Prospective Assessment of Radiation Dose Toxicity Correlations in Patients Who Received Intensity Modulated Total Marrow Irradiation (IM-TMI) as Part of Conditioning Regimen Prior to Stem Cell Transplant

Abstract

Purpose/Objective(s): IM-TMI is utilized to preferentially target hematopoietic tissue while reducing normal tissue toxicities. We conducted a pooled analysis of 2 phase 1 studies in patients with high risk leukemia and relapsed multiple myeloma to determine acute and long term toxicities involving IM-TMI as a conditioning regimen prior to stem cell transplant (SCT). Materials/Methods: The first phase 1 study included 14 patients with leukemia treated with fludarabine 160mg/m2 and targeted busulfan (AUC 4800uM∗minute) with IM-TMI administered 1.5 Gy twice daily at 3Gy, 6 Gy, 9 Gy, and 12 Gy on days -5,-6,-7, and -8 respectively before allogeneic SCT. The second phase one study included eight patients with relapsed multiple myeloma who received melaphalan 200mg/m2 in 2 divided doses and IM-TMI administered 1.5 Gy twice daily at 3, 6, or 9 Gy starting on days -1,-2 and -3 respectively before autogeneic SCT. For the IM-TMI, excluding the mandible, maxilla, arms, and lower extremities, all bones were contoured on CT scan. To create a planning target volume, a 3 mm margin was added to the bones. Organs at risk included the brain, lenses, oral cavity, lungs, heart, liver, kidney, rectum, bladder, and small bowel. Three separate treatment plans, one for the head and neck, one for the chest, and one for the pelvic region were generated. Plans were optimized for 95% planning target volume coverage by the prescription dose. Acute toxicities and late toxicities were scored using the European Cooperative Oncology Group common toxicity criteria. Results: There were a total of 22 patients analyzed in the 2 phase 1 studies. Fourteen patients had leukemia (64% acute myeloid leukemia) and 8 patients had relapsed multiple myeloma. The median follow up was 19.4 months (range 2-74 months). Grade 3 and grade 4 acute toxicities were as follows: bowel (G3 9%, G4 5%), liver (G3: 14%), kidney (G3 9%), and oral cavity (G3: 9%, G4 14%). Late toxicities were as follows: lung (G2: 5%, G3: 14%), liver (G2 5%, G3: 18%), kidney (G2: 9%, G3: 9%), and oral cavity (G2: 5%, G3: 9%). The median dose to the liver across all subjects was 4.2 Gy (Range: 1.6-7.9), and the median dose to the liver was 5.7 Gy (Range 3.8-5.8) in patients who experienced late grade 3 liver toxicity. All late grade 3 liver toxicities occurred in patients who received fludarabine and busulfan. Conclusion: Overall treatment with IM-TMI had acceptable levels of toxicity. This dose analysis suggests that median doses to the liver of less than 5.7 Gy may be associated with a lower rate of toxicity in patients who receive IM-TMI with fludarabine and busulfan.