Myeloablative Fludarabine/ IV Busulfan Combined With Linac Based Intentsity Modulated Total Marrow Irradiation (IM-TMI) In Allogeneic Stem Cell Transplant For High Risk Hematologic Malignancies: A Phase I Study
Authors: Patel Pritesh R. , Oh Annie L. , Koshy Matthew , Aydogan Bulent , Mahmud Nadim , Peace David , Quigley John G. , Saraf Santosh L. , DeMasi Enzo , Weichselbaum Ralph R , Rondelli Damiano 
Published: October 2019

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.