Intensity Modulated Total Marrow Irradiation
We pioneered the first linac based intensity modulated total marrow irradiation (IMTMI) and demonstrated outcome benefits through clinical trials.
The utilization of radiation as a part of conditioning regimens prior to bone marrow transplant in hematological malignancies has been steadily decreasing over the years due to its toxicity. Nevertheless, relapse and poor response to chemotherapy are still very despite the advances. Furthermore, prognosis get worse with each successive transplant. For instance, our institutional historical 2-year overall and progression free survival for AML receiving second transplant are currently 23% and 18%, respectively. We pioneered the first linac based intensity modulated total marrow irradiation (IMTMI). Our work focuses on 1) technically to improve it from being a challenging treatment to a clinically feasible technique that can be used routinely in busy clinics to enable clinical trials and 2) clinically to foster collaborations to elicit clinical trials and to recruit more patients. These efforts resulted in 1) the completion of our first two clinical trials in AML and MM, for which, and publish promising results in 2015 and 2018, respectively. These studies provided the clinical evidence base for the feasibility and tolerability of adding IMTMI to the standard of care transplant regimens in advanced diseases. Based on these encouraging results we have opened two follow up Phase II studies, one for AML and one for MM which are currently accruing patients. In addition, we have recently published results of our last Phase I study which sought to prospectively determine the role of TMI in advanced AML patients who are receiving second or higher transplant. This study demonstrated that adding TMI to standard of care has the ability to substantially improve both 2 years OS (50%) and PSF (48%) compared to our historical outcome data of 23% and 18%, respectively. To date, we have treated over 150 patients, which is the largest patient cohort treated with this technique.
Clinical Protocols
BMT-01: A Phase I Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Busulfan Conditioning for Allogeneic Transplantation for Advanced Hematologic Malignancies
BMT-02: A Phase I Trial of Total Marrow Irradiation in Addition to High Dose Melphalan Conditioning Prior to Autologous Transplant for Multiple Myeloma Following Initial Induction Therapy
BMT-03: Phase I Trial of Total Marrow Irradiation in Addition to High Dose Melphalan Conditioning prior to Autologous Transplant for Patients with Relapsed or Refractory Multiple Myeloma
BMT-04: Phase I Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Cyclophosphamide and Post-Transplant Cyclophosphamide Conditioning for Partially HLA Mismatched (Haploidentical) Allogeneic Transplantation in Patients with Acute Leukemia and MDS
BMT-05: A Phase II Study of Intensity Modulated Total Marrow Irradiation (TMI) in Addition to Fludarabine/ Busulfan Conditioning for Allogeneic Transplantation in High-Risk AML and Myelodysplastic Syndromes
BMT-06: Phase II Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Cyclophosphamide/TBI and Post-Transplant Cyclophosphamide Conditioning for Partially HLA Mismatched (Haploidentical) Allogeneic Transplantation in Patients with Acute Leukemia and MDS
BMT-07 A phase I study of intensity modulated total marrow irradiation added to fludarabine/ melphalan conditioning for second or greater allo-SCT for relapsed disease.
Publications
1: Kavak AG, Surucu M, Ahn KH, Pearson E, Aydogan B. Impact of respiratory motion on lung dose during total marrow irradiation. Front Oncol. 2022 Oct 18;12:924961. doi: 10.3389/fonc.2022.924961. PMID: 36330489; PMCID: PMC9622752.
2: Ahn KH, Rondelli D, Koshy M, Partouche JA, Hasan Y, Liu H, Yenice K, Aydogan Knowledge-based planning for multi-isocenter VMAT total marrow irradiation. Front Oncol. 2022 Oct 4;12:942685. doi: 10.3389/fonc.2022.942685. PMID:36267964; PMCID: PMC9577613.
3: Tran MC, Hasan Y, Wang A, Yenice K, Partouche J, Stock W, Larson RA, Kosuri S, LaBelle JL, Kline J, Riedell PA, Artz AS, Weichselbaum R, Bishop MR, Aydogan B, Liu H. A phase 1 trial utilizing TMI with fludarabine-melphalan in patients with hematologic malignancies undergoing second allo-SCT. Blood Adv. 2023 Feb 14;7(3):285-292. doi: 10.1182/bloodadvances.2022007530. PMID: 35851593; PMCID:PMC9898602.
4: Hara JH, Ahn KH, Aydogan B, Koshy M. Local Recurrence Following Total Marrow Radiation: Implications for Clinical Target Delineation. Cureus. 2020 Sep 22;12(9):e10592. doi: 10.7759/cureus.10592. PMID: 33110728; PMCID: PMC7581219.
5: Patel P, Oh AL, Koshy M, Sweiss K, Saraf SL, Quigley JG, Khan I, Mahmud N, Hacker E, Ozer H, Peace DJ, Weichselbaum RR, Aydogan B, Rondelli D. A phase 1 trial of autologous stem cell transplantation conditioned with melphalan 200 mg/m<sup>2</sup> and total marrow irradiation (TMI) in patients with relapsed/refractory multiple myeloma. Leuk Lymphoma. 2018 Jul;59(7):1666-1671. doi: 10.1080/10428194.2017.1390231. Epub 2017 Oct 25. PMID: 29065747.
6: Patel P, Aydogan B, Koshy M, Mahmud D, Oh A, Saraf SL, Quigley JG, Khan I, Sweiss K, Mahmud N, Peace DJ, DeMasi V, Awan AM, Weichselbaum RR, Rondelli D. Combination of linear accelerator-based intensity-modulated total marrow irradiation and myeloablative fludarabine/busulfan: a phase I study. Biol Blood Marrow Transplant. 2014 Dec;20(12):2034-41. doi: 10.1016/j.bbmt.2014.09.005. Epub 2014 Sep 16. PMID: 25234438.
7: Surucu M, Yeginer M, Kavak GO, Fan J, Radosevich JA, Aydogan B. Verification of dose distribution for volumetric modulated arc therapy total marrow irradiation in a humanlike phantom. Med Phys. 2012 Jan;39(1):281-8. doi: 10.1118/1.3668055. PMID: 22225298.
8: Aydogan B, Yeginer M, Kavak GO, Fan J, Radosevich JA, Gwe-Ya K. Total marrow irradiation with RapidArc volumetric arc therapy. Int J Radiat Oncol Biol Phys. 2011 Oct 1;81(2):592-9. doi: 10.1016/j.ijrobp.2010.11.035. Epub 2011 Feb 23. PMID: 21345619.
9: Yeginer M, Roeske JC, Radosevich JA, Aydogan B. Linear accelerator-based intensity-modulated total marrow irradiation technique for treatment of hematologic malignancies: a dosimetric feasibility study. Int J Radiat Oncol Biol Phys. 2011 Mar 15;79(4):1256-65. doi: 10.1016/j.ijrobp.2010.06.029. Epub 2010 Oct 29. PMID: 21035960.
10: Wilkie JR, Tiryaki H, Smith BD, Roeske JC, Radosevich JA, Aydogan B. Feasibility study for linac-based intensity modulated total marrow irradiation. Med Phys. 2008 Dec;35(12):5609-18. doi: 10.1118/1.2990779. PMID: 19175118.
11: Aydogan B, Mundt AJ, Roeske JC. Linac-based intensity modulated total marrow irradiation (IM-TMI). Technol Cancer Res Treat. 2006 Oct;5(5):513-19. doi: 10.1177/153303460600500508. PMID: 16981794.
12: P. Feranjic,T. Wu, E. Pearson, B Aydogan (Senior Author). An innovative planning technique for implementing pseudo-helical VMAT on a conventional LINAC for total marrow irradiation (TMI). (Accepted for publication in PRO)