Based on earlier clinical and preclinical investigations, we designed two different pilot trials for patients with
nodular lymphoma or
chronic lymphocytic leukemia. These studies evaluated the use of either 41.8 degrees C whole body
hyperthermia (WBH), or the nonmyelosuppressive chemotherapeutic
drug,
lonidamine (LON), as an adjunct to total body irradiation (TBI) (12.5 cGy twice a week, every other week for a planned total dose of 150 cGy). Whole body
hyperthermia was initiated approximately 10 min after total body irradiation;
lonidamine was administered orally (420 mg/m2) on a daily basis. Although entry to the studies was nonrandomized, the two patient populations were accrued during the same time frame and were comparable in terms of histology, stage of disease, performance status, and prior
therapy. Of 8 patients entered on the TBI/WBH study, we observed 3 complete responses (CR), 4 partial responses (PR), and 1 improvement (i.e., a 48% decrease in
tumor burden). Of 10 patients entered in the TBI/LON study, there was 1 CR and 4 PR. For the TBI/WBH study, myelosuppression was not treatment-limiting; there were no instances of
infection or
bleeding and platelet support was never required. The median survival time for the TBI/WBH study is 52.5 months based on Kaplan Meir estimates. Two patients remain in a CR. The median
time to treatment failure (MTTF) is 9.4 months (90% confidence interval = 7-15.4 months). In the TBI/LON study, 50% of patients receiving TBI required treatment modification due to platelet-count depression during
therapy, but there were no instances of
infection or
bleeding. Frequently observed LON-related toxicities included myalgias, testicular
pain,
photophobia and
ototoxicity. For the TBI/LON study, median survival is 7.6 months; MTTF was 2.4 months. In analyzing the results of these pilot studies, our subjective clinical impressions lead to the hypothesis that WBH protected against TBI-induced
thrombocytopenia during
therapy, whereas LON had no effect on TBI-induced myelosuppression. This speculation was tested and confirmed in a series of in vitro and in vivo experiments.