Total body irradiation has been decreasingly utilized in hematopoietic stem cell transplant due to extra-hematologic toxicity. However, patients with a high risk of relapse may benefit from a combination of chemotherapy and radiation. Intensity modulated total marrow irradiation (IM-TMI) represents an innovative technique to irradiate the bone marrow with limited radiation to surrounding tissues and was tested here in combination with fully myeloablative chemotherapy. We designed a phase I trial with escalating doses of IM-TMI to standard myeloablative fludarabine/ IV targeted busulfan conditioning.All patients received fludarabine 40mg/m2 on days -8 to -5 and IV busulfan on days -5 to -2 targeting an AUC of 4800microM/min based on a pretransplant test dose. In addition patients received IM-TMI at one of three dose levels (3Gy, 6Gy or 9Gy). Radiation was delivered in 2 daily doses at 3Gy/day on day -5 (first cohort), days -6 and -5 (second cohort) or days -7 to -5 (third cohort). Graft versus host disease prophylaxis was with standard methotrexate, tacrolimus and ATG in patients receiving unrelated transplants.A total of 13 patients with high risk malignant disease were enrolled in the study with 12 patients receiving a matched related (n=7) or unrelated (n=5) peripheral blood stem cell transplant. One was excluded due to relapse prior to transplant. Median age was 52 years (range 20-65). Patients underwent transplant for ALL (n=1) or AML (n=8) with high risk cytogenetics or >CR1, multiple myeloma (n=2) with high risk cytogenetics and relapse after autologous transplant and accelerated phase CML (n=1) resistant to therapy with tyrosine kinase inhibitor. Three patients were enrolled in cohorts 1 (3Gy) and 2 (6Gy), and 6 patients in cohort 3 (9Gy). Toxicity was measured on the Bearman scale. No grade 3-4 extrahematologic toxicity was observed in any cohort. Grades 1-2 mucositis was observed in 9 patients. Grade 1 gastrointestinal toxicity was observed in 2 patients and 1 patient in cohort 2 had grade 2 cardiac toxicity. All patients engrafted and no patients suffered transplant related mortality on or before day +30. Median time to engraftment of neutrophils >0.5x109/L was 14.5 days (range 10-20 days) and platelets >20x109/L was 14.5 days (range 8-19 days).After median follow up of 692.5 days (range 68-1319 days), 8 patients (66%) are alive and 7 remain in remission. 1 patient with multiple myeloma is alive after relapse. Of 4 deaths, 2 were due to transplant related mortality (liver disease at day 253 and sepsis at day 68) and 2 were due to relapse (1 patient with AML and 1 with ALL). Three patients developed grade 2-4 acute graft versus host disease (GVHD) and 4 patients have extensive chronic GVHD.This is the first study showing that IM-TMI in doses up to 9Gy can be safely added to a busulfan based myeloablative conditioning regimen. It is unknown at this time whether higher doses of IM-TMI can be utilized with myeloablative preparative regimens. The use of a linear accelerator platform to deliver IM-TMI, will allow almost any transplant center to utilize this approach. Disclosures:No relevant conflicts of interest to declare.