GAITHERSBURG, Md—The Oncologic Drugs Advisory Committee (ODAC) has unanimously recommended the approval of Busulfex Injection (busulfan, Orphan Medical) in combination with other chemotherapeutic agents and/or radiation as a conditioning regimen prior to hematopoietic progenitor cell transplantation—but only in chronic myelogenous leukemia (CML).

The panel voted against recommending that the FDA approve Busulfex for use in acute myelogenous leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, and malignant lymphomas. Members found that the company did not provide substantial evidence of the safety and efficacy of the drug in these cancers.

Busulfex is an injectable form of busulfan, an oral drug that has been in use since the 1960s to prepare patients for bone marrow and peripheral blood stem cell transplants. The injectable formulation was developed by researchers at M.D. Anderson to counter the vomiting and difficulties of ensuring a consistent dose that occur with the oral form.

Of the expected 20,000 bone marrow transplants in the United States this year, about 4,000 patients with the five cancers for which Orphan Medical sought approval would be potential candidates for the drug, the company said. “We do not expect the introduction of Busulfex to change standard practice, but rather to be a substitute for the oral product,” said Dayton R. Reardan, PhD, head of regulatory affairs for Orphan Medical.

The company supported its new drug application with two phase II clinical trials that assessed myeloablation, engraftment, and safety in patients treated with Busulfex; clinical studies that assessed the pharmacokinetic profile of the injection form vs the oral form of busulfan; and a literature review to determine in which diseases there existed substantial evidence to support the safety and efficacy of oral busulfan in stem cell transplantation.

The literature review was undertaken after the FDA agreed that a complete and comprehensive literature review could offer evidence of oral busulfan’s efficacy and safety in a transplant setting.

The first study included 42 autologous transplant patients treated at five centers; the second included 61 allogeneic transplant patients treated at seven centers. Patients in each study received 0.8 mg/kg of Busulfex injected every 6 hours for 4 days beginning 7 days before transplant.

All patients in both studies achieved engraftment, Borje S. Andersson, MD, PhD, told the committee. Among autologous patients, the median time to engraftment was 10.5 days with 100% engraftment, compared with median graft times of 25 to 32 days and failures rates of 1.6% to 1.7% with use of the oral agent as found in the autologous literature.

Allogeneic transplant patients had a 13-day median time to engraftment and 100% engraftment, compared with median engraftment times of 19 to 20 days and failure rates of 2.3% to 6.1% with the oral agent as found in the literature.

One autologous patient (2.4%) suffered veno-occlusive disease, compared with rates of 3.2% to 6.1% in the literature. There were no deaths in the first 100 days post-transplant, compared with rates of 6.5% to 15% in the literature.

Among the allogeneic patients, 3 of 61 (4.9%) suffered veno-occlusive disease, according to Jones criteria, compared with 5.9% to 12% in the literature, and eight patients (13.1%) died in the first 100 days, compared with rates of 4.1% to 21% in the literature.

A major problem with oral busulfan is that patients must take huge quantities of the drug—a 154-lb patient would have to take 35 oral busulfan tablets to equal one injection, noted William P. Vaughan, MD, of the University of Alabama.

Another problem is that the oral drug causes frequent vomiting. Orphan Medical presented evidence that Busulfex reduced vomiting. Use of the injectable drug resulted in no loss of drug due to vomiting; consistency of dosing; and stable bioavailability.

The company’s literature review of the use of oral busulfan involved 43 studies published from 1964 to 1997. In its review, FDA included another 16 articles.

FDA reviewer Donna Griebel, MD, said that the agency’s analysis found a similar pharmacokinetics profile for both the oral and injectable formulations, and comparable myeloablation and engraftment. ODAC agreed 15 to 0 that Busulfex has a similar but not superior pharmacokinetic profile to oral busulfan.

However, the FDA staff’s literature review concluded that the evidence only supported the safety and efficiency of oral busulfan in CML, Dr. Griebel said. ODAC members agreed in a 15 to 0 vote. In split votes, they rejected recommending approval of the injectable drug for use in the other four cancers for which the company had sought a marketing indication.

Dr. Griebel also raised a potential safety issue regarding an inactive ingredient in Busulfex, dimethylacetamid (DMA), that has not been FDA approved for use in humans. “Repeated dosing studies have shown hepatic injury in animals and humans,” she said. “Similarly, high doses have been reported to cause neurologic symptoms in humans.”

Robert Temple, MD, of the FDA, assured ODAC members that approval of Busulfex would not give blanket approval to dimethylacetamid.