Impact of Cytomegalovirus Viral Load on Probability of Spontaneous Clearance and Response to Preemptive Therapy in Allogeneic Stem Cell Transplantation Recipients

Abstract

The optimal viral load threshold at which to initiate preemptive cytomegalovirus (CMV) therapy in hematopoietic cell transplantation (HCT) recipients remains to be defined. In an effort to address this question, we conducted a retrospective study of 174 allogeneic HCT recipients who underwent transplantation at a single center between August 2012 and April 2016. During this period, preemptive therapy was initiated at the discretion of the treating clinician. A total of 109 patients (63%) developed CMV viremia. The median time to reactivation was 17 days (interquartile range, IQR, 7-30 days) post-HCT. A peak viremia ≥150 IU/mL was strongly associated with a reduced probability of spontaneous clearance (relative risk, .16; 95% confidence interval, .1-.27), independent of established clinical risk factors, including CMV donor serostatus, exposure to antithymocyte globulin, and underlying lymphoid malignancy. The median time to clearance of viremia was significantly shorter in those who started therapy at CMV <350 IU/mL (19 days; IQR, 11-35 days) compared with those who started antiviral therapy at higher viremia thresholds (33 days; IQR, 21-42 days; P = .02). The occurrence of treatment-associated cytopenias was frequent but similar in patients who started preemptive therapy at CMV <350 IU/mL and those who started at CMV >350 IU/mL (44% versus 57%; P = .42). Unresolved CMV viremia by treatment day 35 was associated with increased risk of therapeutic failure (32% versus 0%; P = .001). Achieving eradication of CMV viremia by treatment day 35 was associated with a 74% reduction in 1-year nonrelapse mortality (NRM) (adjusted hazard ratio [HR], .26; 95% confidence interval [CI], .1-.8; P = .02), whereas therapeutic failure was associated with a significant increase in the probability of 1-year NRM (adjusted HR, 26; 95% CI, 8-87; P <.0001). We conclude that among allogeneic HCT patients, a peak CMV viremia ≥150 IU/mL is associated with a >80% reduction in the probability of spontaneous clearance independent of ATG administration, CMV donor serostatus, and lymphoid malignancy, and is a reasonable cutoff for preemptive therapy. Delaying initiation of therapy until a CMV value ≥350 IU/mL is associated with more protracted CMV viremia, and unresolved viremia by treatment day 35 is associated with a significant increase in NRM.

Use of maintenance therapy and incidence of recurrent Cytomegalovirus DNAemia among allogeneic hematopoietic cell transplant recipients

“…A total of 174 consecutive HCT patients transplanted between September 2012 and April 2016 were reviewed. The general characteristics of this cohort have been published previously . Of these patients, 78 (44.8%) patients were treated for an episode of early CMV reactivation with a median viral load at initiation of therapy of 700 IU/mL (IQR, 348‐1398).…”

“…Current treatment guidelines state the use of maintenance therapy could be considered following clearance of DNAemia; yet, the effectiveness of maintenance therapy is not well defined. The rate of recurrence after clearance of initial CMV DNAemia can be as high as 50‐70% in allogenic HCT patients and there are no data indicating that maintenance therapy does indeed reduce such risk of recurrence. Prolonged duration of antiviral therapy can be associated with adverse events, emergence of antiviral resistance, and significant added cost.…”

Spontaneously‐resolving episodes of cytomegalovirus DNAemia in allogeneic hematopoietic stem cell transplant recipients: Virological features and clinical outcomes

“…It should be highlighted that both this approach and ours spare the need for PET administration in a notable percentage of patients who are capable of controlling CMV replication by themselves, thus potentially reducing the toxicity inherent in the use of nucleoside analog anti‐CMV drugs. Other studies, in contrast, advocate initiating PET at very low CMV DNA loads (<150 IU/mL) aimed at reducing the length of antiviral treatment needed to clear CMV DNAemia . Unfortunately, a direct comparison between these studies and ours is not straightforward because of a number of factors, including the use of different PCR assays and criteria for initiation of PET and patients’ baseline and post‐transplant characteristics in each cohort.…”

“…Two recent reports support the suitability of this approach; Tan and colleagues showed that initiation of PET at low CMV DNA loads results in shorter episodes of CMV DNAemia and courses of antiviral therapy. In turn, Camargo et al concluded that CMV DNA peak levels ≥ 150 IU/mL associate with a drastically reduced probability of spontaneous CMV DNAemia clearance . PET initiation at low CMV DNA levels may lead to unnecessary use of antivirals for episodes that might clear spontaneously.…”

“…Currently, PET consists of administrating antivirals with intrinsic activity against CMV upon detection of a certain CMV DNA load level in the blood compartment, as quantified by real‐time polymerase chain reaction (RT‐PCR) assays. CMV DNA load thresholds for PET initiation vary widely across centers, usually ranging between 25 to 1500 IU/mL when plasma is the chosen specimen type . Recently published data point to an association between very low CMV DNA loads (≥250 IU/mL) and increased risk of overall and nonrelapse mortality within the first year of allo‐HSCT, particularly in the early days (day 0–60) after the transplantation .…”