Dose Escalation of Total Marrow and Lymphoid Irradiation in Advanced Acute Leukemia

Abstract

For patients with relapsed/refractory active leukemia undergoing hematopoietic stem cell transplantation (HSCT), conditioning regimens at present fail to provide acceptable disease control. A proposed solution has been to intensify chemotherapy and/or total body irradiation (TBI); however, increased toxicities offset gains from therapy, resulting in a lack of survival benefit. Total marrow and lymphoid irradiation, or TMLI, is a technique that permits precise delivery and increased intensity treatment via sculpting radiation to sites with high disease burden or high risk for disease involvement. Normal tissue is avoided. We conducted a phase I trial in 51 patients with relapsed/refractory acute leukemia undergoing HSCT using a matched related, matched unrelated, or one-allele mismatched unrelated donor. Escalating doses of TMLI (range 1200–2000 cGy) were combined with cyclophosphamide (CY) and etoposide (VP16). Only one dose-limiting toxicity, at 1500 cGy, was observed. We declared the maximum tolerated dose to be 2000 cGy, as TMLI simulation studies indicated that >2000 cGy may deliver toxic doses to normal organs. The posttransplant nonrelapse mortality (NRM) rate was only 3.9% at day +100 and 8.1% at 1 year. The rates of acute and chronic graft-versus-host disease (GVHD) were in line with traditional conditioning regimens. At day +30, 88% of all patients achieved a complete remission (CR), which was also achieved by 100% of patients treated at 2000 cGy. The estimated 1-year overall survival was 55.5%. We followed this trial with a phase II study, in which we obtained 2-year estimates of OS and progression-free survival (PFS) of 41% and 27%, respectively. The estimates of NRM at 100 days and 2 years were 6% and 9%, respectively. Toxicities continued to be moderate and manageable. The TMLI/CY/VP16 conditioning regimen is well tolerated at TMLI doses up to 2000 cGy, with low NRM rate and no increased risk of GVHD.