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.
Underlying diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS),
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
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
Single group
Proton Total Marrow Irradiation
RadiationProton 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.
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
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
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
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
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
Incidence of primary graft failure
Incidence of primary graft failure following allogeneic hematopoietic stem cell transplantation. Unit of Measure: Percentage of participants
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Institute of Hematology and Blood Transfusion, Czech Republic
Lead sponsor
Proton Therapy Center Czech s.r.o.
Collaborator
