SUMMARY/ABSTRACT Total body irradiation (TBI) remains an essential part of hematopoietic cell transplantation (HCT) for patients with high risk acute leukemia. Unfortunately, older patients or those with comorbidities cannot tolerate TBI-related toxicities. Reduced intensity conditioning regimens are better tolerated by these patients but are associated with significant increase in relapse rate. Therefore, It is imperative to develop innovative targeted, organ sparing forms of radiotherapy, such as tumor-specific radioimmunotherapy (RIT) and total marrow irradiation (TMLI), to allow for safe dose intensification to disease sites while reducing toxicities, especially in older patients or those with comorbidities. TMLI targets radiation to user-defined target regions (i.e. bone marrow), using CT image guided intensity modulated radiotherapy. Our team has previously reported that adding 12 Gy TMLI to the reduced intensity conditioning regimen of fludarabine (flu) and melphalan (mel) is feasible with acceptable toxicity similar to flu-mel alone, and encouraging 2-year OS and RFS of 54% and 49%, respectively (NCT00544466). However, TMLI dose escalation with flu/mel in patients > 60 years old is challenging due to mucositis, suggesting that delivering other forms of targeted radiotherapy complementary to TMLI may be beneficial in this patient population. CD25 might be an ideal RIT target given its high expression in a subset of acute leukemias, association with low survival rates, and preferential expression by leukemia stem cells. We have filed an IND (115386) for yttrium-90 (90Y)-labeled-DOTA-anti-CD25 basiliximab and have recently completed two Phase I trials with this agent combined with BEAM in patients with Hodgkin’s (NCT01476839) and non-Hodgkin’s lymphoma (NCT02342782) undergoing autologous HCT. Here, we propose to add anti-CD25 RIT to our established conditioning regimen of TMLI 12 Gy/ flu/ mel for patients with relapsed/refractory (R/R) CD25- expressing acute leukemia who are > 60 years old. We hypothesize that the combination of dose escalated 90Y- DOTA-basiliximab RIT administered one week prior to an established allogeneic HCT regimen of TMLI 12 Gy- flu-mel is feasible and associated with acceptable toxicities and non-relapse mortality (NRM) rates, and that we will be able to define an RIT dose to carry forward into larger efficacy trials. In our aim 1, we are going to describe safety and establish appropriate dosing of 90Y-basiliximab when combined with TMLI-flu-mel (at the fixed dose of 12 Gy) in patients ≥ 60 years old undergoing alloHCT for R/R acute leukemia. Our primary objective is to define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of 90Y-basiliximab. In specific aim 2 we will conduct correlative studies investigating the biodistribution (BD) and pharmacokinetics (PK) of 90Y-basiliximab. This trial will serve as proof of principal for a novel method of combining two complementary forms of targeted radioth...