Evaluating the Clinical Utility of the T-SPOT.CMV Assay for the Prediction of CMV Reactivation Among Pediatric Patients Undergoing Hematopoietic Cell Transplant

Study Overview
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Brief Summary
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The ability to distinguish allogeneic hematopoietic cell transplantation (allo-HCT) recipients at risk for cytomegalovirus (CMV) reactivation from those who are not is central for optimal CMV management strategies. Measuring this cell mediated immunity has been proposed as a potent tool to predict those patients at highest risk of CMV reactivation and disease. This study will evaluate the ability of the T-SPOT.CMV test to predict Cytomegalovirus (CMV) reactivation in allogeneic hematopoietic cell transplantation (allo-HCT) pediatric recipients. Primary Objectives: To evaluate feasibility of T-SPOT.CMV spot count test in allo-HCT pediatric recipients. To evaluate association of T-SPOT.CMV spot count in the first sample collected after patient has engrafted with subsequent CMV reactivation in allo-HCT pediatric recipients. Secondary Objectives: To evaluate the correlation between T-SPOT.CMV spot count in donors with subsequent recipient CMV spot count. To explore the relationship between recipient T-SPOT.CMV spot counts and subsequent CMV infection related morbidity and treatment outcomes among pediatric all-HCT recipients.

Detailed Description
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T-SPOT response will be measured using the results from the T-SPOT.CMV blood test in both HCT recipients and HCT donors. A blood sample for the T-SPOT.CMV blood test will be collected from the HCT donor prior to transplant. Blood specimens will be collected for the T-SPOT.CMV blood test from HCT recipients over the course of 6 months, starting weekly at Day +1, biweekly starting at Day +45, and monthly starting at day +120. HCT recipient participant demographic and clinical characteristics will be collected at enrollment. Additional clinical information will be abstracted from the HCT recipient participants medical record during the study follow-up period. This will include information related to transplant history and outcome, infections, antimicrobial exposure, chemotherapy, and laboratory values related to infectious diseases and immunosuppression. The feasibility of the T-SPOT.CMV spot count test will be evaluated once the first 30 participants enrolled on study reach day +90. If 75% of patients have at least 1 evaluable samples after engraftment (> 75,000 per microtiter wells), we will proceed with enrollment. If more >25% of patients have all their samples deemed not evaluable due to insufficient mononuclear cell count (<75,000 per microtiter wells) the study will be stopped and concluded as not feasible.

Official Title
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Evaluating the Clinical Utility of the T-SPOT.CMV Assay for the Prediction of CMV Reactivation Among Pediatric Patients Undergoing Hematopoietic Cell Transplant

Conditions
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CMV

Intervention / Treatment
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* Diagnostic Test: T-SPOT®.CMV Test


Participation Criteria
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Eligibility Criteria
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HCT Recipient Inclusion Criteria Less than 18 years old at the time of study enrollment Scheduled to receive allogeneic HCT at St Jude Children's Research Hospital HCT recipient has a documented seropositive CMV result prior to enrollment OR The HCT recipient is seronegative, but the HCT donor has a seropositive CMV result as documented in the recipient's medical record. HCT Recipient Exclusion Criteria Any condition or therapy that would, in the opinion of the investigator, place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the study, or impact the outcome of the study. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent. HCT Donor Inclusion Criteria • Approved allogeneic HCT donor for a HCT recipient enrolled on the SPOTCMV protocol HCT Donor Exclusion Criteria • Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| HCT Recipient<br>All participants who meet eligibility criteria and consent to enrollment on study. Blood specimens will be collected for the T-SPOT.CMV blood test from HCT recipients over the course of 6 months, starting weekly at Day +1, biweekly starting at Day +45, and monthly starting at day +120. The amount of blood collected at each visit will be based on age. | Diagnostic Test: T-SPOT®.CMV Test<br>* The T-SPOT.CMV test (Oxford Diagnostic Laboratories) measures the strength of T cell responses to CMV specific antigens. Using whole blood samples obtained through a standard blood collection tube, white blood cells (WBC's) are separated and purified. The cells are quantified and placed into specially designed plates where they are challenged with antigens specific to the disease under study. Disease-specific cells responding to these antigens will release immune messenger molecules, called cytokines. We then use chemistry to allow us to visualize those WBCs releasing cytokines (and hence those which react to the antigen), resulting in a spot on the bottom of the plate, corresponding to the footprint of an individual reacting WBC. Finally, we use an automated image analysis system to identify and count each of these spots to give a quantitative readout. That quantitative readout gives us the frequency of responsive disease-specific cells (Oxford Immunotec, 2017).<br>|
| HCT Donor<br>Approved allogeneic HCT donor for a HCT recipient enrolled on the SPOTCMV protocol A blood sample for the T-SPOT.CMV blood test will be collected from the HCT donor prior to transplant | Diagnostic Test: T-SPOT®.CMV Test<br>* The T-SPOT.CMV test (Oxford Diagnostic Laboratories) measures the strength of T cell responses to CMV specific antigens. Using whole blood samples obtained through a standard blood collection tube, white blood cells (WBC's) are separated and purified. The cells are quantified and placed into specially designed plates where they are challenged with antigens specific to the disease under study. Disease-specific cells responding to these antigens will release immune messenger molecules, called cytokines. We then use chemistry to allow us to visualize those WBCs releasing cytokines (and hence those which react to the antigen), resulting in a spot on the bottom of the plate, corresponding to the footprint of an individual reacting WBC. Finally, we use an automated image analysis system to identify and count each of these spots to give a quantitative readout. That quantitative readout gives us the frequency of responsive disease-specific cells (Oxford Immunotec, 2017).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of the first 30 participants with at least one evaluable sample | Percentage of the first 30 participants enrolled on study reach day +90 with at least one evaluable sample will be reported. | Day +90 after transplant | 
| Odds ratio of subsequent reactivation | We define the primary endpoint to the T-SPOT CMV count in the first sample collected after patient has engrafted, which is the time point when one establishes his/her post-transplant immunity. If the count in this sample is less than or equal to 100, the participant will be noted as low response, while an individual with a spot count greater than 100 will be noted as high response. Odds ratio of having subsequent CMV reactivation between low response and high response groups will be estimated. | Up to 180 days after enrollment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation coefficient of T-SPOT.CMV spot count in donors with subsequent recipient CMV spot count | The correlation coefficient between T-SPOT.CMV spot count in donors (one-time measure) and maximal recipient's CMV spot count will be calculated with Pearson's or Spearman's correlation coefficient. | Up to 180 days after enrollment. | 
| Odds ratio of morbidity | The odds ratio with 95% CI of morbidity will be reported from multiple logistic regression. | Up to 180 days after enrollment. | 
| Odds ratio of treatment outcomes | The odds ratio with 95% CI of treatment outcomes will be reported from multiple logistic regression. | Up to 180 days after enrollment. | 
| Hazard ratio of morbidity | The hazard ratio with 95% CI of morbidity will be reported from Cox regression model. | Up to 180 days after enrollment. | 
| Hazard ratio of treatment outcomes | The hazard ratio with 95% CI of treatment outcomes will be reported from Cox regression model. | Up to 180 days after enrollment. |