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

Study Overview
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Brief Summary
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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)

Detailed Description
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndromes, Myeloproliferative Disorder, Chronic Lymphocytic Leukemia, B-cell Lymphoma, T-cell Lymphoma, Non Hodgkin Lymphoma, Hodgkin Lymphoma, Chronic Myelomonocytic Leukemia

Intervention / Treatment
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* Radiation: Total body irradiation (TBI)
* Drug: Anti-thymocyte globulin (ATG)
* Drug: Tacrolimus
* Drug: Mycophenolate mofetil (MMF)
* Radiation: Total lymphoid irradiation (TLI)


Participation Criteria
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Eligibility Criteria
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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%

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TBI+TLI<br>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)<br>* Administer Total body irradiation (TBI) 80 cGy on Day 1 of standard TLI ATG conditioning<br>Drug: Anti-thymocyte globulin (ATG)<br>* Given intravenous (IV), Dose 1.5 mg/kg x 5 days<br>Drug: Tacrolimus<br>* Oral, Dose 0.05 mg/kg twice daily, can be given intravenous (IV)<br>* Other names: Fujimycin;Drug: Mycophenolate mofetil (MMF)<br>* 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.<br>* Other names: MMF;Radiation: Total lymphoid irradiation (TLI)<br>* 9 x 120 cGy over 11 days<br>|

What is the study measuring?
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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 |