ALLOGENEIC MARROW TRANSPLANTATION FOLLOWING CYCLOPHOSPHAMIDE AND ESCALATING DOSES OF HYPERFRACTIONATED TOTAL-BODY IRRADIATION IN PATIENTS WITH ADVANCED LYMPHOID MALIGNANCIES - A PHASE I II TRIAL/

Purpose: To define the maximum tolerated dose (MTD) of unshielded tota l body irradiation (TBI) delivered from dual C-60 sources at an exposu re rate of 0.08 Gy/min and given in thrice daily fractions of 1.2 Gy i n patients with advanced lymphoid malignancies. Methods and Materials: Forty-four patients with a median age of 28 (range 6-48) years were e ntered into a Phase I/II study. All patients received cyclophosphamide (CY), 120 mg/kg administered over 2 days before TBI. Marrow from huma n leukocyte antigen (HLA) identical siblings was infused following the last dose of TBI. An escalation-deescalation schema designed to not e xceed an incidence of 25% of Grade 3-4 regimen-related toxicities (RRT s) was used. The first dose level tested was 13.2 Gy followed by 14.4 Gy. Results: None of the four patients at the dose level of 13.2 Gy de veloped Grade 3-4 RRT. Two of the first eight patients receiving 14.4 Gy developed Grade 3-4 RRT, establishing this as the MTD. An additiona l 32 patients were evaluated at the 14.4 Gy level to confirm these ini tial observations. Of 40 patients receiving 14.4 Gy, 13 (32.5%) develo ped Grade 3-4 RRTs; 46% in adults and 12% in children. The primary dos e limiting toxicity was Grade 3-4 hepatic toxicity, which occurred in 12.5% of patients. Noninfectious Grade 3-4 interstitial pneumonia synd rome occurred in 5% of patients. The actuarial probabilities of event- free survival, relapse, and nonrelapse mortality at 2 years were 0.10, 0.81, and 0.47, respectively, for patients who received 14.4 Gy of TB I. Conclusions: The outcome for patients receiving 14.4 Gy of TBI was not different from previous studies of other CY and TBI regimens in pa tients with advanced lymphoid malignancies. These data showed that the incidence of Grade 3-4 RRTs in adults was greater than the 25% maximu m set as the goal of this study, suggesting that 13.2 Gy is a more app ropriate dose of TBI for adults, while 14.4 Gy is an appropriate dose for children.