Total marrow irradiation (TMI): Addressing an unmet need in hematopoietic cell transplantation - a single institution experience review

Abstract

PurposeTMI utilizes IMRT to deliver organ sparing targeted radiotherapy in patients undergoing hematopoietic cell transplantation (HCT). TMI addresses an unmet need, specifically patients with refractory or relapsed (R/R) hematologic malignancies who have poor outcomes with standard HCT regimens and where attempts to improve outcomes by adding or dose escalating TBI are not possible due to increased toxicities. Over 500 patients have received TMI at this center. This review summarizes this experience including planning and delivery, clinical results, and future directions.MethodsPatients were treated on prospective allogeneic HCT trials using helical tomographic or VMAT IMRT delivery. Target structures included the bone/marrow only (TMI), or the addition of lymph nodes, and spleen (total marrow and lymphoid irradiation, TMLI). Total dose ranged from 12 to 20 Gy at 1.5-2.0 Gy fractions twice daily.ResultsTrials demonstrate engraftment in all patients and a low incidence of radiation related toxicities and extramedullary relapses. In R/R acute leukemia TMLI 20 Gy, etoposide, and cyclophosphamide (Cy) results in a 1-year non-relapse mortality (NRM) rate of 6% and 2-year overall survival (OS) of 48%; TMLI 12 Gy added to fludarabine (flu) and melphalan (mel) in older patients (≥ 60 years old) results in a NRM rate of 33% comparable to flu/mel alone, and 5-year OS of 42%; and TMLI 20 Gy/flu/Cy and post-transplant Cy (PTCy) in haplo-identical HCT results in a 2-year NRM rate of 13% and 1-year OS of 83%. In AML in complete remission, TMLI 20 Gy and PTCy results in 2-year NRM, OS, and GVHD free/relapse-free survival (GRFS) rates of 0%, 86·7%, and 59.3%, respectively.ConclusionTMI/TMLI shows significant promise, low NRM rates, the ability to offer myeloablative radiation containing regimens to older patients, the ability to dose escalate, and response and survival rates that compare favorably to published results. Collaboration between radiation oncology and hematology is key to successful implementation. TMI/TMLI represents a paradigm shift from TBI towards novel strategies to integrate a safer and more effective target-specific radiation therapy into HCT conditioning beyond what is possible with TBI and will help expand and redefine the role of radiotherapy in HCT.

Maintain Efficacy and Spare Toxicity: Traditional and New Radiation-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation

“…The clinical target volume (CTV) for TMI is skeletal bone, with the addition of the major lymph node chains of the spleen and liver (and, eventually, “sanctuary sites” like testes and brain) for TMLI. Colleagues from City of Hope, who first developed the TMI technique [ 51 ], suggest omitting the mandible in the CTV to reduce the likelihood of severe oral mucositis [ 93 ]. The expansion margins from the CTV to the planning target volume (PTV) vary across institutions (between 5 and 10 mm) [ 94 , 95 , 96 , 97 ].…”

Total marrow irradiation in hematopoietic stem cell transplantation for hematologic malignancies

“…Depending on the institution's protocol, the liver, brain, and testes may also be included. There are several protocols with different radiation dose prescriptions, ranging from 6 to 20 Gy ( 5 , 6 ). The irradiation protocol starts with the simulation, outline of targets and organs at risk (OAR), planning (dose calculation) and, finally, the delivery of the treatment.…”

“…Patients usually stay in the supine position, with immobilization devices such as vacuum bags and/or thermoplastic masks. In addition, 4D CT scans of the chest and abdomen may be utilized to account for any organ movement during respiration ( 5 ).…”

“…The lower extremities are planned and treated with junctioned AP-PA fields ( 7 , 8 ). Volumetric imaging (image-guided radiation therapy – IGRT) is used for daily patient setup ( 5 ).…”

“…Total marrow irradiation was usually used in autologous HCT for multiple myeloma and TMLI in allogeneic HCT ( 5 ). Data from different studies show that TMI and TMLI can be safely delivered at an escalated dose in association with different chemotherapy conditioning regimen protocols.…”