Proton-Based Total Marrow Irradiation for Allogeneic Transplantation in High-Risk AML/MDS (UHKT-PTC-TMI-1)

Proton Total Marrow Irradiation-Based Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

This is an open-label, single-center, non-randomized phase I/II pilot study evaluating proton-based Total Marrow Irradiation (TMI) as part of the conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adult patients with high-risk or relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). These patients have an unfavorable prognosis with standard conditioning approaches.

Participants will receive a standard conditioning regimen consisting of either myeloablative or reduced-intensity chemotherapy, selected according to age and comorbidities, combined with proton TMI delivered at a total dose of 12 Gy in three fractions. Graft-versus-host disease (GvHD) prophylaxis will be administered according to institutional standards, preferentially using post-transplant cyclophosphamide. Patients will subsequently undergo standard allo-HSCT and will be followed for at least 24 months after transplantation.

The primary objective of the study is to assess the safety and tolerability of proton TMI added to standard conditioning, as measured by non-relapse mortality and treatment-related toxicity within the first 100 days after transplantation. Secondary objectives include evaluation of engraftment kinetics, incidence of relapse, overall and relapse-free survival, GvHD outcomes, and quality of life. Study outcomes will be analyzed descriptively and compared with a matched historical cohort.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia (AML); Proton Therapy; MDS and AML Prior to Allogeneic SCT; Myelodysplastic Neoplasm; Myelodysplastic Syndrome (MDS)/AML
• Intervention / Treatment: Radiation: Proton Total Marrow Irradiation

Detailed Description

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a potentially curative treatment for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, outcomes in patients with high-risk, relapsed, or refractory disease remain poor, largely due to a high incidence of post-transplant relapse and treatment-related toxicity. Attempts to intensify standard conditioning regimens, including escalation of total body irradiation (TBI) doses, have been associated with increased non-relapse mortality (NRM), limiting their clinical applicability.

Total Marrow Irradiation (TMI) is an advanced form of targeted radiotherapy that selectively irradiates the bone marrow while reducing radiation exposure to surrounding organs at risk. Using intensity-modulated planning techniques, TMI enables improved dose conformity compared with conventional TBI. Proton-based TMI may further enhance organ sparing due to the favorable physical dose distribution of protons, potentially reducing both acute and late toxicities while maintaining or increasing antileukemic efficacy.

This study is an open-label, single-center, non-randomized phase I/II pilot trial designed to evaluate proton-based TMI as part of the conditioning regimen prior to allo-HSCT in adult patients with high-risk AML or MDS. Eligible patients include those with relapsed or refractory AML, high-risk AML in complete remission as defined by adverse genetic or molecular features or measurable residual disease, and patients with high-risk or very high-risk MDS according to IPSS-M criteria. All patients must be considered eligible for allo-HSCT based on institutional standards.

Participants will receive one of two conditioning regimens selected according to age, performance status, and comorbidities: a myeloablative regimen consisting of fludarabine, busulfan, and post-transplant cyclophosphamide, or a reduced-intensity regimen consisting of fludarabine, melphalan, and post-transplant cyclophosphamide. In both regimens, proton TMI will be administered at a total dose of 12 Gy (cobalt gray equivalent) delivered in three daily fractions of 4 Gy prior to transplantation. In selected cases with extramedullary disease or central nervous system involvement, additional site-specific irradiation may be incorporated according to protocol-defined rules.

All patients will undergo standard allo-HSCT on day 0 following completion of conditioning. Graft-versus-host disease (GvHD) prophylaxis will be administered according to institutional practice, preferentially using post-transplant cyclophosphamide, with anti-thymocyte globulin permitted in patients at increased risk of cardiotoxicity. Supportive care, infection prophylaxis, and management of transplant-related complications will follow established institutional guidelines.

Patients will be monitored closely during hospitalization and subsequently followed in the outpatient setting. Safety assessments will include systematic recording of adverse events and serious adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Non-relapse mortality will be assessed with relapse treated as a competing risk. Acute and chronic GvHD will be evaluated using established international criteria. Follow-up visits are scheduled through day 100 and at months 6, 12, and 24 after transplantation, with assessments of engraftment, organ function, disease status, survival, and quality of life.

The primary objective of the study is to assess the safety and tolerability of proton-based TMI added to standard conditioning, as measured by non-relapse mortality and treatment-related toxicity within the first 100 days after transplantation. Secondary objectives include evaluation of engraftment kinetics and graft failure, cumulative incidence of relapse, overall survival, relapse-free survival, GvHD-free/relapse-free survival, incidence of acute and chronic GvHD, and patient-reported quality of life.

Given the pilot nature of the study and the limited sample size, outcomes will be analyzed descriptively. Where appropriate, results will be compared with a matched historical cohort of patients treated at the same institution using propensity score matching and Bayesian power prior methodology. The findings of this study are intended to inform the feasibility, safety, and future development of proton-based TMI as a conditioning strategy for high-risk AML and MDS.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Veronika Valkova, Assoc. Prof., MD, PhD; Phone Number: +420 221 977 301; Email: Veronika.Valkova@uhkt.cz
• Study Contact Backup: Name: Jan Vydra, MD, PhD.; Phone Number: +420 221 977 290; Email: Jan.Vydra@uhkt.cz

Study Locations

• Czechia
  • Prague, Czechia, 12800
    • Recruiting
    • Institute of Hematology and Blood Transfusion
    • Contact: Jan Vydra, MD, PhD; Phone Number: +420 221 977 290; Email: Jan.Vydra@uhkt.cz
    • Contact: Veronika Valkova, Assoc.Prof., MD, PhD; Phone Number: +420 221 977 301; Email: Veronika.Valkova@uhkt.cz
    • Principal Investigator: Veronika Valkova, Assoc.Prof., MD, PhD.
  • Prague, Czechia, 18000
    • Recruiting
    • Proton Therapy Center Czech
    • Contact: Katerina Dedeckova, MD, PhD; Email: Katerina.Dedeckova@ptc.cz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Underlying diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS),

   A) Acute Myeloid Leukemia (AML), meeting at least one of the following criteria:

   i. Relapsed disease after a prior complete remission (CR) or

   ii. Disease refractory to at least two cycles of intensive chemotherapy or

   iii. High-risk AML in complete remission (CR), defined by at least one of the following:

   iii a) Adverse molecular or cytogenetic risk according to ELN 2022 classification or

   iii b) Presence of measurable/minimal residual disease (MRD).

   B) Myelodysplastic Syndrome (MDS), meeting at least one of the following criteria:

   i. Relapsed MDS with increased blasts (MDS-IB) or

   ii. MDS-IB2 without reduction of bone marrow blasts below 10% after induction chemotherapy or after at least two cycles of azacitidine or

   iii. IPSS-M score > 0.5 (high-risk or very high-risk disease).

2. Eligibility confirmed by the institutionalal Transplant Indication Committee according to standard criteria.
3. Age ≥ 18 years and ≤ 65 years
4. Ability to understand and voluntarily sign written informed consent

Exclusion Criteria:

Severe comorbidity, defined as the presence of one or more of the following conditions:

1. Left ventricular ejection fraction (LVEF) < 40%
2. Creatinine clearance < 0.5 mL/s
3. Total bilirubin > 40 µmol/L (unless attributable to Gilbert's syndrome or hemolysis) and alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 × upper limit of normal (ULN)
4. Pulmonary function impairment defined as forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) < 50% of predicted value, or diffusing capacity of the lung for carbon monoxide (DLCO) < 50% of predicted value after correction for anemia
5. Karnofsky Performance Status < 70%
6. Active viral hepatitis or human immunodeficiency virus (HIV) infection
7. Presence of liver cirrhosis
8. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Proton TMI Conditioning Regimen; Participants receive proton total marrow irradiation (TMI) added to a standard chemotherapy-based conditioning regimen prior to allogeneic hematopoietic stem cell transplantation.

Radiation: Proton Total Marrow Irradiation; Proton total marrow irradiation (TMI) is administered as part of the conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. TMI is delivered to a total dose of 12 cobalt gray equivalents (CGE) in 3 fractions of 4 CGE once daily. In patients with extramedullary disease or central nervous system involvement, additional site-specific irradiation may be administered prior to TMI (10 CGE in 5 fractions), with a simultaneous integrated boost to involved sites during TMI (3 fractions of 3.5 CGE). TMI is combined with standard chemotherapy-based conditioning regimens, including a myeloablative regimen (fludarabine, busulfan, post-transplant cyclophosphamide) or a reduced-intensity regimen (fludarabine, melphalan, post-transplant cyclophosphamide), according to institutional standards.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events (AEs) and serious adverse events (SAEs)	Incidence of treatment-related adverse events and serious adverse events occurring after conditioning including proton total marrow irradiation (TMI) added to standard conditioning prior to allogeneic hematopoietic stem cell transplantation; Incidence of Grade ≥3 adverse events according to CTCAE v5.0. Unit of Measure: Number of participants with at least one adverse event	Up to 100 days post-transplantation
Non-relapse mortality (NRM)	Proportion of participants who die without prior disease relapse following allogeneic hematopoietic stem cell transplantation after conditioning including proton total marrow irradiation (TMI). Unit of Measure: Percentage of participants	Up to 100 days post-transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of neutrophil engraftment	Cumulative incidence of neutrophil engraftment following allogeneic hematopoietic stem cell transplantation, defined as the first of three consecutive days with an absolute neutrophil count ≥500/µL. Unit of Measure: Percentage of participants	Up to 100 days post-transplantation
Cumulative incidence of platelet engraftment	Cumulative incidence of platelet engraftment following transplantation, defined as the first of seven consecutive days with platelet count ≥20,000/µL without platelet transfusion support. Unit of Measure: Percentage of participants	Up to 100 days post-transplantation
Transfusion independence	Proportion of participants who achieve independence from red blood cell and platelet transfusions following transplantation. Definition: No transfusion requirement for at least 7 consecutive days. Unit of Measure: Percentage of participants	Up to 100 days post-transplantation
Incidence of primary graft failure	Incidence of primary graft failure following allogeneic hematopoietic stem cell transplantation. Unit of Measure: Percentage of participants	Up to 100 days post-transplantation
Cumulative incidence of relapse at 12 months	Cumulative incidence of disease relapse following allogeneic hematopoietic stem cell transplantation. Unit of Measure: Percentage of participants	12 months post-transplantation
Cumulative incidence of relapse at 24 months	Cumulative incidence of disease relapse following allogeneic hematopoietic stem cell transplantation. Unit of Measure: Percentage of participants	24 months post-transplantation
Relapse-Free Survival (RFS) at 12 months	Relapse-free survival defined as time from transplantation to either disease relapse or death from any cause, whichever occurs first. Unit of Measure: Percentage of participants alive without relapse	12 months post-transplantation
Relapse-Free Survival (RFS) at 24 months	Relapse-free survival defined as time from transplantation to either disease relapse or death from any cause, whichever occurs first. Unit of Measure: Percentage of participants alive without relapse	24 months post-transplantation
Overall Survival (OS) at 12 months	Overall survival defined as time from transplantation to death from any cause. Unit of Measure: Percentage of participants	12 months post-transplantation
Overall Survival (OS) at 24 months	Overall survival defined as time from transplantation to death from any cause. Unit of Measure: Percentage of participants	24 months post-transplantation
GVHD-Free, Relapse-Free Survival (GRFS) at 12 months	GVHD-free, relapse-free survival defined as survival without grade III-IV acute GVHD, chronic GVHD requiring systemic therapy, disease relapse, or death. Unit of Measure: Percentage of participants	12 months post-transplantation
GVHD-Free, Relapse-Free Survival (GRFS) at 24 months	GVHD-free, relapse-free survival defined as survival without grade III-IV acute GVHD, chronic GVHD requiring systemic therapy, disease relapse, or death. Unit of Measure: Percentage of participants	24 months post transplantation
Cumulative incidence of severe acute graft-versus-host disease (GvHD) (Grade III-IV)	Cumulative incidence of grade III-IV acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation, defined as the proportion of participants who develop acute GVHD during the observation period. Unit of Measure: Percentage of participants	Up to 100 days post-transplantation
Cumulative incidence of chronic graft-versus-host disease	Cumulative incidence of chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Unit of Measure: Percentage of participants	Up to 24 months post-transplantation
Functional Assessment of Cancer Therapy - General (FACT-G)	Description: Assessment of patient-reported quality of life using the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire. Total score ranges from 0 to 108, with higher scores indicating better quality of life. Unit of Measure: Score	Baseline and up to 24 months post-transplantation
Karnofsky Performance Status (KPS)	Assessment of functional status using the Karnofsky Performance Status (KPS) scale. Scores range from 0 to 100 in 10-point increments, with higher scores indicating better functional status. Unit of Measure: Score	Baseline and up to 24 months post-transplantation

Collaborators and Investigators

• Sponsor: Institute of Hematology and Blood Transfusion, Czech Republic
• Collaborators: Proton Therapy Center Czech s.r.o.

Publications and helpful links

General Publications

• Taccone A, Oddone M, Dell'Acqua AD, Occhi M, Ciccone MA. MRI "road-map" of normal age-related bone marrow. II. Thorax, pelvis and extremities. Pediatr Radiol. 1995;25(8):596-606. doi: 10.1007/BF02011826.
• Stein A, Palmer J, Tsai NC, Al Malki MM, Aldoss I, Ali H, Aribi A, Farol L, Karanes C, Khaled S, Liu A, O'Donnell M, Parker P, Pawlowska A, Pullarkat V, Radany E, Rosenthal J, Sahebi F, Salhotra A, Sanchez JF, Schultheiss T, Spielberger R, Thomas SH, Snyder D, Nakamura R, Marcucci G, Forman SJ, Wong J. Phase I Trial of Total Marrow and Lymphoid Irradiation Transplantation Conditioning in Patients with Relapsed/Refractory Acute Leukemia. Biol Blood Marrow Transplant. 2017 Apr;23(4):618-624. doi: 10.1016/j.bbmt.2017.01.067. Epub 2017 Jan 10.
• The EBMT Handbook Textbook Open Access 2024
• FILIPOVICH AH, WEISDORF D, PAVLETIC S et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005: 11: 945.
• Harris AC, Young R, Devine S, et al. International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016 Jan;22(1):4-10. doi: 10.1016/j.bbmt.2015.09.001. Epub 2015 Sep 16.
• Corvò R, Zeverino M, Vagge S et al. Helical tomotherapy targeting total bone marrow after total body irradiation for patients with relapsed acute leukemia undergoing an allogeneic stem cell transplant. Radiother Oncol. 2011 Mar;98(3):382-6. doi: 10.1016/j.radonc.2011.01.016.
• Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010 Aug 10;28(23):3730-8. doi: 10.1200/JCO.2010.28.8852.
• Dominietto A, Vagge S, di Grazia C, Bregante S, Raiola AM, Varaldo R, Gualandi F, Gusinu M, Barra S, Agostinelli S, Angelucci E, Hui S. Total Marrow Irradiation for Second Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Advanced Acute Leukemia. Transplant Cell Ther. 2023 Aug;29(8):506.e1-506.e6. doi: 10.1016/j.jtct.2023.04.014. Epub 2023 Apr 23.
• Hui S, Brunstein C, Takahashi Y, DeFor T, Holtan SG, Bachanova V, Wilke C, Zuro D, Ustun C, Weisdorf D, Dusenbery K, Verneris MR. Dose Escalation of Total Marrow Irradiation in High-Risk Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2017 Jul;23(7):1110-1116. doi: 10.1016/j.bbmt.2017.04.002. Epub 2017 Apr 7.
• 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.
• Brown RA, Wolff SN, Fay JW, Pineiro L, Collins RH Jr, Lynch JP, Stevens D, Greer J, Herzig RH, Herzig GP. High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group. Blood. 1995 Mar 1;85(5):1391-5.
• Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, Anasetti C, Beatty P, Bensinger WI, Doney K, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990 Nov 1;76(9):1867-71.
• Michallet M, Thomas X, Vernant JP, Kuentz M, Socie G, Esperou-Bourdeau H, Milpied N, Blaise D, Rio B, Reiffers J, Jouet JP, Cahn JY, Bourhis JH, Lioure B, Leporrier M, Sotto JJ, Souillet G, Sutton L, Bordigoni P, Dreyfus F, Tilly H, Gratecos N, Attal M, Leprise PY, Demeocq F, Michel G, Buzyn A, Delmas-Marsalet B, Bernaudin F, Ifrah N, Sadoun A, Guyotat D, Cavazzana-Cavo M, Caillot D, De Revel T, Vannier JP, Baruchel A, Fegueux N, Tanguy ML, Thiebaut A, Belhabri A, Archimbaud E. Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: a retrospective study of 379 patients reported to the Societe Francaise de Greffe de Moelle (SFGM). Bone Marrow Transplant. 2000 Dec;26(11):1157-63. doi: 10.1038/sj.bmt.1702690.
• Sharma DS, Manikandan A, Singh G, Gayen S, Sundar S, G A, S R, Suhail M, S R, Krishnan G, Raj R, Chilukuri S, Easow J, Jalali R. Improving total bone marrow and lymphoid irradiation: feasibility of intensity-modulated proton therapy (IMPT) and dosimetric comparison with helical tomotherapy (HT). Radiat Oncol. 2025 May 21;20(1):84. doi: 10.1186/s13014-024-02572-w.
• Zuro DM, Vidal G, Cantrell JN, Chen Y, Han C, Henson C, Ahmad S, Hui S, Ali I. Treatment planning of total marrow irradiation with intensity-modulated spot-scanning proton therapy. Front Oncol. 2022 Jul 28;12:955004. doi: 10.3389/fonc.2022.955004. eCollection 2022.
• Wong JYC, Liu A, Han C, Dandapani S, Schultheiss T, Palmer J, Yang D, Somlo G, Salhotra A, Hui S, Al Malki MM, Rosenthal J, Stein A. Total marrow irradiation (TMI): Addressing an unmet need in hematopoietic cell transplantation - a single institution experience review. Front Oncol. 2022 Oct 3;12:1003908. doi: 10.3389/fonc.2022.1003908. eCollection 2022.
• Dogliotti I, Levis M, Martin A, Bartoncini S, Felicetti F, Cavallin C, Maffini E, Cerrano M, Bruno B, Ricardi U, Giaccone L. Maintain Efficacy and Spare Toxicity: Traditional and New Radiation-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation. Cancers (Basel). 2024 Feb 21;16(5):865. doi: 10.3390/cancers16050865.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2025
• Primary Completion (Estimated): November 1, 2029
• Study Completion (Estimated): November 1, 2029

Study Registration Dates

• First Submitted: February 12, 2026
• First Submitted That Met QC Criteria: April 9, 2026
• First Posted (Actual): April 16, 2026

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: HSCT; Proton Therapy; Conditioning Regimen; Total Marrow Irradiation; Targeted Radiotherapy; High-Risk Hematologic Malignancy; TMI
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Anemia; Leukemia; Anemia, Refractory; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Anemia, Refractory, with Excess of Blasts
• Other Study ID Numbers: UHKT-PTC-TMI-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared. Aggregated and anonymized data may be presented in scientific publications and presentations.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No