Clinical and Biologic Activity of the Heat Shock Protein-90 (HSP-90) Inhibitor 17-AAG in Patients with Relapsed Lymphoma.

Abstract 3744

Poster Board III-680

HSP-90 is abundantly expressed in a variety of cancer cells, including lymphoma. HSP-90 chaperones several client proteins that are involved in the oncogenic process, and therefore has become an appealing target for cancer therapy. Previous in vitro studies demonstrated that inhibition of HSP-90 by the small molecule 17-AAG (17-allylamino-17-demethoxy-geldanamycin) can induce apoptosis in a dose and time dependent manner by reducing the cellular contents of critical survival proteins, including Akt and cyclin D1 in a variety of lymphoma cell lines. With this background, we conducted a phase II study of 17-AAG in adults with relapsed/refractory mantle cell or Hodgkin lymphoma. Patients were eligible if they had a relapsed disease, and adequate organ function. Patients who had primary refractory disease were required to have a maximum of 4 prior treatment regimens. Twenty-two patients were enrolled (13 classical Hodgkin lymphoma, and 9 mantle cell lymphoma) with a median age of 49.5 years. Median prior treatments were 3 (range 1-4) and 36% (n=8) received prior autologous stem cell transplant. 17AAG was given at 220 mg/m2 by intravenous infusions, initially over 1hour, and subsequently over 6 hours. Doses were given on days 1, 4, 8 and 11 of 21-day cycles. Twenty-two patients received at least one dose of 17AAG and were evaluable for toxicity. The most common non-hematologic toxicity were diarrhea (n=8), fatigue (n=7), nausea (n=6), and fever (n=6). Grade 3 and 4 toxicities occurred in 8 patients; pain and thrombocytopenia being the most common. Three patients who were treated with the 1 hour infusion died after receiving 1-2 doses of therapy. One patient had extensive lung disease, including pleural effusions, developed worsening of respiratory symptoms requiring intubation, a second patient had extensive disease in the mediastinum and large pleural effusion who also complained of worsening shortness of breath that was associated with nausea and vomiting few hours after the first dose of 17-AAG requiring visit to the emergency center, an EKG showed no major abnormalities, however he had a cardiac arrest shortly thereafter, and a third patient with primary refractory extensive disease also had pulmonary and liver disease complained of chest pain and subsequently had a cardiac arrest. After revising the study to prolong the infusion time to 3 to 6 hours, and to exclude patients with pulmonary and cardiac diseases, no additional deaths were observed. Eighteen of the 22 patients enrolled were evaluable for treatment response, of whom, 7 (39%) had reduction in their tumor measurement, and 2 (11%) achieved partial remissions. Paired core needle biopsies from diseased lymph nodes were obtained from selected patients before and within 24 hours of the first infusion of 17-AAG, and tissue sections were evaluated by immunohistochemistry for changes in the expression of selected client proteins. Remarkably, even after one dose of therapy, 17-AAG downregulated cyclin D1 and Akt proteins in tumor cells, decreased the percentage of tumor cells expressing Ki-67, and increased the percentage of cells expressing activated caspase-3. Collectively, these data demonstrate for the first time that targeting HSP-90 can modulate the level of several client proteins in lymphoma cells in vivo, and can achieve clinical responses in patients with relapsed lymphoma, providing a proof-of-principle for further developing HSP-90 targeted therapy in patients with lymphoma.