Steven M. Devine

A Pilot Study of Prophylactic Aerosolized Amphotericin B In Patients at Risk for Prolonged Neutropenia

Invasive aspergillosis continues to be a significant cause of morbidity and mortality in patients with prolonged neutropenia. We performed a phase I trial of escalating doses of aerosolized amphotericin B given by a face mask nebulizer system with a disposable bacterial exhale filter. Five, 10, 15, and 20 mg of drug were dissolved in sterile water and inhaled over 10 to 15 minutes twice daily. Tolerance was studied in 26 patients (18 transplant recipients, and 8 leukemia patients). No side effects were observed at any dose level. Prophylactic treatment ended for 14 patients (54%) when intravenous (IV) amphotericin B was begun empirically for antifungal coverage following fevers. Eleven patients (43%) continued inhaled amphotericin B until blood counts recovered. One patient was taken off study when she developed cardiogenic pulmonary edema. No patient developed clinically suspicious or pathologically documented infection with invasive aspergillosis. Prophylactic aerosolized amphotericin B is well tolerated at 5, 10, 15, and 20 mg twice daily dosing. In addition, prophylactic aerosolized amphotericin B does not appear to sensitize patients to the subsequent use of IV amphotericin B. Although this study suggests that prophylactic inhaled amphotericin B is well tolerated and effective, a large scale controlled trial is needed.

Viral infections in severely immunocompromised cancer patients

Immunocompromised cancer patients are susceptible to infection by many viral pathogens. The most serious morbidity results from active infection by members of the herpes virus family. Reactivation of latent virus occurs as a sequela of cytotoxic therapy and deficiency of cell-mediated immunity, especially cytotoxic responses, the major host protective defense. Herpes simplex virus and varicella zoster virus infections are problematic in patients with all types of cancer; cytomegalovirus infections cause life-threatening morbidity in bone marrow transplant patients. Several antiviral agents are highly active against these pathogens and different strategies of using them have resulted in reduced morbidity and mortality. Ultimately, the resolution of these infections is dependent on the control of the malignancy and the ability of the patient to mount an adequate immune response.

High Dose Chemotherapy Without Hematopoietic Cell Support for the Treatment of Refractory Lymphoma

Conventional dose combination chemotherapy for patients with relapsed or refractory lymphoma is rarely curative. High dose chemotherapy followed by hematopoietic progenitor cell transplant (HPCT) has a clearly defined role in patients who have first relapsed after standard CHOP chemotherapy for lymphoma. However, the role of HPCT is less well defined for patients with chemo-resistant, or chemo-refractory disease. Sixteen patients (15 Non-Hodgkins, 1 Hodgkins Disease) were entered into a phase II study to determine if a dose intensive induction regimen in heavily pre-treated refractory lymphoma patients could permit further consolidation with HPCT. The primary endpoints were survival, response, tox-icity, and resource utilization. The regimen consisted of continuous infusion etoposide I or 2 gm/m2/72 hours, idarubicin 12mg/m2/d for 3 days followed by cytarabine 2gm/m2/72 hours on days 8,9, and 10 (VIC). Fifteen patients were evaluable for objective response. The overall response rate was 53% with 7 patients achieving a partial response and 1 patient achieving a complete response. Of the 8 responders, 6 patients subsequently received high dose chemotherapy followed by HPCT (4 autologous, 2 allogeneic). The median survival was 176 days for the non-responders contrasted with 722 days for the responders. The average duration of hospitalization was 38 days. Toxicity was mainfest primarily as mucositis with a median grade of 3 among the first 13 patients, and a median grade of 2 in three subsequent patients who received an etoposide dose of lgm/m2/72 hours. All patients had an episode of neutro-penic fever and 5 patients developed clinically significant pneumonitis during therapy. The VIC regimen is active in the treatment of chemo-refractory lymphoma with clinically significant differences in survival for patients who respond to therapy. Further modifications to the regimen could include the addition of a topoisomerase I inhibitor for synergy with etoposide, and using VIC as part of a tandem transplant regimen where response to VIC would allow further therapy with a myeloablative induction followed by HPCT.