SAN FRANCISCOAmifostine (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 studyone at 220
mg/m2 and two at 300 mg/m2medical 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 cancernot ovarian
cancerbut 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."