Combination of Linear Accelerator–Based Intensity-Modulated Total Marrow Irradiation and Myeloablative Fludarabine/Busulfan: A Phase I Study

Abstract

Here we examined the addition of intensity-modulated total marrow irradiation (TMI) delivered using a linear accelerator to a myeloablative chemotherapy conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT). In this phase I study, we enrolled 14 patients with high-risk hematologic malignancies who received escalating doses of TMI at 3 Gy (n = 3), 6 Gy (n = 3), 9 Gy (n = 6), and 12 Gy (n = 2) in combination with intravenous (i.v.) fludarabine 160 mg/m(2) and targeted busulfan (area under the curve, 4800 μM*minute). Peripheral blood mobilized stem cells were obtained from HLA-matched related (n = 9) or unrelated (n = 4) or 1 antigen-mismatched unrelated (n = 1) donors. All patients rapidly engrafted and recovered their immune cells. Overall, Bearman extrahematologic toxicity were limited to grades 1 or 2, with oral mucositis grade 1 in 64% and grade 2 in 36% of the patients. With a median follow-up of 1126 days (range, 362 to 1469) for living patients, the overall survival was 50% and relapse-free survival was 43%. Of 7 deaths, 3 were due to relapse and 4 to transplantation-related complications. We conclude that 9 Gy TMI can be combined with myeloablative chemotherapy in the design of new preparative regimens for HSCT. This study was registered at clinicaltrials.gov as NCT00988013.

Dose Escalation of Total Marrow Irradiation in High-Risk Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

“…Recently, other investigators have also explored the use of TMI in preparative regimens 29–31 . The timing of dose-escalated irradiation relative to chemotherapy seems to be an important consideration as in some studies, dose escalation was feasible and well tolerated, while in others dose-limiting toxicities were striking.…”

“…While the chemotherapeutic agents were different, the first trial was well tolerated, with dose escalation up to 15Gy, while the second resulted in significant, grade 4 dose limiting toxicities. Similarly, Patel et al used a linac-based TMI method where irradiation and fludarabine were given simultaneously, followed by Busulfan 31 . These investigators found dose limiting toxicities at 12 Gy and concluded that 9 Gy was the MTD.…”

Organ sparing of linac‐based targeted marrow irradiation over total body irradiation

“…Although multiple groups have reported posttransplant relapse as a major detriment to survival in a patient with hematologic malignancies, escalation of the conditioning regimen, either through more intense chemotherapy or an increased TBI dose, has typically increased serious or fatal treatment‐related complications . Targeted marrow irradiation as a component in the conditioning regimen is therefore attractive as a means of escalating dose to hematologic tissues while limiting dose to critical structures to an acceptable level, hopefully improving survival .…”

Development of total body irradiation method. From history to the present

“…В данной работе авторы демонстрируют техническую возможность применения Томотерапии для ТОТ и отмечают, что клиническая валидация этого подхода будет представлять несомненный интерес. Недавние исследования убедительно продемонстрировали, что ТОКМ и ТОТ, выполненные на современных классических линейных ускорителях с использованием VMAT, могут обеспечить адекватное покрытие мишени и снижение дозы в органах риска по сравнению со стандартными методиками ТОТ [42][43][44][45][46][47][48][49].…”