Proton Total Marrow Irradiation-Based Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 16
- 试验地点
- 2
- 主要终点
- Incidence of adverse events (AEs) and serious adverse events (SAEs)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
- •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
排除标准
- •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%
- •Active viral hepatitis or human immunodeficiency virus (HIV) infection
- •Presence of liver cirrhosis
研究组 & 干预措施
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.
干预措施: Proton Total Marrow Irradiation (Radiation)
结局指标
主要结局
Incidence of adverse events (AEs) and serious adverse events (SAEs)
时间窗: 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)
时间窗: 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
次要结局
- Cumulative incidence of neutrophil engraftment(Up to 100 days post-transplantation)
- Cumulative incidence of platelet engraftment(Up to 100 days post-transplantation)
- Transfusion independence(Up to 100 days post-transplantation)
- Incidence of primary graft failure(Up to 100 days post-transplantation)
- Cumulative incidence of relapse at 12 months(12 months post-transplantation)
- Cumulative incidence of relapse at 24 months(24 months post-transplantation)
- Relapse-Free Survival (RFS) at 12 months(12 months post-transplantation)
- Relapse-Free Survival (RFS) at 24 months(24 months post-transplantation)
- Overall Survival (OS) at 12 months(12 months post-transplantation)
- Overall Survival (OS) at 24 months(24 months post-transplantation)
- GVHD-Free, Relapse-Free Survival (GRFS) at 12 months(12 months post-transplantation)
- GVHD-Free, Relapse-Free Survival (GRFS) at 24 months(24 months post transplantation)
- Cumulative incidence of severe acute graft-versus-host disease (GvHD) (Grade III-IV)(Up to 100 days post-transplantation)
- Cumulative incidence of chronic graft-versus-host disease(Up to 24 months post-transplantation)
- Functional Assessment of Cancer Therapy - General (FACT-G)(Baseline and up to 24 months post-transplantation)
- Karnofsky Performance Status (KPS)(Baseline and up to 24 months post-transplantation)