Dataset Information

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

ABSTRACT:

Purpose

TMI 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.

Methods

Patients 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.

Results

Trials 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.

Conclusion

TMI/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.

SUBMITTER: Wong JYC

PROVIDER: S-EPMC9574324 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

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

Wong Jeffrey Y C JYC Liu An A Han Chunhui C Dandapani Savita S Schultheiss Timothy T Palmer Joycelynne J Yang Dongyun D Somlo George G Salhotra Amandeep A Hui Susanta S Al Malki Monzr M MM Rosenthal Joseph J Stein Anthony A

Frontiers in oncology 20221003

<h4>Purpose</h4>TMI 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 t ...[more]

PMID: 36263219

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Project description:We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens.Trial 1 consisted of TMI on Days -10 to -6, etoposide (VP16) on Day -5 (60 mg/kg), and cyclophosphamide (CY) on Day -3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days -12 to -8 (800 ?M min), TMI on Days -8 to -4, and VP16 on Day -3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily.Trial 1 had 12 patients with a median age of 33 years. Six patients had induction failures (IF), and 6 had first relapses (1RL), 9 with leukemia blast involvement of bone marrow ranging from 10%-98%, 5 with circulating blasts (24%-85%), and 2 with chloromas. No dose-limiting toxicities were observed. Eleven patients achieved complete remission at Day 30. With a median follow-up of 14.75 months, 5 patients remained in complete remission from 13.5-37.7 months. Trial 2 had 20 patients with a median age of 41 years. Thirteen patients had IF, and 5 had 1RL, 2 in second relapse, 19 with marrow blasts (3%-100%) and 13 with peripheral blasts (6%-63%). Grade 4 dose-limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials.TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to dose-limiting toxicities. Future efforts will focus on whether further dose escalation with CY/VP16 is safe, with the goal of improving disease control in this high-risk population.

Project description:PurposeTotal marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models.Methods and materialsA Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry.ResultsMultimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI.ConclusionsA novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.

Project description:Allogeneic hematopoietic cell transplantation (alloHCT) is a resource-intensive procedure and the sole potentially curative treatment available for patients with acute myelogenous leukemia (AML). Although Medicare coverage may help address a major financial barrier to accessing alloHCT, there remains an unmet need for alloHCT owing to sociodemographic disparities. This study examined trends and factors associated with the utilization of alloHCT and the estimated unmet need for alloHCT among Medicare beneficiaries with AML. This retrospective cohort study included patients (age 65 to 74 years) with a diagnosis of AML identified in Medicare claims data from 2010 through 2016. To study trends in utilization, transplantation rates were calculated as the number of patients who underwent alloHCT within 180 days and 1 year of diagnosis (numerator) divided by the total number of patients with AML within each diagnosis year (denominator). A multivariable logistic regression was used to identify factors associated with the likelihood of undergoing alloHCT within 1 year of diagnosis. Two approaches were applied to estimate the unmet need for alloHCT. The first approach used claims data to identify the potential need for alloHCT among patients who achieved complete remission for at least 90 days. The second approach used established National Marrow Donor Program (NMDP) methodology, which considers estimates of risk level, response to treatment, comorbidity, and early mortality, to identify the potential and unmet need for alloHCT. The overall estimated need and unmet need from 2010 to 2015 and over different time periods were evaluated for both approaches. The alloHCT rate within 180 days of diagnosis increased from 8% in 2010 to 15.8% in 2016 (P < .001), and the 1-year alloHCT rate also increased over time, from 11.9% in 2010 to 20.0% in 2015 (P < .001). The likelihood of undergoing alloHCT within 1 year of diagnosis was associated with diagnosis year, age, race, geographic region, Elixhauser Comorbidity Index, and population-level median household income. Between 2010 and 2015, the claims data approach estimated a lower potential need for alloHCT compared with the NMDP methodology estimate (27% versus 36%); both approaches estimated that 43% to 44% of patients with a potential need for alloHCT had an unmet treatment need. Despite the differences in estimated potential need between the 2 approaches, both showed a sustained unmet need but with a downward trend over time. Our data show that utilization of alloHCT has increased over time among Medicare beneficiaries with AML. Two approaches of need analysis were conducted for validation of estimated need and unmet need for alloHCT using claim-identified remission status, given the lack of cytogenetics and molecular information in claims data. Both approaches to estimating the unmet need for alloHCT found a downward trend over time; however, there are differences in utilization of alloHCT by age, race, geographic region, comorbidity, and socioeconomic status, indicating disparities in access to alloHCT among Medicare beneficiaries with AML. This suggests the need for policy efforts, research, and continued education to improve access to alloHCT and to close the gap between the actual utilization of alloHCT and the unmet need.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

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