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.

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.

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

Individual participant data will not be shared. Aggregated and anonymized data may be presented in scientific publications and presentations.