Acute Myeloid Leukemia (AML)Phase 1/2UHKT-PTC-TMI-1NCT07532824
Proton-Based Total Marrow Irradiation for Allogeneic Transplantation in High-Risk AML/MDS
A Phase 1/2 study testing Proton Total Marrow Irradiation in people with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)/AML, run by Institute of Hematology and Blood Transfusion, Czech Republic at 2 sites in Czechia.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS)/AML, Proton Therapy
- What is being tested?
- Proton Total Marrow Irradiation
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 2 sitesCzechia
- Study dates
- 21 Nov 2025to Nov 2029
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Underlying diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS),
- Acute Myeloid Leukemia (AML), meeting at least one of the following criteria:
- Relapsed disease after a prior complete remission (CR) or
- Disease refractory to at least two cycles of intensive chemotherapy or
- 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
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- iii b) Presence of measurable/minimal residual disease (MRD).
- Myelodysplastic Syndrome (MDS), meeting at least one of the following criteria:
- Relapsed MDS with increased blasts (MDS-IB) or
- MDS-IB2 without reduction of bone marrow blasts below 10% after induction chemotherapy or after at least two cycles of azacitidine or
- IPSS-M score > 0.5 (high-risk or very high-risk disease).
- Eligibility confirmed by the institutionalal Transplant Indication Committee according to standard criteria.
- Age ≥ 18 years and ≤ 65 years
- Ability to understand and voluntarily sign written informed consent
Who cannot join
- Severe comorbidity, defined as the presence of one or more of the following conditions:
- Left ventricular ejection fraction (LVEF) < 40%
- Creatinine clearance < 0.5 mL/s
- 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)
- 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
- Karnofsky Performance Status < 70%
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- Active viral hepatitis or human immunodeficiency virus (HIV) infection
- Presence of liver cirrhosis
- Pregnancy
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Czechia2 sites, 2 recruiting
- Recruiting
Institute of Hematology and Blood Transfusion
Prague, 12800
Jan Vydra, MD, PhD, +420 221 977 290, Jan.Vydra@uhkt.cz
Veronika Valkova, Assoc.Prof., MD, PhD, +420 221 977 301, Veronika.Valkova@uhkt.cz
- Recruiting
Proton Therapy Center Czech
Prague, 18000
Katerina Dedeckova, MD, PhD, Katerina.Dedeckova@ptc.cz
About this study
Official title: 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.
Read the 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.
- Conditions
- Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS)/AML, Proton Therapy, MDS and AML Prior to Allogeneic SCT, Myelodysplastic Neoplasm
- Being tested
- Proton Total Marrow Irradiation
- Keywords
- High-Risk Hematologic Malignancy, Total Marrow Irradiation, TMI, Proton Therapy, Conditioning Regimen, Targeted Radiotherapy, HSCT
- Medical subject headings
- Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Anemia, Refractory, with Excess of Blasts
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Proton Total Marrow IrradiationRadiation
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.
| Study group | Role | What they receive |
|---|---|---|
| Proton TMI Conditioning Regimen | Experimental | Participants receive proton total marrow irradiation (TMI) added to a standard chemotherapy-based conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. Receives: Radiation: Proton Total Marrow Irradiation |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: Up to 100 days post-transplantation
Secondary outcomes (16)
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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Baseline and up to 24 months post-transplantation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Apr 2026
- Study start21 Nov 2025
- Primary completionNov 2029 (estimated)
- Study completionNov 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (17)Papers the sponsor has linked to this study.
- Other trials for Acute Myeloid Leukemia (AML)Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- All participants receive proton total marrow irradiation (TMI) added to standard pre-transplant conditioning prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). This open-label, non-randomized pilot study evaluates safety and tolerability of proton TMI in high-risk acute myeloid leukemia or myelodysplastic syndrome. No control group is used. Participants are followed throughout conditioning, transplantation, and post-transplant period to monitor engraftment, relapse, survival, graft-versus-host disease, and treatment-related adverse events.
- Masking
- None (open label)
- Enrolment
- 16 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institute of Hematology and Blood Transfusion, Czech Republic
- Sponsor type
- University, hospital or other
- Collaborators
- Proton Therapy Center Czech s.r.o.
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07532824
- Sponsor's protocol ID
- UHKT-PTC-TMI-01
- Acronym
- UHKT-PTC-TMI-1
- Status last verified
- Apr 2026
- First submitted
- 12 Feb 2026
- Last updated
- 16 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Individual participant data will not be shared. Aggregated and anonymized data may be presented in scientific publications and presentations.
Publications
The EBMT Handbook Textbook Open Access 2024
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. 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 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.
PubMed 16338616Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, Chanswangphuwana C, Efebera YA, Holler E, Litzow M, Ordemann R, Qayed M, Renteria AS, Reshef R, Wolfl M, Chen YB, Goldstein S, Jagasia M, Locatelli F, Mielke S, Porter D, Schechter T, Shekhovtsova Z, Ferrara JL, Levine JE. 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.
PubMed 26386318Corvo R, Zeverino M, Vagge S, Agostinelli S, Barra S, Taccini G, Van Lint MT, Frassoni F, Bacigalupo A. 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. Epub 2011 Feb 19.
PubMed 21339008Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM, Kamble R, Copelan E, de Lima M, Gupta V, Keating A, Lazarus HM, Litzow MR, Marks DI, Maziarz RT, Rizzieri DA, Schiller G, Schultz KR, Tallman MS, Weisdorf D. 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. Epub 2010 Jul 12.
PubMed 20625136Dominietto 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.
PubMed 37094701Taccone 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.
PubMed 8570312Stein 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.
PubMed 28087456Hui 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.
PubMed 28396164Patel 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.
PubMed 25234438Brown 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.
PubMed 7858269Clift 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.
PubMed 2224134Michallet 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.
PubMed 11149725Sharma 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.
PubMed 40399957Zuro 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.
PubMed 35965505
Study at a glance
From the registry record, last updated by the sponsor on 16 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Proton Total Marrow Irradiation-Based Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome
- ClinicalTrials.gov ID
- NCT07532824
- Acronym / sponsor ID
- UHKT-PTC-TMI-1 / UHKT-PTC-TMI-01
- Conditions
- Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS)/AML, Proton Therapy, MDS and AML Prior to Allogeneic SCT, Myelodysplastic Neoplasm
- Keywords
- High-Risk Hematologic Malignancy, Total Marrow Irradiation, TMI, Proton Therapy, Conditioning Regimen, Targeted Radiotherapy, HSCT
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 16 participants (estimated)
- Lead sponsor
- Institute of Hematology and Blood Transfusion, Czech RepublicUniversity, hospital or other
- Collaborators
- Proton Therapy Center Czech s.r.o.
- Study start
- 21 Nov 2025 (actual)
- Primary completion
- Nov 2029 (estimated)
- Study completion
- Nov 2029 (estimated)
- First posted
- 16 Apr 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- All participants receive proton total marrow irradiation (TMI) added to standard pre-transplant conditioning prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). This open-label, non-randomized pilot study evaluates safety and tolerability of proton TMI in high-risk acute myeloid leukemia or myelodysplastic syndrome. No control group is used. Participants are followed throughout conditioning, transplantation, and post-transplant period to monitor engraftment, relapse, survival, graft-versus-host disease, and treatment-related adverse events.
| Arm | Type | Receives |
|---|---|---|
| Proton TMI Conditioning Regimen | Experimental | Radiation: Proton Total Marrow IrradiationParticipants receive proton total marrow irradiation (TMI) added to a standard chemotherapy-based conditioning regimen prior to allogeneic hematopoietic stem cell transplantation. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Underlying diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS),
- iii a) Adverse molecular or cytogenetic risk according to ELN 2022 classification or
- iii b) Presence of measurable/minimal residual disease (MRD).
- Eligibility confirmed by the institutionalal Transplant Indication Committee according to standard criteria.
- Age ≥ 18 years and ≤ 65 years
Key exclusion criteria (9 listed)
- Left ventricular ejection fraction (LVEF) < 40%
- Creatinine clearance < 0.5 mL/s
- 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)
- 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
- Karnofsky Performance Status < 70%
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Proton Total Marrow IrradiationProton 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. | Radiation | Proton TMI Conditioning Regimen |
Primary outcome
Incidence of adverse events (AEs) and serious adverse events (SAEs)
Time frame: Up to 100 days post-transplantation
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
Non-relapse mortality (NRM)
Time frame: Up to 100 days post-transplantation
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
16 secondary outcomes
Cumulative incidence of neutrophil engraftment
Time frame: Up to 100 days post-transplantation
Cumulative incidence of platelet engraftment
Time frame: Up to 100 days post-transplantation
Transfusion independence
Time frame: Up to 100 days post-transplantation
Incidence of primary graft failure
Time frame: Up to 100 days post-transplantation
Cumulative incidence of relapse at 12 months
Time frame: 12 months post-transplantation
Cumulative incidence of relapse at 24 months
Time frame: 24 months post-transplantation
Relapse-Free Survival (RFS) at 12 months
Time frame: 12 months post-transplantation
Relapse-Free Survival (RFS) at 24 months
Time frame: 24 months post-transplantation
Overall Survival (OS) at 12 months
Time frame: 12 months post-transplantation
Overall Survival (OS) at 24 months
Time frame: 24 months post-transplantation
GVHD-Free, Relapse-Free Survival (GRFS) at 12 months
Time frame: 12 months post-transplantation
GVHD-Free, Relapse-Free Survival (GRFS) at 24 months
Time frame: 24 months post transplantation
Cumulative incidence of severe acute graft-versus-host disease (GvHD) (Grade III-IV)
Time frame: Up to 100 days post-transplantation
Cumulative incidence of chronic graft-versus-host disease
Time frame: Up to 24 months post-transplantation
Functional Assessment of Cancer Therapy - General (FACT-G)
Time frame: Baseline and up to 24 months post-transplantation
Karnofsky Performance Status (KPS)
Time frame: Baseline and up to 24 months post-transplantation
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Apr 2026.
- BackgroundThe EBMT Handbook Textbook Open Access 2024
- Background: PubMed 16338616Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. 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 Dec;11(12):945-56. doi: 10.1016/j.bbmt.2005.09.004.
- Background: PubMed 26386318Harris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, Chanswangphuwana C, Efebera YA, Holler E, Litzow M, Ordemann R, Qayed M, Renteria AS, Reshef R, Wolfl M, Chen YB, Goldstein S, Jagasia M, Locatelli F, Mielke S, Porter D, Schechter T, Shekhovtsova Z, Ferrara JL, Levine JE. 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.
- Background: PubMed 21339008Corvo R, Zeverino M, Vagge S, Agostinelli S, Barra S, Taccini G, Van Lint MT, Frassoni F, Bacigalupo A. 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. Epub 2011 Feb 19.
- Background: PubMed 20625136Duval M, Klein JP, He W, Cahn JY, Cairo M, Camitta BM, Kamble R, Copelan E, de Lima M, Gupta V, Keating A, Lazarus HM, Litzow MR, Marks DI, Maziarz RT, Rizzieri DA, Schiller G, Schultz KR, Tallman MS, Weisdorf D. 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. Epub 2010 Jul 12.
- Background: PubMed 37094701Dominietto 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.
- Background: PubMed 8570312Taccone 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.
- Background: PubMed 28087456Stein 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.
- Background: PubMed 28396164Hui 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.
- Background: PubMed 25234438Patel 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.
- Background: PubMed 7858269Brown 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.
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- Individual participant dataSharing planned: No. Individual participant data will not be shared. Aggregated and anonymized data may be presented in scientific publications and presentations.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Proton Total Marrow Irradiation in people with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)/AML, run by Institute of Hematology and Blood Transfusion, Czech Republic at 2 sites in Czechia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 16 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Czechia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Veronika Valkova, Assoc. Prof., MD, PhD (+420 221 977 301, Veronika.Valkova@uhkt.cz), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of adverse events (AEs) and serious adverse events (SAEs) (time frame: Up to 100 days post-transplantation). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07532824, which also lists 17 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Apr 2026.