Total Marrow Irradiation: Redefining the Role of Radiotherapy in Bone Marrow Transplantation

Abstract

Total body irradiation (TBI) is an important part of the conditioning regimen for patients undergoing hematopoietic cell transplantation (HCT), but its use is declining due to a lack of new strategies to reduce TBI toxicities and the introduction of alternative non-TBI approaches. More targeted forms of TBI are needed to address these challenges and to redefine and expand the role of radiotherapy in HCT. Recent image-guided intensity-modulated radiation therapy (IG-IMRT) to large regions of the body now allows for more targeted forms of TBI and is often referred to as total marrow irradiation (TMI) or total marrow and lymphoid irradiation (TMLI) and represents a spectrum of targeted TBI dose distributions. This approach offers the radiation oncologist and transplant team unprecedented control of radiation dose delivery to target regions and organs, which is not possible with any other form of biologically targeted therapy or radiopharmaceutical. The physician can simultaneously reduce dose to critical organs or any other user-defined avoidance structure, while simultaneously increasing dose to particular target regions depending on the tumor burden and clinical situation. TMI is now being performed at multiple centers worldwide and can be delivered using a helical tomographic or volumetric arc-based IMRT approach. Clinical strategies which are being actively evaluated include (1) TMI dose escalation to improve disease control in advanced refractory patients, (2) TMI added to reduced-intensity conditioning (RIC) regimens, (3) TMI added to regimens that utilize post-HCT strategies to reduce GVHD, (4) TMI to improve disease control in standard risk patients as an alternative to current standard of care HCT regimens, and (5) IMRT to deliver TBI to improve dose uniformity and reduce toxicities given its superiority in organ dose reduction compared to conventional TBI. Clinical results have been encouraging and demonstrate feasibility, acceptable toxicities, the ability to offer radiation containing conditioning regimens in older patients or those with comorbidities, the ability to dose escalate safely, and encouraging response and survival rates in advanced disease. Intermediate and long-term toxicities have been shown to be reduced compared to conventional TBI. Initial concerns that the higher dose rate and organ sparing associated with TMI will increase toxicities or relapse rates have not been observed. The use of IMRT to deliver TMI, TMLI, and TBI holds significant promise and will help to redefine and expand the role of radiotherapy in HCT.