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Amifostine Supports Melphalan Dose Escalation in Stem Cell Transplantation

Amifostine Supports Melphalan Dose Escalation in Stem Cell Transplantation

SAN FRANCISCO—Amifostine (Ethyol) provided cytoprotection and allowed the maximum tolerated dose of melphalan (Alkeran) to be increased to 280 mg/m2 for cancer patients receiving autologous hematopoietic stem cell transplantation in a phase I and II study. Dose-limiting toxicity of melphalan was not able to be clearly determined from the trial, however, and might be higher, according to Gordon L. Phillips II, MD, director of the bone marrow transplantation program of the Greenebaum Cancer Center at the University of Maryland in Baltimore.

The high-dose melphalan regimen was toxic primarily to the mucosa, he explained, but the amount of toxicity varied among patients at all dose levels tested. Though three patients died during the study—one at 220 mg/m2 and two at 300 mg/m2—medical records suggest their deaths might have resulted from other causes. The patient who died of cardiotoxicity at the lowest dose was found to have known anthracycline-induced cardiomyopathy, and one of the others died of complicated multi-organ failure, Dr. Phillips said.

"Melphalan at 280 mg/m2 with traditional stem cell support and amifostine can be given to patients with very advanced malignancies with substantial mucosal morbidity but very little mortality," he concluded. "And I would emphasize there are now 27 patients that have been treated at this level without severe toxicity."

Two Doses of Amifostine

All told, 48 patients with advanced malignancies were enrolled in the trial: 5 patients with acute myelogenous leukemia, 11 with metastatic breast cancer, 14 with myeloma, 14 with non-Hodgkin’s lymphoma, 2 with Hodgkin’s disease, and 2 with ovarian cancer. The median age was 50 years.

Clinicians treated the patients in cohorts of four at each dose level, starting at 220 mg/m2. Each cohort was followed for 30 days before the investigators decided whether to escalate the dose by 20 mg/m2, Dr. Phillips explained. Nineteen patients were still alive at the time Dr. Phillips reported to the American Society of Clinical Oncology meeting, including one who had not experienced relapse or progression.

Two doses of amifostine (740 mg/m2 via 15-minute intravenous infusion) were given: the first one 24 hours before and the second immediately before delivery of the high-dose melphalan, also in a 15-minute intravenous infusion. "Many patients were symptomatic, but in brief there were no showstoppers," Dr. Phillips said in a summation of toxic responses that included hypertension, sneezing, nausea, vomiting and, despite a pretreatment calcium infusion, four cases of symptomatic hypocalcemia.

Most patients had either grade 1 or grade 2 mucositis, according to Dr. Phillips. "I would certainly emphasize that this is not an outpatient regimen," he said. "Those patients who were discharged early all came back in with mucosal problems."

Phase II Encouraging

Although focusing on phase I results, Dr. Phillips suggested that phase II results were also encouraging. "I emphasize there are patients who achieved complete responses and are alive at all dose levels. There was such a mix of diagnoses; I would like not to go beyond that. We’ve seen response in myeloma, lymphoma, metastatic breast cancer—not ovarian cancer—but I will emphasize these are all on very short follow up."

Whatever the results to come, Dr. Phillips said that investigators should be encouraged to look for new ways to reduce toxicity and increase doses of antineoplastic agents. "Even if amifostine and MEL 280 doesn’t cure all patients who are now relapsing after transplantation," he concluded, "I hope it provides an example that regimen-related toxicities, like other ‘barriers,’ can be overcome, perhaps with new strategies and new techniques."

 
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