Biotech firm, Times at odds over details of story

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Cell Therapeutics yesterday took out a newspaper ad to dispute some details of a Seattle Times story about a woman who died from high doses of chemotherapy in a breast-cancer study at the Fred Hutchinson Cancer Research Center.

The details in dispute are related to research on drugs used in the study and to the involvement of the company and its founder, Dr. James Bianco, in that study.

The Times stands by the March 13 story on each issue raised by the company.

"We would not have published these details unless we had documented them carefully in the first place," said Executive Editor Michael Fancher. "In reviewing them again yesterday, we remain secure in their accuracy."

The story focused on Kathryn Hamilton, a patient at "The Hutch" who died in 1993 from high doses of chemotherapy she was given as part of a clinical trial. That trial included experimental "rescue drugs" being tested to see if they would protect patients from potentially lethal doses of chemo.

Bianco formed Cell Therapeutics Inc. (CTI) in September 1991 to develop and market the same rescue drugs being used in the breast-cancer experiment. He gave The Hutch stock in his company and an annual license fee from which the center eventually made nearly $2 million.

Hamilton's doctor, C. Dean Buckner, and E. Donnall Thomas, a Nobel laureate at The Hutch, served as consultants to CTI and received stock options.

As reported, Hamilton and her family were told in informed-consent papers that research had found one of the rescue drugs to be effective, even though more recent research had indicated that the drug, pentoxifylline (PTX), didn't work and might actually increase the damage from chemo.

In its ad in yesterday's Times, CTI said: "The Seattle Times report implied that PTX did not work in any studies."

In fact, the story reported that there was one study that showed PTX to be effective. It was done in 1990 and led by Bianco while he was a researcher at The Hutch.

However, a more rigorous follow-up study of 101 patients at The Hutch showed that PTX was not effective. The follow-up study was done in 1991, but the results were not published until 1993.

CTI in its ad also said that PTX research was part of a $15 million Adult Leukemia Center grant that was widely praised. That federal grant funded the first PTX study as well as numerous other studies not involving PTX.

Bianco incorporated CTI a month before the breast-cancer study started. In a taped interview conducted by The Times in preparing last week's story, Bianco said: "In 1991 when we started, we, for all intents and purposes, in our minds, had pretty much written off pentoxifylline by itself."

Hamilton entered the study in January 1993 but was told in the informed-consent form that studies showed PTX by itself was successful.

Hamilton's doctor, Buckner, acknowledged in interviews for last week's story that he knew when the breast-cancer study started that PTX by itself didn't work. But he said he was relying on evidence from Bianco that showed that when PTX was given along with an antibiotic called ciprofloxacin (Cipro), it might protect patients from high doses of chemotherapy.

As the story reported, CTI quickly abandoned that combination of rescue drugs for scientific and commercial reasons.

In its ad, CTI asserted that the company did not abandon that research until 1999. That's when CTI gave up on a drug called Lisofylline, a derivative created when PTX and Cipro are combined.

However, in four hours of interviews, Bianco provided a detailed account of how the federal Food and Drug Administration wouldn't approve the combination of PTX and Cipro. The agency considered it unreliable because genetic differences among patients would change the way the drugs metabolized in each patient. It also said that giving the antibiotic Cipro for something other than treating infections wasn't safe because patients might develop a resistance to the drug.

"We learned out of our studies that we had done right after starting the company," Bianco said, "that the utility of combining these two agents ... was limited by the genetic differences in people in terms of how they metabolize these drugs."

The FDA urged CTI to identify the compound created when the two drugs were mixed that might be helping patients. Bianco said he had done that by August 1992. That's when he changed the name of the company from Combined Therapeutics to Cell Therapeutics, because it was clear the company was changing directions from combining two drugs to focusing on a single compound, Lisofylline.

"In retrospect, the FDA was absolutely right," Bianco said. "It would have been a nightmare from a safety, from a consumer-safety perspective, to try to manipulate the metabolism of the drug by combining another drug that wasn't invented for that purpose."

Additionally, in the 1998 book "Hematopoietic Cell Transplantation," Bianco and colleague Dr. Jack Singer recount that when PTX and Cipro are mixed, they don't produce enough Lisofylline to be effective. He stressed that point in interviews with The Times.

Other issues raised by CTI in the ad:

• CTI said because PTX and Cipro were both owned by other drug companies, no one could have profited from the drugs.

Bianco said in the interviews that he originally formed CTI in hopes of negotiating a license agreement with the other drug companies to combine PTX and Cipro.

• CTI denied that Bianco was involved in the breast-cancer study.

The Times' story did not say flatly that he was. Rather, the story reported, accurately, that his is the second name among the investigators listed on the official protocol document for the experiment, Protocol 681. The story also reported that Bianco denied being involved in the experiment.

The ad accurately points out that Bianco is not listed on Kathryn Hamilton's informed-consent document.

• CTI denied that it was supplying the intravenous form of PTX for the breast-cancer study.

However, the informed-consent document from the breast-cancer study says that patients' medical records would be shared with CTI because that company was supplying the IV form of PTX. Also, the chief investigators on the breast-cancer study at The Hutch, including Dr. William Bensinger, confirmed that they were getting the IV form from CTI.

Efforts to reach Bianco yesterday for comment were unsuccessful.

The Times has posted relevant documentation online.

David Heath can be reached at 206-464-2136 or dheath@seattletimes.com.