Work

Phase I Trial of Escalated Doses of Targeted Marrow Radiation Delivered By Tomotherapy Combined With Etoposide and Cyclophosphamide; an Allogeneic HCT Preparative Regimen for Patients With Advanced Leukemia

Year: 2011

Type: article

Abstract: Overall survival (OS) for acute leukemia in relapse (RL) or induction failure (IF) treated with HSCT is 16-19% [Duval et al JCO.2010]. While randomized studies have shown a dose response relationship, with higher doses of radiation resulting in decreased relapse, this benefit is offset by increased mortality. We report the initial results of a Phase I trial of 12 patients transplanted between 3/2008 and 7/2010 in which escalated doses of targeted whole body radiation to marrow bearing areas delivered by Tomotherapy on days -10 to -6 was added to etoposide 60mg/kg [adj bw] day -5 and cyclophosphamide 100mg/kg [ideal bw] day -3. Radiation was started at 1200cGy delivered in 150cGy fractions twice a day. Dose of radiation was escalated in increments of 150cGy using cohorts of 3 patients until dose limiting toxicity was reached according to Bearman grading scale. All patients received peripheral stem cells on day 0. GVHD prophylaxis consists of tacrolimus and sirolimus. Patient characteristics are as follows: age 33 yrs(20-54); AML 5, ALL 5, Biphenotypic 2; Disease stage IF 7, 1 RL 5; Donor source sibling 8, matched unrelated 1, mismatched (1 allele) unrelated donor 3; WBC at HCT 1.4(0.2-100.0), blasts in blood 18(0-77%), marrow blasts 30(0-95%). Two patients with no marrow blasts had persistent extramedullary disease at HCT. With a median follow-up for alive patients of 9.2 months (2.9- 27) the overall survival and cumulative incidence of relapse at 6 months are 63% (CI 41%; 78%) and 17% (CI 4%; 50%), respectively. Six patients were treated at 1500cGy without reaching DLT. Four (33%) patients developed acute GVHD, 1 (8%) developed Grade 3-4. The day 30 and day 100 NRM was 0% and 8%, respectively. Most common toxicity was grade 2 stomatitis Causes of death were disease progression 3, GVHD 2 and infection 1. These preliminary results suggest that 1.) doses of targeted marrow radiation delivered by Tomotherapy can be safely escalated to 1500cGy in combination with etoposide and cyclophosphamide (DLT not reached); and that 2.) a reduction in relapse/progression can be achieved without increasing NRM in this high risk patient population. This observation needs to be confirmed in a larger group of patients.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2010.12.285