Journal of Clinical Oncology, Vol 1, 359-367, Copyright © 1983 by American Society of Clinical Oncology
Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer
HM Lazarus, RH Herzig, J Graham-Pole, SN Wolff, GL Phillips, S Strandjord, D Hurd, W Forman, EM Gordon and P Coccia
Thirty-three adult and pediatric patients with refractory malignancies were
treated with escalating doses of melphalan (120-225 mg/m2 IV over 3 days)
followed by reinfusion of previously harvested and cryopreserved autologous
marrow. The hematological and nonhematological toxicities and the
therapeutic effects of this regimen were evaluated. Increasing doses of
melphalan did not alter the rate of decline nor the recovery of peripheral
blood counts. Granulocyte (greater than 500/microL) and platelet count
(greater than 20,000/microL) recovery occurred in a median of 19 (range
12-54) and 24 (range: 12-54) days after bone marrow transplantation,
respectively. Five patients experienced severe infection, three of which
were fatal, and one patient died due to thrombocytopenic hemorrhage.
Toxicity to the gastrointestinal system was dose limiting. The maximum
tolerated dose of melphalan was 180 mg/m2; only three of 24 patients
experienced severe stomatitis, esophagitis, and diarrhea at this level or
less, while eight of nine patients at 225 mg/m2 were affected (p less than
0.005). Administration of cyclophosphamide (300 mg/m2 IV) 1 week before
melphalan therapy did not reduce the incidence of severe gastrointestinal
toxicity. Plasma melphalan concentration peaked 30-60 min after infusion
(4.8-11.5 micrograms/mL) but declined rapidly. Cerebrospinal fluid
concentration was 10% of the corresponding plasma concentration and was
undetectable at 3 hours. Antitumor responses occurred in nine of 13
patients with malignant melanoma (five complete and four partial
remissions), and ranged 2-12+ months with a median of 5 months. Four of six
neuroblastomas demonstrated responses (three complete and one partial
remission( lasting a median of 7.5 (range: 5- 10) months. Other tumors in
which this regimen had activity included breast cancer and Ewing's sarcoma.
The overall response rate for the 33 patients was 30% complete remissions
(10 patients) and 21% partial remissions (seven patients). High dose
melphalan and autologous bone marrow transplantation is a promising therapy
for patients with malignancies for which no effective treatment is known or
for patients whose cancer is refractory to conventional therapeutic agents.
