress, had surrendered. And Pesando said they never knew at the time that Storb, too, opposed Protocol 126.
Kaplan, assured by president Day that there would be a scientific review and that the experiment would stop immediately if it had two more graft failures, approved Protocol 126.1, the next stage of the trial, on behalf of the IRB on June 1, 1984.
Those graft failures came quickly.
Dr. John Draheim, 36, a physician for the U.S. Navy in Bremerton, and Seci Cay, 31, owner of an export-import business in Turkey, came to The Hutch for chemotherapy, radiation and transplants in the fall of 1984. When their T-cell-depleted marrow failed to engraft in December, the trial was halted again.
Kaplan wrote Day "once again" objecting to the protocol on scientific and ethical grounds.
"Monoclonal antibodies are being used in what appears to be a completely uncontrolled fashion ... " Kaplan wrote. "Alternative therapy seems downplayed in importance. ... In addition, the board is concerned about authorizing protocols in which the apparent successful use of an agent could be potentially beneficial financially to many of the investigators listed on the study."
Dr. Frederick Appelbaum, head of the clinical-research division, replied on Day's behalf, telling Kaplan to stop complaining about financial conflicts. He said the IRB must either express concern about all types of financial conflicts, such as the possibility of researchers losing their jobs if patients stopped enrolling in the experiments, or "accept the fact that those of us in cancer research are intrinsically honest individuals who are trying our best."
Martin proposed further human experiments. Admitting "graft failure represents a highly unusual outcome," Martin said he would add methotrexate, one of the drugs Storb was studying, to aid engraftment.
In January 1985, the IRB approved Protocol 126.2, the next stage.
Two weeks before that approval, Draheim died, with Hansen himself the attending doctor. Two weeks afterward, Cay died. They were at least the eighth and ninth victims of graft failure caused by the treatment.
"Each successive protocol was a variation on some aspect of the treatment, with the goal of asking would this change make a difference in the outcome," Martin said later. "And recurrently, the answer was no."
In other words, no matter what they tried, the treatment wasn't helping patients.
'She never got better'
Elizabeth Almeida, 35, was a strong-willed single woman about to adopt her foster child, a 13-year-old boy, when she was diagnosed with leukemia.
While the first patients were dying of T-cell depletion in Seattle, she was undergoing chemotherapy in Boston, about an hour from her home in New Bedford, Mass. The cancer disappeared, then re-emerged, then disappeared after more chemo, but the prognosis was grim.
Her doctor told Almeida that her best chance for survival was a bone-marrow transplant at the Hutchinson Center in Seattle. She had a perfectly matched sibling, James, to donate bone marrow. If she could survive even more chemotherapy and radiation, James' donated blood could help her start manufacturing new, clean blood.
Almeida and her mother and brother traveled across the country in March 1985. In a conference with a Hutch doctor, they were offered the "informed-consent" documents for Protocol 126.2.
That form had not been updated as the IRB had ordered, a technical violation of federal human-protection rules. Again, it described graft failure as merely possible and correctable, and failed to mention the higher risks of new or recurring cancers.
Though Protocol 126 was a highly experimental procedure, the statement of risks on the patient-consent form was more serene than the warnings on many drugstore medicines.
The Times, with the family's permission, obtained Almeida's 1,833-page medical file. It offers no evidence that anyone ever told her or her family about the then-obvious risks of dying from the treatment, nor of the availability of Storb's more successful alternative treatment.
After some initial hesitation, and after being promised a conference with Martin, which she never got, Almeida agreed to participate in the experiment. She entered Swedish Medical Center in outward good health, with her disease in complete remission.
"Delightful," a nurse described her. "Looks well."
After a week of drugs and radiation, she grew weak and nauseated, then developed severe mouth pain, fevers, pneumonia and kidney failure.
Transplants have been compared with killing patients and then bringing them back to life. Almeida never came fully back. Her marrow never did restore its blood-making capacity after she got her brother's cells.
She recovered enough to return to Massachusetts, but the transplant ultimately failed to engraft and the leukemia returned.
"She never got better," Billy Tatro, a longtime friend, recalls. "When it was obvious the transplant was failing, it really wasn't apparent to anyone why. The doctor said there was only one possibility, and that was a second attempt. So he sent her back to Seattle."
Almeida was pale, frail and feverish when she checked back into Swedish.
"Bright, frightened woman," a social worker wrote.
She never got the second transplant. She died first, on Oct. 3, 1985.
Annmarie Ridings of Mattapoisett, Mass., didn't know her sister Elizabeth had been part of any experiment, let alone one with such a grim record.
"As you can imagine, this information has upset my family," she says.
"My family continues to feel the effects of her death fourteen years ago. I do not believe that my sister would have agreed to participate in a study that she knew had such a high failure rate."
A 100 percent risk of relapse
Among the people Elizabeth Almeida had met in the leukemia ward were the couple from Alabama, Pete and Becky Wright.
Becky was a mother of three, a runner, a dancer, who had been diagnosed with chronic myelogenous leukemia in March 1985. Like Almeida, she and her husband came to The Hutch for the best treatment money (about $200,000) could buy.
Dr. C. Dean Buckner discussed treatment options with the Wrights. His dictated notes were released by Swedish Medical Center with permission of Pete Wright.
Buckner told Becky she would not be cured by conventional chemotherapy, but stood a good chance of survival with a bone-marrow transplant. More than half the patients with diagnoses similar to hers were still alive after getting transplants, he said.
Buckner predicted only a 15 percent probability of leukemia recurring over the next two to three years for Becky. However, he added, she had "high probability" of getting GVHD because of her age, 37, and he suggested she enlist in Protocol 126.
Pete Wright recalls: "We had been out there for a month waiting for a bed, and I remember talking about the protocol. We were told this was the best way to avoid GVHD, and from some of the pictures we'd seen and the things we'd heard, we definitely wanted to avoid that."
The consent form the Wrights were given emphasized the benefits. Under "Risks," it said: "Graft rejection has occurred following such treatment. In this case, a second marrow transplant would be necessary."
Pete Wright says - and the records indicate - that Buckner mentioned the risk of graft failure but did not say that more than a quarter of the transplants in Protocol 126 so far had failed. Nor did he say that second transplants were 95 percent fatal. He apparently did not mention the risk of relapse or new cancers at rates significantly higher than in standard transplants.
Buckner now says he was "one of the bigger skeptics" about Protocol 126 but "I didn't find anything unscientific or unethical about any of this. We were all trying to make people better. And at that time, it was felt that T-cell depletion was the greatest thing since sliced bread. And it wasn't."
In fact, as Martin, Thomas, Buckner and other Hutch doctors outlined in a journal article on chronic myelogenous leukemia published three years later:
"The actuarial relapse risk 2.5 years posttransplant was 100 percent in patients administered T-cell-depleted marrow as compared with 25 percent in patients administered unmodified marrow."
A 100 percent risk of relapse. Every patient like Becky Wright, if he or she lived long enough, saw the nightmare of leukemia return.
The statistic shocked Pete Wright when he saw it years later. The relapses in Protocol 126 included eight patients before Becky walked in the door, and six afterward. She was not the only one, nor was she the last.
Pete Wright said Becky didn't give much thought to the protocol, trusting doctors to act in her best interest. She signed most of the forms before even talking with Buckner.
"She knew this was her one shot to live," Pete Wright said. "She was upbeat. She was psyched up and ready to go."
'The pain never really dies'
Becky Wright told Pete she never imagined she would feel so bad.
Chemotherapy not only kills cancer cells, it assaults normal tissue in hair follicles, the mouth, the digestive system and the bone marrow. Wright suffered painful lesions, systemic infections, diarrhea, organ damage.
But if she could be cured, it would be worth it.
On June 17, 1985, she received her sister's marrow, which had been treated with the eight antibodies and was devoid of T-cells.
She was luckier than some: The graft took; her white cells propagated and her sores and infections healed. Becky Wright checked out of the hospital a month after the transplant and flew home to Heflin, where life more or less returned to normal.
But when she flew back to Seattle the following year, a checkup showed her leukemia had returned. Doctors recommended a second transplant, this time with T-cells. She got it, but was too weak to survive a graft-versus-host reaction and bloodstream infections.
"I can hardly take deep breaths; it's too painful," she told a nurse.
She missed her children. She wanted to go home to Heflin. There was nothing The Hutch could do to help her. And on the day before Mother's Day, 1987, Becky Wright hemorrhaged and died in a hospital bed in Birmingham, Ala.
Whether she would have survived with standard treatment will never be known. But based on the evidence, her widower feels his wife was deprived of her optimal shot for survival.
At the very least, he said, they were deprived of crucial information they deserved to know.
Earlier this year, Pete Wright was shown Pesando's letters and studies on T-cell depletion. The understated risks and undisclosed financial interests infuriated him.
"My grandfather was a doctor, an active doctor for 62 years," Wright said. "He would be doing back flips in his grave if he heard about this."
Pete Wright is remarried and trying to move on with his life. He doesn't want Becky's ghost to haunt his new family. But he says, "The pain never really dies. The truth definitely needs to come out on this."
The experiment ends
In October 1985, Bristol-Myers bought Genetic Systems for $294 million, or $10.50 per share. The purchase raised the value of Hansen's original stock holding to $1.8 million, Thomas' to $1.05 million, Martin's to $105,000 and the foundation's to $502,000.
Protocol 126 lasted 12 years - an extraordinarily long time for a clinical trial - even as deaths mounted.
Each new phase tested slightly different combinations of chemotherapy, radiation or immune-system suppression, but all were built around the same antibodies.
The later versions of Protocol 126 ended with graft failures in two of 12 patients, two of nine, two of eight, two of nine, two of two, and one of one, respectively. Overall graft failure was at least 24 percent, vs. the expected 1 percent.
And even when the transplants took, the cancer came back. Of those with chronic leukemia, 100 percent suffered relapses, vs. the expected 25 percent.
As the failures mounted, the description of the study in filings with the National Cancer Institute changed: It began as an experiment in whether T-cell depletion would prevent GVHD. It ended as an experiment that showed T-cells were necessary to engraft and to fight spare leukemia cells.
The consent form in the final phase of the study, approved by The Hutch in 1991 and 1992 for up to 20 patients, warned that patients "often reject the marrow," leading to death, and that T-cell removal "may increase the risk of relapse."
Finally, it revealed: "In this situation, there is a high chance of infections, bleeding and death."
The first patient in the final phase, a 30-year-old man with a mismatched donor, experienced graft failure. The protocol was ended forever.
Records reflect that at least 20 patients died from graft failure in the experiment between 1981 and 1993. The first seven of those had forms of cancer with a cure rate of about 50 percent with standard treatment.
In the end, the experiment was almost uniformly fatal.
Martin, Hansen and Thomas never did write a final report on Protocol 126. Martin says he discarded his files when he moved to a new office in 1998.
But Martin disclosed the final toll: 82 people from around the world enrolled in the Seattle experiment; 80 of them are dead today. And the Hutchinson Center has become a leading voice against T-cell depletion.
"We worked very hard to remove every T-cell from the graft and we found out that wasn't a bright thing to do," Martin says now.
He wishes he had set up a better mechanism for ending the stages of the experiment as they proved unsuccessful. He blames his inexperience, and a lack of guidance from The Hutch.
"I don't know that I was trained as well as I would have liked at the time," he says. "Nobody told me what to do."
Martin passionately insists, though, that his persistence down the path of T-cell depletion was motivated by science, not by business.
"I want to assert definitively that the clinical trials were motivated by scientific evidence suggesting that the results of bone-marrow transplant could be dramatically improved by removing the T-cells from the graft," he said.
Martin's mentor, Hansen, is less emphatic in his denial of financial motivation. Asked whether the doctors' personal investment in Genetic Systems affected the experiment, he replied: "I don't think so. I don't think so."
Asked if Genetic Systems stood to make money if the antibodies proved successful, Hansen said: "Well, of course that was the idea. You start a company to make a profit."
Duff Wilson's phone number is 206-464-2288. His e-mail address is firstname.lastname@example.org.
David Heath's phone message number is 206-464-2136. His e-mail address is email@example.com.