Implementation of CMV-T-Track® in Clinical Routine to Guide Management of CMV Reactivation

Background: Despite Letermovir prophylaxis, reactivation of cytomegalovirus (CMV), requiring close monitoring and preemptive antiviral treatment, remains to be an issue after allogeneic hematopoietic stem cell transplantation (HSCT). Monitoring CMV-specific cellular immunity can help to identify patients at risk and may guide monitoring intervals and therapeutic decisions.

CMV T-Track®, a standardized IFN-γ ELISpot assay, conducted after the end of treatment of a first CMV reactivation was shown to identify patients at risk of recurrent reactivation with a positive predictive value (patients with a negative test after the first CMV reactivation had a subsequent recurrent CMV reactivation) of 80%.

As these results originate from a clinical trial with a distinct patient population, we analyzed its usefulness and value within the clinical routine.

Here we describe the results within the clinical routine in an unselected patient cohort and the influence of different GvHD prophylaxis on T-Track® outcome, as well as factors promoting CMV reactivation despite positive test results.

Methods: In total, 169 patients were monitored for CMV reactivation with CMV-PCR for 365 days after HSCT and CMV immunity was measured using CMV T-Track® at d+100. CMV T-Track® was repeated at d+200 and+ 300 in case of a negative first test result d+100.

Patient characteristics: 125 patients received ATG, 24 Alemtuzumab i.v. and 12 ptCy. 8 patients were transplanted from an HLA-identical sibling and received no T cell depleting (TCD) agent. CMV-serostatus: Donor(D)+/recipient(R)+ in 123, D+/R- in 9, D-/R+ in 34 and D-/R- in 3 patients. All CMVpos recipients received Letermovir prophylaxis until d+100.

Results: At d+100 164/169 tests produced a robust result, only 5 tests were invalid.

110 patients had a positive T-Track® at d+100, with a higher percentage in patients with a CMVpos donor (99/132 (75%) vs. (10/37 (27%)).

After Alemtuzumab we observed the lowest rate of positive T-Track® 10/24 (42%) at d+100, followed by ATG 83/125 (66%), whereas pTCy showed a good response 11/12 (92%). Only 5/8 (63%) patients without TCD had a positive test result.

9/10 (90%) of patients with a positive T-Track® d+100 despite a CMVneg donor had a positive CMV-PCR before d+100, whereas only 3/27 (11%) CMVireamias were detected in those without CMV immunity.

In patients with a CMVpos donor 59/108 (55%) had a documented reactivation leading to a positive T Track®, in contrast to 9/33 (27%) with a negative T-Track®.

18/20 (90%) patients developed a positive T-Track® at d+200 after CMViraemia between d+100 and d+200. 24 patients were persistently negative at d+300.

Despite a positive T-Track® at d+100, 28/110 (25%) patients needed treatment for CMV reactivation. In most of them immunosuppressive treatment for GvHD was initiated after d+100: 20/28 (71%) high dose corticosteroids, 1/28 (4%) Ruxolitinib.

Excluding patients, that received additional immunosuppression after d+100 only 7/89 (8%) developed a CMV reactivation despite a positive d+100 T-Track®. This yields a negative predictive value of 0,921 for the result of T-Track® at d+100.

25/59 (42%) patients with a negative T-Track® at d+100 subsequently developed a treatment requiring CMV reactivation.

Discussion/Conclusion:

CMV T-Track® is feasible in clinical routine and can help identify patients at risk for CMV reactivation. In our cohort 110/169 (65%) patients showed a cellular immune response against CMV at day +100. Excluding patients that received additional immunosuppression in the later course, only 7/89 (8%) developed a CMV reactivation after a positive d+100 T-Track®.

With this T-Track® result at d+100 has a negative predictive value of 0,921.

CMV negative donor was the strongest predictor for a negative test result. Alemtuzumab was the only TCD associated with a negative impact.

CMVireamia increases CMV immune response and is mandatory in patients with a CMV negative donor to establish CMV-immunity.

We therefore consider CMV T-Track® a useful tool in clinical routine to identify patients with sufficient CMV-immunity at d+100. This could help to guide monitoring intervals or therapeutic decisions such as prolonged prophylaxis or need for preemptive treatment.