Low-Dose Total Lymphoid Irradiation in Treating Patients With Refractory Chronic Graft-versus-Host Disease After Donor Stem Cell Transplant

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of low-dose total lymphoid irradiation (LD-TLI) in treating patients with chronic graft-versus-host disease that has not responded to treatment with steroids. LD-TLI is a procedure in which all of the body's major lymph nodes are treated with small doses of radiation in order to reset the dysfunctional immune system. LD-TLI may work as a treatment for graft-versus-host disease caused by a bone marrow or stem cell transplant.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety of total lymphoid irradiation (TLI) in cohorts of a selected population of refractory chronic graft-versus-host disease (GvHD) patients, given to cohorts with a total cumulative doses of TLI of 100, 150, 200, 250 or 300 centigray (cGy). SECONDARY OBJECTIVES: I. To evaluate the efficacy (failure free survival [FFS] at 6 months) of this therapy in the study population. II. Approximate the efficacy at different dose levels using the GvHD summary scores. TERTIARY OBJECTIVES: I. Determine the effect of this therapy on relevant subpopulations of immune cells in an attempt to elucidate a mechanism of action. OUTLINE: This is a dose-escalation study. Patients undergo LD-TLI daily for 1-2 days. After completion of study treatment, patients are followed up on day 45, at 3 and 6 months, at 1 year, and then every 6 months thereafter.

Official Title
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A Phase I Study: Low-Dose Total Lymphoid Irradiation in the Treatment of Refractory Chronic Graft Versus Host Disease

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Radiation: total nodal irradiation
* Other: laboratory biomarker analysis
* Other: questionnaire administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients may have received a prior allogeneic hematopoietic stem cell transplant (alloHSCT) for any indication and from any donor Patients must have a diagnosis of cGvHD, in accordance with National Institutes of Health (NIH) guidelines; patients with overlap syndrome are also eligible; NOTE: Patients with recurrent, late onset and/or persistent acute GvHD (alone) are not eligible Patients with chronic GvHD who have been exposed to two or more lines of therapy, including at least one of which was composed of a glucocorticoid and a calcineurin inhibitor are eligible. Patients must have active, but not rapidly progressive, refractory cGvHD; any degree of severity (as per NIH criteria) and/or pattern of organ involvement may be considered; that said, patients with more severe and/or extensive chronic GvHD are expected to be the usual candidates for therapy As above, GvHD should be controlled to a degree that would potentially allow no additional requirement for systemic IST before and following TLI =< -15 and >= day (d) +45, respectively The ability to administer protocol doses of TLI (i.e., 100, 200 or 300 cGy) without exceeding cumulative doses of radiation must be established; for patients with prior radiotherapy exposure, this determination will be made by Dr. Greven (or her designee) using published guidelines for excessive organ exposure Karnofsky performance status (KPS) >= 60% White blood cells >= 3,000/mcL Absolute neutrophil count >= 1,500/mcL Hemoglobin >= 10.0 g/dL Platelets >= 100,000/mcL NOTE: If such hematologic abnormalities are present and deemed due to the process of cGvHD, such requirements may be waived with the approval of the PI Patients must have non-hematologic organ function as defined below: Left ventricular ejection fraction (LVEF) > 40% Key pulmonary function tests (PFTs) > 40% No further criteria for non-hematologic organ function are specified; however, if moderate-to-severe (major) organ function is present, such should be discussed with the PI, as various degrees of non-hematologic organ dysfunction may compromise either (or both) outcomes and toxicity evaluation If there is concern regarding potential reversibility of any specific organ dysfunction, this issue should be addressed by consultation with an appropriate sub-specialist Ability to understand and the willingness to sign an institutional review board (IRB)-approved informed consent document Exclusion Criteria: Patients with evidence of persistent or active malignancy or uncontrolled infection at the time of study entry Patients who are pregnant or breastfeeding

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: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supportive Care (TLI)<br>Patients undergo LD-TLI daily for 1-2 days. | Radiation: total nodal irradiation<br>* Undergo TLI<br>* Other names: total lymphoid irradiation;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: questionnaire administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure Free Survival (FFS) as Assessed by Scoring for Chronic GvHD - Specific Core Measures | Estimated along with 95% confidence intervals (CI). Descriptive statistics will be calculated and presented for GvHD summary scores by dose level and visit. | Time from baseline to date of last follow-up or failure event, assessed at day 180 | 
| Incidence of Adverse Events, Scored as Per Common Toxicity Criteria Version 4.0 | Toxicities (grade 2 and higher) will be reported as number of occurrences. | At day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunomodulatory/Immuno-suppressive Effects | T, natural killer (NK)T, regulatory T cell (Treg), B, NK, dendritic cell (DC) cell subsets, cell activation status and functional potential through cytokine and chemokine expression will be identified. Descriptive statistics (with 95% confidence intervals) will be calculated at each assessment time point. | Up to 1 year |