Total Body Irradiation +/- Total Lymphoid Irradiation & Anti-Thymocyte Globulin in Non-myeloablative Hematopoietic Cell Transplantation

Very Low-dose Total Body Irradiation in Combination With Total Lymphoid Irradiation and Anti-Thymocyte Globulin to Improve Donor Engraftment in Patients Undergoing Non-Myeloablative Hematopoietic Cell Transplantation

The purpose of this study is to evaluate whether addition of a low dose of total body irradiation (TBI) to a standard preparation for transplant [total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG)] conditioning will help to augment donor chimerism without reducing tolerability of this regimen or increasing the risk of graft-vs-host disease (GVHD)

Study Overview

• Status: Completed
• Conditions: B-cell Lymphoma; Acute Myeloid Leukemia; Myelodysplastic Syndromes; Hodgkin Lymphoma; Chronic Myelomonocytic Leukemia; Chronic Lymphocytic Leukemia; Non Hodgkin Lymphoma; Myeloproliferative Disorder; T-cell Lymphoma
• Intervention / Treatment: Radiation: Total body irradiation (TBI); Drug: Anti-thymocyte globulin (ATG); Drug: Tacrolimus; Drug: Mycophenolate mofetil (MMF); Radiation: Total lymphoid irradiation (TLI)

Detailed Description

Primary Objective:

• Determine the proportion of patients with full donor T-cell chimerism at Day 28 following hematopoietic cell transplantation.

Secondary Objectives:

• Determine the risk of disease progression, overall and event free survival, and non-relapse mortality, following treatment with TLI; ATG; and TBI.
• Determine the incidence of acute and chronic GVHD following treatment with TLI; ATG; and TBI.

Exploratory Objectives:

• Determine the changes in frequency of hematopoietic stem, progenitor, and mature cell subsets and the changes in cytokine milieu and cellular architecture in the bone marrow of patients receiving TLI compared to TLI+TBI.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

INCLUSION CRITERIA

• Has a human leukocyte antigen (HLA)-matched or single allele mismatched adult sibling donor or unrelated donor.
• Acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); myeloproliferative disease syndrome (MPD)]; chronic lymphocytic leukemia (CLL); B- or T-cell non Hodgkin lymphoma (NHL); Hodgkin lymphoma (HL); or chronic myelomonocytic leukemia (CMML), suitable for treatment with allogeneic transplant after TLI and ATG reduced intensity conditioning.
• Considered at high-risk for regimen-related toxicity from fully-ablative transplant conditioning (therefore reduced-intensity conditioning is recommended).
• Ability to understand and the willingness to sign a written informed consent document. Patients must have signed informed consent to participate in the trial.

EXCLUSION CRITERIA

• Uncontrolled bacterial, viral or fungal infection defined as currently taking medication and progression of clinical symptoms.
• Progressive hemato lymphoid malignancy despite conventional therapy.
• Chronic myelogenous leukemia (CML).
• Active CNS involvement of the underlying malignancy.
• HIV positive
• Pregnant or lactating
• Prior malignancy (EXCEPTION: diagnosed > 5 years ago without evidence of disease, OR treated ≤ 5 years ago but have a greater than 50% chance of life expectancy of ≥ 5 years for that malignancy).
• Have a psychiatric disorder(s) or psychosocial circumstance(s) which in the opinion of the primary physician would place the patient at an unacceptable risk from transplant.
• Left ventricular ejection fraction (LEVF) < 30%, or uncontrolled cardiac failure
• Diffusing capacity of lung for carbon monoxide (DLCO) < 40% predicted
• Total bilirubin > 3 mg/dL
• Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic-pyruvic transaminase (SGPT) > 4 x upper limit of normal (ULN)
• Creatinine > 2 mg/dL and an estimated creatinine clearance < 40 mL/min
• Poorly-controlled hypertension despite multiple antihypertensive medications
• Karnofsky Performance Status (KPS) < 60%

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: TBI+TLI; TBI, single exposure on Day -1, 80 centigray (cGy) in addition to total lymphoid irradiation (TLI, 120 cGy/day for 9 days, weekends excluded) and anti-thymocyte globulin (ATG) 1.5 mg/kg (conditioning regimen)

Radiation: Total body irradiation (TBI); Administer Total body irradiation (TBI) 80 cGy on Day 1 of standard TLI ATG conditioning; Drug: Anti-thymocyte globulin (ATG); Given intravenous (IV), Dose 1.5 mg/kg x 5 days; Drug: Tacrolimus; Oral, Dose 0.05 mg/kg twice daily, can be given intravenous (IV); Other Names: Fujimycin; Drug: Mycophenolate mofetil (MMF); Given Oral, 15 mg/k every 2 hours for peripheral blood stem cells (PBSC) from matched related donors; 15 mg/kg every 8 hours for PBSC from unrelated donors (URDs) or mismatched related donors.; Other Names: Cellcept; MMF; Radiation: Total lymphoid irradiation (TLI); 9 x 120 cGy over 11 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Full-dose Donor Chimerism (FDC) at Day 28 Following TLI/ATG/TBI Conditioning.	Subsequent to TLI/ATG/TBI conditioning, the proportion of participants with full dose donor chimerism (FDC) will be determined by Day 28. FDC is defined as achieving ≥ 95% donor type in the CD3+ lineage within 28 days of donor cell infusion, as assessed by short tandem repeat (STR) testing. The outcome will be expressed as the number of participants that achieve FDC by Day 28, a number without dispersion.	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Progression	Transplant recipients will be assessed for disease progression at 1 year after hematopoietic cell transplantation (HCT). The outcome is reported as the number of transplant recipients who experienced disease progression.	1 year
Overall Survival (OS)	Overall survival (OS) is defined as the number of transplant recipients remaining alive at 12 months after transplant. The outcome is expressed as the number of transplant recipients who remained alive at 12 months after treatment, a number without dispersion.	1 year
Event-free Survival (EFS) at 1 Year	Event-free survival (EFS) is defined as the number of transplant recipients remaining alive at 12 months after transplant and who did not experience disease relapse defined as blasts < 5%. The outcome is expressed as the number of transplant recipients remaining alive at 12 months after transplant without disease relapse, a number without dispersion.	1 year
Non-relapse Mortality (NRM)	Non-relapse mortality (NRM) is defined as death without known disease relapse or recurrence. The outcome is expressed as the number of transplant recipients whose cause of death was not disease relapse or recurrence, a number without dispersion.	1 year
Graft vs Host Disease (GvHD)	Recipients will be monitored for Grade 2 to 4 graft vs host disease (GvHD). The outcome is reported as the number of transplant recipients who experienced acute GvHD grades 2 to 4, the number of transplant recipients who experienced chronic and extensive GvHD. In addition, the number of transplant recipients with chronic and extensive GvHD that was refractory to treatment ("persistent") is reported. Per protocol, the result for chronic extensive and persistent GvHD is based on the subset of participants that had chronic and extensive GvHD.	1 year

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Robert Lowsky, MD, Stanford University

Study record dates

Study Major Dates

• Study Start (Actual): November 5, 2018
• Primary Completion (Actual): December 26, 2019
• Study Completion (Actual): November 17, 2020

Study Registration Dates

• First Submitted: November 6, 2018
• First Submitted That Met QC Criteria: November 6, 2018
• First Posted (Actual): November 8, 2018

Study Record Updates

• Last Update Posted (Actual): December 12, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic-Myeloproliferative Diseases; Leukemia, Lymphoid; Leukemia, B-Cell; Leukemia, Myeloid; Chronic Disease; Lymphoma; Myelodysplastic Syndromes; Leukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Antilymphocyte Serum
• Other Study ID Numbers: IRB-47407 (Other Identifier: Stanford IRB); BMT330 (Other Identifier: OnCore ID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No