Phase II Study of Dose Escalated Total Marrow and Lymphoid Irradiation (TMLI) in Combination with Cyclophosphamide and Etoposide in Patients with Poor-Risk Acute Leukemia

Wong, Jeffrey Y.C.; Tsai, Nicole; Han, Chunhui; Palmer, Joycelynne; Liu, A.; Malki, Monzr Al; Dandapani, Savita; Radany, Eric H.; Salhotra, Amandeep; Nakamura, Ryotaro; Song, Hui; Rosenthal, Joseph; Forman, Stephen J.; Stein, Anthony S.

doi:10.1016/j.ijrobp.2020.07.912

Cited by 4 publications

(3 citation statements)

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“…A subsequent phase II trial evaluating the same regimen is currently ongoing at this center (NCT 02094794). A recent analysis of the first 57 patients with AML (n=43) and ALL (n=14) treated with TMLI doses of 20 Gy reported a 1-year NRM rate of 6% and 2-year OS and PFS of 48% and 33%, respectively, which compare favorably to published results ( 12 , 33 ). All patients engrafted.…”

Section: Review Of Clinical Resultssupporting

confidence: 74%

“…Most patients treated on TMLI trials at this center are patients with R/R acute leukemia who have no standard-of-care HCT options. The results in this population are very encouraging when compared to historical results and demonstrate that: 1) TMLI results in lower incidences of toxicities compared to TBI ( 61 ); 2) all patients have successfully engrafted; 3) extramedullary relapses are infrequent and comparable to other conditioning regimens ( 75 ); 4) TMLI doses to 20 Gy, with etoposide and cyclophosphamide in younger patients (< 60 years old) is safe with a 1-year NRM rate of 6% and 2-year OS and PFS of 48% and 33%, respectively ( 12 , 33 ); and 5) in older patients (≥ 60 years old), adding 12 Gy TMLI to fludarabine and melphalan is feasible with an NRM rate similar to fludarabine-melphalan alone, and with encouraging 5-year OS and EFS of 42% and 41%, respectively ( 15 ). The results of these studies warrant larger scale multi-center trials to confirm that these single center results can be reproduced.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

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

Wong

Liu²,

Han³

et al. 2022

Front. Oncol.

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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.

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Section: Review Of Clinical Resultssupporting

confidence: 74%

Section: Discussion and Future Directionsmentioning

confidence: 99%

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

Wong

Liu²,

Han³

et al. 2022

Front. Oncol.

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show abstract

“…Initial clinical trials have demonstrated that the TMI-inclusive transplant regimens are safe and feasible ( 22 – 24 , 45 ). Several Phase 2 studies are ongoing to establish the outcome benefit of adding TMI to the current standard of care ( 46 – 48 ). Furthermore, there is an increased interest in dose escalation studies based on the reports that a TBI dose of 15.6 Gy (30% more than the standard dose of 12 Gy) halved the relapse rate ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

Impact of respiratory motion on lung dose during total marrow irradiation

Kavak

Sürücü²,

Ahn³

et al. 2022

Front. Oncol.

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We evaluated the impact of respiratory motion on the lung dose during linac-based intensity-modulated total marrow irradiation (IMTMI) using two different approaches: (1) measurement of doses within the lungs of an anthropomorphic phantom using thermoluminescent detectors (TLDs) and (2) treatment delivery measurements using ArcCHECK where gamma passing rates (GPRs) and the mean lung doses were calculated and compared with and without motion. In the first approach, respiratory motions were simulated using a programmable motion platform by using typical published peak-to-peak motion amplitudes of 5, 8, and 12 mm in the craniocaudal (CC) direction, denoted here as M1, M2, and M3, respectively, with 2 mm in both anteroposterior (AP) and lateral (LAT) directions. TLDs were placed in five selected locations in the lungs of a RANDO phantom. Average TLD measurements obtained with motion were normalized to those obtained with static phantom delivery. The mean dose ratios were 1.01 (0.98–1.03), 1.04 (1.01–1.09), and 1.08 (1.04–1.12) for respiratory motions M1, M2, and M3, respectively. To determine the impact of directional respiratory motion, we repeated the experiment with 5-, 8-, and 12-mm motion in the CC direction only. The differences in average TLD doses were less than 1% when compared with the M1, M2, and M3 motions indicating a minimal impact from CC motion on lung dose during IMTMI. In the second experimental approach, we evaluated extreme respiratory motion 15 mm excursion in only the CC direction. We placed an ArcCHECK device on a commercial motion platform and delivered the clinical IMTMI plans of five patients. We compared, with and without motion, the dose volume histograms (DVHs) and mean lung dose calculated with the ArcCHECK-3DVH tool as well as GPR with 3%, 5%, and 10% dose agreements and a 3-mm constant distance to agreement (DTA). GPR differed by 11.1 ± 2.1%, 3.8 ± 1.5%, and 0.1 ± 0.2% with dose agreement criteria of 3%, 5%, and 10%, respectively. This indicates that respiratory motion impacts dose distribution in small and isolated parts of the lungs. More importantly, the impact of respiratory motion on the mean lung dose, a critical indicator for toxicity in IMTMI, was not statistically significant (p > 0.05) based on the Student’s t-test. We conclude that most patients treated with IMTMI will have negligible dose uncertainty due to respiratory motion. This is particularly reassuring as lung toxicity is the main concern for future IMTMI dose escalation studies.

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Total Marrow and Lymphoid Irradiation with Post-Transplantation Cyclophosphamide for Patients with AML in Remission

Stein

Malki

Yang

et al. 2022

Transplantation and Cellular Therapy

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Phase II Study of Dose Escalated Total Marrow and Lymphoid Irradiation (TMLI) in Combination with Cyclophosphamide and Etoposide in Patients with Poor-Risk Acute Leukemia

Cited by 4 publications

References 0 publications

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

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

Impact of respiratory motion on lung dose during total marrow irradiation

Total Marrow and Lymphoid Irradiation with Post-Transplantation Cyclophosphamide for Patients with AML in Remission

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