Automated Total Marrow and Lymphoid Irradiation for Allogeneic Hematopoietic Cell Transplant

Intensive conditioning regimens used in allogeneic hematopoietic cell transplant (HCT) help to eliminate hematologic tumors and reduce the risk of relapse, but are also characterized by high toxicity. Total marrow and lymphoid irradiation (TMLI) is a specialized radiation technique that specifically targets marrow and lymphoid tissue to maximize antitumor efficacy while reducing off target toxicity. Despite these benefits, TMLI is technically challenging and time consuming. The radiation oncology team at Stanford has developed an automated TMLI platform to overcome these challenges. In this phase II trial, automation will be incorporated into a previously validated conditioning regimen of fludarabine/cyclophosphamide/TMLI HCT with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis to confirm the feasibility and safety of automation in patients receiving allogeneic HCT for high-risk myeloid malignancies.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Myeloproliferative Neoplasm
• Intervention / Treatment: Radiation: VMAT-Based Total Marrow and Lymphoid Irradiation (TMLI); Drug: Fludarabine; Drug: Cyclophosphamide; Biological: Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT); Drug: Mycophenolate mofetil (MMF); Drug: Tacrolimus

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hany Elmariah; Phone Number: 650-723-0822; Email: he3@stanford.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
      • Contact: Hany Elmariah, MD; Phone Number: 650-723-0822; Email: he3@stanford.edu
      • Principal Investigator: Hany Elmariah, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for 20 Gy Arm (Cohort A)

1. Age, Performance Status, and Graft Criteria require all of the following bullet points:

   • Age 18 to 60 years (inclusive)
   • HCT Co-Morbidity score (HCT-CI) < 5 (http://www.qxmd.com/calculate-online/hematology/hct-ci)(31)
   • Adequate performance status is defined as Karnofsky score ≥ 70%
   • Patients must be receiving an allogeneic peripheral blood stem cell graft
   • Patients and selected donor must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1. Donors may be an 8/8 matched sibling donor, 8/8 matched unrelated donor, haploidentical related donor, or 7/8 mismatched unrelated donor.

2. Eligible Diseases (Any one of the following)

   Acute Myeloid Leukemia (AML) Must have at least one of the following characteristics:

   • Blasts >5% in the peripheral blood and/or bone marrow after >2 prior lines of AML directed therapy, present during the trial screening window
   • Adverse plus risk by AlloHCT Refined ELN Criteria: defined as having complex cytogenetics, TP53 mutation, or MECOM rearrangement confirmed at any time point.(32)

   Myelodysplastic syndrome Must have at least one of the following characteristics at the time of conditioning:

   • Blasts >10% in the peripheral blood and/or bone marrow after >1 prior line of therapy.
   • TP53 mutation confirmed at any time point

   Myeloproliferative neoplasms (MPN) or MDS/MPN overlap. Must have at least one of the following characteristics:

   • Blasts >10% in the peripheral blood and/or bone marrow during the trial screening window
   • TP53 mutation confirmed at any time point

3. Adequate organ function is defined as all of the following:

   Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction > 45% confirmed by MUGA or echocardiography Pulmonary: DLCO, FEV1, FVC > 50% predicted, and absence of O2 requirements. Liver: Transaminases < 3 x upper limit of normal (ULN) and total bilirubin ≤ 2 mg/dL except for patients with Gilbert's syndrome or hemolysis (as indicated by provider documentation).

   Renal: Creatinine < 2.0 mg/dL (adults) and creatinine clearance > 40 mL/min.

4. Must be FIRST allogeneic HCT
5. Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment.
6. Voluntary written consent

Inclusion Criteria for 12 Gy Arm (Cohort B)

1. Age, Performance Status, and Graft Criteria require all of the following bullet points:

   Age 18 to 70 years (inclusive) Adequate performance status is defined as Karnofsky score ≥ 70% Patients must be receiving an allogeneic peripheral blood stem cell graft Patients and selected donor must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1. Donors may be an 8/8 matched sibling donor, 8/8 matched unrelated donor, haploidentical related donor, or 7/8 mismatched unrelated donor.

2. Eligible Diseases (Any of the following) Acute Myeloid Leukemia (AML) Myelodysplastic syndrome Myeloproliferative neoplasm MDS/MPN overlap
3. Must have relapse after prior allo HCT

4. Adequate organ function is defined as all of the following:

   Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction > 40% confirmed by MUGA or echocardiography Pulmonary: DLCO, FEV1, FVC > 40% predicted, and absence of O2 requirements. Liver: Transaminases < 3 x upper limit of normal (ULN) and total bilirubin ≤ 2 mg/dL except for patients with Gilbert's syndrome or hemolysis (as indicated by provider documentation).

   Renal: Creatinine < 2.0 mg/dL (adults) and creatinine clearance > 40 mL/min. Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment.

5. Voluntary written consent

Exclusion Criteria:

1. Pregnant or breast feeding. The agents used in this study include Pregnancy Category D: known to cause harm to a fetus. Females of childbearing potential must have a negative pregnancy test prior to starting therapy.
2. Untreated active infection. Controlled or asymptomatic infections requiring continued antimicrobial therapy are permissible.
3. Active HIV infection, defined as HIV infection with detectable viral load
4. Active central nervous system malignancy
5. GVHD requiring systemic therapy including > 0.25 mg/kg prednisone (or equivalent) or other systemic therapy for GVHD (e.g., tacrolimus, sirolimus, ruxolitinib, belumosodil, ibrutinib, axatilimab).
6. Any other medical or psychological condition that is deemed serious and unsafe for clinical trial participation.
7. Exposure to prior radiation that is deemed unsafe for clinical trial participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A: Total Marrow and Lymphoid Irradiation (TMLI) 200 cGy BID Conditioning Regimen; Participants receive fludarabine, cyclophosphamide, and TMLI 200 cGy BID conditioning followed by allogeneic peripheral blood stem cell transplantation (PBSCT). Post-transplant GVHD prophylaxis includes cyclophosphamide, mycophenolate mofetil, and tacrolimus.	Radiation: VMAT-Based Total Marrow and Lymphoid Irradiation (TMLI); Patients receive VMAT-based TMLI with daily image-guided radiation therapy (IGRT) for treatment localization and verification prior to radiation delivery.; Drug: Fludarabine; Fludarabine 25 mg/m² IV administered daily on Days -7 through -3.; Drug: Cyclophosphamide; Cyclophosphamide 14.5 mg/kg IV on Days -7 and -6 as part of conditioning and 50 mg/kg IV on Days +3 and +4 as post-transplant GVHD prophylaxis.; Biological: Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT); Allogeneic peripheral blood stem cell transplantation administered on Day 0.; Drug: Mycophenolate mofetil (MMF); Mycophenolate mofetil initiated on Day +5 and continued through Day +35 for GVHD prophylaxis.; Drug: Tacrolimus; Mycophenolate mofetil initiated on Day +5 and continued through Day +35 for GVHD prophylaxis.
Experimental: Cohort B: Total Marrow and Lymphoid Irradiation 150 cGy BID Conditioning Regimen; Participants receive fludarabine, cyclophosphamide, and TMLI 150 cGy BID conditioning followed by allogeneic peripheral blood stem cell transplantation (PBSCT). Post-transplant GVHD prophylaxis includes cyclophosphamide, mycophenolate mofetil, and tacrolimus.	Radiation: VMAT-Based Total Marrow and Lymphoid Irradiation (TMLI); Patients receive VMAT-based TMLI with daily image-guided radiation therapy (IGRT) for treatment localization and verification prior to radiation delivery.; Drug: Fludarabine; Fludarabine 25 mg/m² IV administered daily on Days -7 through -3.; Drug: Cyclophosphamide; Cyclophosphamide 14.5 mg/kg IV on Days -7 and -6 as part of conditioning and 50 mg/kg IV on Days +3 and +4 as post-transplant GVHD prophylaxis.; Biological: Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT); Allogeneic peripheral blood stem cell transplantation administered on Day 0.; Drug: Mycophenolate mofetil (MMF); Mycophenolate mofetil initiated on Day +5 and continued through Day +35 for GVHD prophylaxis.; Drug: Tacrolimus; Mycophenolate mofetil initiated on Day +5 and continued through Day +35 for GVHD prophylaxis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-Relapse Mortality (NRM)	Death without prior disease relapse following allogeneic peripheral blood stem cell transplantation.	Day 100 after transplantation
Neutrophil Engraftment	Neutrophil engraftment following allogeneic peripheral blood stem cell transplantation.	Through Day 100 after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk of Relapse	Disease relapse following allogeneic peripheral blood stem cell transplantation.	Day 100 post-transplant
Disease-Free Survival (DFS)	Disease-free survival following allogeneic peripheral blood stem cell transplantation.	Day 100 post-transplant
Overall Survival (OS)	Overall survival following allogeneic peripheral blood stem cell transplantation.	Day 100 post-transplant
Incidence of Grade II-IV Acute Graft-versus-Host Disease (GVHD)	Incidence and severity of Grade II-IV acute graft-versus-host disease following allogeneic peripheral blood stem cell transplantation.	Day 100 post-transplant
Incidence of Grade III-IV Acute Graft-versus-Host Disease (GVHD)	Incidence and severity of Grade III-IV acute graft-versus-host disease following allogeneic peripheral blood stem cell transplantation.	Day 100 post-transplant
Bearman Regimen-Related Toxicity	Regimen-related toxicity assessed using the Bearman Toxicity Scale. Toxicity will be evaluated by organ system and graded according to severity (Grades I-IV).	Day 100 post-transplant

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Hany Elmariah, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: June 4, 2026
• First Submitted That Met QC Criteria: June 4, 2026
• First Posted (Actual): June 9, 2026

Study Record Updates

• Last Update Posted (Actual): June 9, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloproliferative Disorders; Organic Chemicals; Therapeutics; Fatty Acids; Lipids; Hydrocarbons; Acids, Acyclic; Carboxylic Acids; Macrolides; Lactones; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Caproates; Cyclophosphamide; Mycophenolic Acid; Tacrolimus; fludarabine; Lymphatic Irradiation
• Other Study ID Numbers: IRB-86777

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No