Proton-Based Total Marrow Irradiation for Allogeneic Transplantation in High-Risk AML/MDS

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.

Sex

All

Minimum age

18 Years

Maximum age

65 Years

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

• BACKGROUNDThe EBMT Handbook Textbook Open Access 2024
• BACKGROUNDFilipovich 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. PMID 16338616
• BACKGROUNDHarris 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. PMID 26386318
• BACKGROUNDCorvo 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. PMID 21339008
• BACKGROUNDDuval 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. PMID 20625136
• 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.