IMMUNEX/HOECHST GM-CSF ALLOWS HIGH-DOSE CHEMOTHERAPY IN SARCOMA

IMMUNEX/HOECHST GM-CSF ALLOWS HIGH-DOSE CHEMOTHERAPY IN SARCOMA patients, according to results of two studies presented at the May 19-21 American Society for Clinical Oncology annual meeting. In one study, adjuvant treatment with a granulocyte macrophage-colony stimulating factor (Immunex' Leukine/Hoechst- Roussel Pharmaceuticals' Prokine) allowed administration of a 25% higher than standard dose of chemotherapy, while in the other study, the growth factor allowed high-dose chemo to be given in previously unacceptably toxic combinations. The first study, presented by Saroj Vadhan-Raj, MD, M.D. Anderson Cancer Center, examined two cycles of chemotherapy in conjunction with GM-CSF therapy. In the first cycle, GM-CSF was given for 14 days up to one week prior to chemotherapy and then two days after a five-day course of CYADIC chemotherapy consisting of Cytoxin 750 mg/m, Adriamycin 75 mg/m and DCIT 1,000 mg/m. In that cycle, GM-CSF enhanced the rate of neutrophil recovery in seven patients who had previously experienced more modest neutrophil recovery. However, GM-CSF did not eliminate the neutrophil nadir. In the second cycle of the M.D. Anderson study, 17 patients were treated with a compressed schedule of CYADIC chemotherapy for three days, with GM-CSF administered on the fourth day. Sarcoma patients treated according to the second schedule had nadir white cell counts two-fold higher and nadir neutrophil counts three-fold higher than patients treated in cycle one, Vadhan-Raj reported. The duration of neutropenia was also reduced from six to three days. At the optimal dose level of 750 mg/m, GM-CSF abrogated severe myeloid leukopenia in 100% of patients. The overall reponse rate to treatment was over 60%. Administration of GM-CSF according to cycle two also reduced the incidence of severe febrile neutropenia to 18% from 36% in cycle one. The incidence of mucositis was reduced from 65% to 35% from cyle one to cycle two. GM-CSF also allowed an increase in the Adriamycin dose from 75 to 90 mg/m in some patients. "These findings raise the exciting possibility that GM-CSF may allow intensification of chemotherapy either by increasing the dose or by decreasing the interval between courses," Vadhan-Raj commented. Vadhan-Raj was asked by an oncologist in the audience why M.D. Anderson is testing GM-CSF, which is approved only for bone marrow transplants, when G-CSF (Amgen's Neupogen) is available for most chemotherapies. The researcher responded that the center had been impressed by the fact that GM-CSF not only increased neutrophils but also raised the levels of monocytes and eosinophils. Additionally, she noted: "We were able to demonstrate that these other myeloid cells such as monocytes were primed to express the enhanced levels of interleukin-1 beta, [tumor necrosis factor] alpha, and various other cytokines which may be important in patients suffering from malignancy." In the second study, a Phase II trial, presented by W.P. Steward, MD, Beatson Oncology Center in Glasgow, Scotland, 104 patients with advanced soft tissue sarcomas were treated with 75 mg/m doxorubicin and 5 mg/m ifosfamide over three weeks followed by 14 days of GM-CSF, in single subcutaneous injections of 250 mg/m or twice daily injections of 125 mg/m. Normally, this regimen of doxorubicin and ifosfamide could not be given in combination because of severe toxicity, Steward noted. However, "GM-CSF in both schedules allowed full protocol dose intensity of administration of chemotherapy to the vast majority of our patients," Steward said. Infections occurred less frequently in this study than in studies with lower doses of chemotherapy, Steward said. The rate of complete remissions was 11% and the overall response rate was 46.5%. "The response rate of nearly 47% that we saw [in the study] is the highest we have seen within the EORTC soft tissue and bone sarcoma group," Steward observed. Schering-Plough seemed to be having some difficulty getting results of its randomized GM-CSF trials reported at ASCO. Researchers from Memorial Sloan-Kettering and Indiana University refused to present data from a trial in 107 germ cell tumor patients receiving vinblastine, or VP-16, plus ifosfamide, cisplatin, and Schering's GM-CSF (Leucomax). The study closed to accrual in late 1990. During the past six months, Schering has been collecting and analyzing the data, the scientists noted. "Unfortunately, despite protests, we have not been able to review these data ourselves," the researchers said. Schering finally supplied the scientists, shortly before the meeting, with copies of the data.