Systematic review on efficacy and safety of empirical versus pre-emptive antifungal therapy among children with febrile neutropenia reveals paucity of data.

BACKGROUND: Two approaches are used to manage invasive fungal disease (IFD) in febrile neutropenic patients viz. empirical therapy (without attempting to confirm the diagnosis), or pre-emptive therapy (after screening tests for IFD). OBJECTIVE: This systematic review was undertaken to compare these approaches in children. METHODS: We searched PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, CINAHL, Clinical Trial Registries and grey literature, for randomized controlled trials (RCT) comparing empirical versus pre-emptive antifungal therapy in children with FN suspected to have IFD. We used the Cochrane Risk of bias 2 tool for quality assessment, and evaluated the certainty of evidence using the GRADE approach. RESULTS: We identified 7989 citations. Stepwise screening identified only one relevant RCT that administered empirical (n = 73) or pre-emptive (n = 76) antifungal therapy. There were no significant differences in all-cause mortality (RR 1.56, 95% CI: 0.46, 5.31), IFD mortality (RR 1.04, 95% CI:0.15, 7.20) and other clinically important outcomes such as duration of fever, duration of hospitalization and proportion requiring ICU admission. There were no safety data reported. The number of days of antifungal therapy was significantly lower in the pre-emptive therapy arm. The certainty of evidence for all outcomes was 'moderate'. CONCLUSIONS: This systematic review highlighted the paucity of data, comparing empirical versus pre-emptive antifungal therapy in children with febrile neutropenia having suspected invasive fungal disease. Data from a single included trial suggests that both approaches may be comparable in research settings. Robust trials are warranted to address the gap in existing knowledge about the optimal approach in clinical practice.

A practical guide to real-world implementation of pre-emptive therapy for Cytomegalovirus disease prevention in high-risk seronegative liver transplant recipients with seropositive donors.

The Comparison of Antiviral Preventative Strategies In Liver Transplant (CAPSIL) study showed pre-emptive therapy (PET) to be superior to antiviral prophylaxis for Cytomegalovirus (CMV) disease prevention in high-risk CMV seronegative liver transplant recipients (LTRs) with seropositive donors (D+ R- ). Despite the statistical superiority of PET over prophylaxis in research settings, PET is perceived as a logistically more complex strategy that requires careful coordination of weekly CMV PCR testing, prompt initiation of CMV antivirals upon viremia detection, and timely cessation of antivirals following viremia resolution. Transplant centers may be hesitant to use PET for CMV disease prevention in D+ R- LTRs out of concern that PET coordination is not feasible in clinical practice. We recently described our experience using PET in CMV D+ R- LTRs in a real-world setting, and found it to be as effective for CMV disease prevention as PET performed as part of a clinical trial. Here, we describe a systematic approach for PET implementation in real-world settings and provide practical tools to address anticipated challenges. This framework can support transplant programs in overcoming logistical barriers to PET and incorporating an evidence-based and cost-effective CMV prevention strategy into routine care for high-risk CMV D+ R- LTRs.

Pre-exposure prophylaxis of non-HIV viral infections and the role of long-acting antivirals.

Viruses cause a large burden of human infectious diseases. During the past 50 years, antivirals have been developed to treat many pathogenic viruses, including herpesviruses, retroviruses, hepatitis viruses, and influenza. Besides being used as treatment, antivirals have shown efficacy for preventing certain viral infections. Following the success in the HIV field, a renewed interest has emerged on the use of antivirals as prophylaxis for other viruses. The development of formulations with extended half-life has pushed further this consideration in persons at risk for a wide range of viral infections. In this way, long-acting antivirals might behave as "chemovaccines" when classical vaccines do not exist, cannot be recommended, immune responses are suboptimal, escape mutants emerge, and/or immunity wanes. Five main caveats would temper its use, namely, selection of drug resistance, drug interactions, short- and long-term side effects, potential teratogenicity in women of child-bearing age, and high cost. Herein, we discuss the prospects for long-acting antivirals as prophylaxis of human viral infections other than HIV.

The pattern of cytomegalovirus replication in post-renal transplant recipients with pre-emptive therapy strategy during the 1st year of post-transplantation.

Objectives: The prevalence and reactivating pattern of cytomegalovirus (CMV) among renal transplant recipients in Sri Lanka is scarce. The study was aimed to describe the replication patterns of CMV in post-renal transplant recipients who were on pre-emptive therapy and identify the risk factors and time period for CMV reactivating during the 1st year of transplantation and provide an insight into the selection of pre-emptive therapy in the local setting. Methods: A retrospective and cohort study was conducted, enrolling renal transplant recipients who have completed routine 1-year follow-up for pre-emptive management at the National Hospital, Kandy, from January 2016 to January 2021. CMV quantitative polymerase chain reaction results and demographic data of enrolled recipients were analyzed to investigate the CMV replication pattern and risk factors. Categorical data were analyzed using Pearson's Chi-square test, considering P < 0.05 statistically significant. Continuous variables were presented as percentages. Results: Two hundred and fifty-one renal transplant recipients' data were included in the study. Of them, 75.70% were male patients, and the mean age of the study population was 43.25 years. CMV DNAemia incidence was 56.57% during the 1st year of post-renal transplantation. Only 9.16% had developed more than 104 IU/mL or significant DNAemia. Sex and donor type were not risk factors for CMV reactivation. However, the recipient's age was significantly associated with CMV viraemia among renal transplant recipients. Conclusion: Considering the low incidence of significant viraemia among the study population, pre-emptive treatment would be the cost-effective strategy for management of the post-renal transplant recipients in local settings.

Letermovir for pre-emptive cytomegalovirus therapy after allogeneic hematopoietic cell transplantation.

BACKGROUND: Cytomegalovirus (CMV) is a common cause of morbidity after allogeneic haematopoietic cell transplantation (alloHCT). Pre-emptive therapy (PET) with valganciclovir (VGC) is associated with haematological toxicity. METHODS: We included alloHCT patients from 2018 to 2021 where letermovir (LTV) was used for CMV PET because of cytopenias. RESULTS: Ten patients were included. Six received VGC prior to LTV. VGC was commenced at median d42, given for median 40 days. LTV was commenced at median d90, given for median 54 days. At commencement of antiviral, CMV viral load was higher for VGC at 3.7 log10 IU/mL, compared to LTV at 2.9 log10 IU/mL. Viral load reduction occurred at 0.18 log10 IU/mL per week for VGC, compared to 0.17 log10 IU/mL per week for LTV. There was no clinically significant CMV viremia after stopping LTV. Cytopenias improved on LTV. CONCLUSION: LTV was effective in controlling CMV viremia when it was given at a lower starting CMV viral load and later post alloHCT than VGC. Further study is required of LTV as upfront PET following alloHCT.

Multicenter study of universal prophylaxis versus pre-emptive therapy for patients at intermediate risk (R+) for CMV following heart transplantation.

INTRODUCTION: Heart transplant (HT) recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Consensus guidelines allow for either universal prophylaxis (UP) or preemptive therapy (PET) (serial CMV testing) approaches to CMV prevention in such patients. Whether an optimal approach to mitigate CMV related risks exists in this setting remains uncertain. We therefore assessed the utility of PET as compared to UP in CMV R+ HT recipients. METHODS: Retrospective analysis of all CMV R+ HT recipients from 6 U.S. centers between 2010 and 2018 was performed. The primary outcome was the development of CMV DNAemia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary outcome was CMV-related hospitalization. Additional outcomes included incidence of acute cellular rejection (ACR) ≥ grade 2R, death, cardiac allograft vasculopathy (CAV), and leukopenia. RESULTS: Of 563 CMV R+ HT recipients, 344 (61.1%) received UP. PET was associated with increased risk for the primary (adjusted HR 3.95, 95% CI: 2.65-5.88, p < .001) and secondary (adjusted HR 3.19, 95% CI: 1.47-6.94, p = .004) outcomes, and with increased ACR ≥ grade 2R (PET 59.4% vs. UP 34.4%, p < .001). Incidence of detectable CAV was similar at 1 year (PET 8.2% vs. UP 9.5%, p = .698). UP was associated with increased incidence of leukopenia within 6 months post-HT (PET 34.7% vs. UP 43.6%, p = .036). CONCLUSION: The use of a PET CMV prophylaxis strategy in intermediate risk HT recipients associated with increased risk of CMV infection and CMV-related hospitalization, and may associate with worse post-HT graft outcomes.

Bone marrow CD34+ molecular chimerism as an early predictor of relapse after allogeneic stem cell transplantation in patients with acute myeloid leukemia.

Background: Minimal residual disease (MRD) monitoring is an important tool to optimally address post-transplant management of acute myeloid leukemia (AML) patients. Methods: We retrospectively analyzed the impact of bone marrow CD34+ molecular chimerism and WT1 on the outcome of a consecutive series of 168 AML patients submitted to allogeneic stem cell transplantation. Results: The cumulative incidence of relapse (CIR) was significantly lower in patients with donor chimerism on CD34+ cells ≥ 97.5% and WT1 < 213 copies/ABL x 10^4 both at 1st month (p=0.008 and p<0.001) and at 3rd month (p<0.001 for both). By combining chimerism and WT1 at 3rd month, 13 patients with chimerism < 97.5% or WT1 > 213 showed intermediate prognosis. 12 of these patients fell in this category because of molecular chimerism < 97.5% at a time-point in which WT1 was < 213. Conclusions: Our results confirm that lineage-specific molecular chimerism and WT1 after allo-SCT (1st and 3rd month) are useful MRD markers. When considered together at 3rd month, CD34+ molecular chimerism could represent an earlier predictor of relapse compared to WT1. Further studies are necessary to confirm this preliminary observation.

ELISPOT assays with pp65 peptides or whole HCMV antigen are reliable predictors of immune control of HCMV infection in seropositive kidney transplant recipients.

Human cytomegalovirus (HCMV) infection represents a major complication for solid organ transplant recipients. The aim of this study was to verify if the measurement of HCMV-specific T-cells could help to identify patients protected against HCMV disease cytokine flow cytometry using infected dendritic cells as stimulus (CFC-iDC, which discriminates between CD4+ and CD8+ T cells), and ELISPOT, using infected cell lysate (ELISPOT-iCL) or pp65 (ELISPOT-pp65) as stimulus, were adopted. Among the 47 kidney transplant recipients (KTR) enrolled, 29 had a self-resolving HCMV infection (Controllers) and 18 required antiviral treatment (Non-Controllers). HCMV-specific T-cell frequency at the peak of HCMV infection identified Controllers and Non-Controllers, although the diagnostic performance of CD8+ CFC-iDC (area under the curve [AUC] of the receiver-operator characteristic curve: 0.65) was lower than that of CD4+ CFC-iDC (AUC: 0.83), ELISPOT-iCL (AUC: 0.83) and ELISPOT-pp65 (AUC: 0.80). CFC-iDC detected a protective immune reconstitution significantly earlier (median time: 38 days) than ELISPOT-iCL and ELISPOT-pp65 (median time: 126 and 133 days, respectively). Time to protective immune reconstitution in Non-Controllers was significantly longer than in Controllers with the ELISPOT and the CD4+ CFC-iDC assays, but not with CD8+ CFC-iDC. The majority of patients did not require antiviral treatment after protective immune reconstitution, with the exception of five patients according to CFC-iDC assay, one patient according to ELISPOT-iCL assay and three patients according to ELISPOT-pp65 assay. Monitoring the HCMV-specific immunological reconstitution with is effective in discriminating KTR at risk of or protected from HCMV disease and the ELISPOT assays are suitable for implementation in the clinical setting.

Fifteen-Year Surveillance of LTR Receiving Pre-Emptive Therapy for CMV Infection: Prevention of CMV Disease and Incidence of CLAD.

The efficacy of pre-emptive therapy in the prevention of cytomegalovirus (CMV) disease and the potential association of CMV infection with the occurrence of chronic lung allograft dysfunction (CLAD) was evaluated in 129 lung transplant recipients receiving pre-emptive therapy based on pp65-antigenemia or CMV-DNA in the blood and in the bronchoalveolar lavage. Seventy-one (55%) patients received pre-emptive ganciclovir/valganciclovir (GCV/VGCV) for CMV infection for a median of 28 (9-191) days. Possible CMV disease occurred in six (5%) patients and was healed after the GCV/VGCV therapy. The cumulative incidence of CLAD was 38% and 54% at 5 and 10 years. Acute rejection and CMV load in the blood (but not in the lung) were independent predictors of the occurrence of CLAD. Pre-emptive therapy is highly effective in preventing CMV disease in lung recipients and does not induce a superior incidence of CLAD compared to what reported for other cohorts of patients who received an extended antiviral prophylaxis.

Cytomegalovirus Management in Solid Organ Transplant Recipients: A Pre-COVID-19 Survey From the Working Group of the European Society for Organ Transplantation.

Infections are leading causes of morbidity/mortality following solid organ transplantation (SOT) and cytomegalovirus (CMV) is among the most frequent pathogens, causing a considerable threat to SOT recipients. A survey was conducted 19 July-31 October 2019 to capture clinical practices about CMV in SOT recipients (e.g., how practices aligned with guidelines, how adequately treatments met patients' needs, and respondents' expectations for future developments). Transplant professionals completed a ∼30-minute online questionnaire: 224 responses were included, representing 160 hospitals and 197 SOT programs (41 countries; 167[83%] European programs). Findings revealed a heterogenous approach to CMV diagnosis and management and, sometimes, significant divergence from international guidelines. Valganciclovir prophylaxis (of variable duration) was administered by 201/224 (90%) respondents in D+/R- SOT and by 40% in R+ cases, with pre-emptive strategies generally reserved for R+ cases: DNA thresholds to initiate treatment ranged across 10-10,000 copies/ml. Ganciclovir-resistant CMV strains were still perceived as major challenges, and tailored treatment was one of the most important unmet needs for CMV management. These findings may help to design studies to evaluate safety and efficacy of new strategies to prevent CMV disease in SOT recipients, and target specific educational activities to harmonize CMV management in this challenging population.

Ultra-long-acting antivirals as chemical vaccines to prevent viral diseases.

For two centuries, vaccines have been successful in the fight against viruses, triggering immune protection. Indeed, the elimination of smallpox, the only infectious disease eradicated to date, was made possible through vaccination. For measles, polio and hepatitis B, vaccines are available but significant challenges exist for universal coverage. For other viruses, such as HIV and hepatitis C, vaccines have remained elusive. Recent advances in medicinal chemistry have resulted in the production of antivirals that can extend activity for months. We envision the use of ultra-long-acting antivirals for the prevention of certain viral illnesses, halting either contagions or reactivations under immunosuppression. Such 'chemical vaccines' would fill an immediate need in providing protection when classic vaccines do not exist, responses are suboptimal, escape mutants emerge or immunity wanes.

Safety of direct acting antiviral treatment for hepatitis C in oncologic setting: A clinical experience and a literature review.

With a globally estimated 58 million people affected by, chronic hepatitis C virus (HCV) infection still represents a hard challenge for scientific community. A chronic course can occur among patients with a weak innate ad adaptive response with cirrhosis and malignancies as main consequences. Oncologic patients undergoing chemotherapy represent a special immunocompromised population predisposed to HCV reactivation (HCVr) with undesirable changes in cancer treatment and outcome. Aim of the study highlight the possibility of HCVr in oncologic population eligible to chemotherapy and its threatening consequences on cancer treatment; underline the importance of HCV screening before oncologic therapy and the utility of direct aging antivirals (DAAs). A comprehensive overview of scientific literature has been made. Terms searched in PubMed were: "HCV reactivation in oncologic setting" "HCV screening", "second generation DAAs". Pharmacokinetic and Pharmacodynamics characteristics of DAAs are reported, along with drug - drug interactions among chemotherapeutic drug classes regimens and DAAs. Clinical trials conducted among oncologic adults with HCV infection eligible to both chemotherapy and DAAs were analyzed. Viral eradication with DAAs in oncologic patients affected by HCV infection is safe and helps liver recovery, allowing the initiation of cancer treatment no compromising its course and success.

Advances in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Leukemia.

In acute leukemia, advances have been made in therapeutic strategies centered on allogeneic hematopoietic stem cell transplantation (allo-SCT), three of which are presented here. The indication of allo-SCT for acute myeloid leukemia (AML) in 1st complete remission (CR1) has been debated. Genomic medicine has helped us gain a deeper understanding of this disease, some of which may serve as prognostic factors. Such genetic abnormalities could also help measure minimal residual disease (MRD) and provide additional clues to estimate the efficacy of chemotherapy. Combined with existing prognostic factors, these data can be used to construct a more accurate prognostic model, providing an optimal indication of allo-SCT for AML in CR1. Furthermore, overall treatment algorithms for high-risk AML after allo-SCT should include prophylactic and pre-emptive treatment to prevent relapse. These include immunotherapy using donor lymphocyte infusion (DLI), FLT3 inhibitors in FLT3-mutated AML, hypomethylating agents, or a combination of DLI with these agents. Clinical trials are currently ongoing to elucidate the role of these strategies, which will lead to a risk-adapted treatment for preventing relapse in high-risk AML. CD19-targeted chimeric antigen receptor (CAR) T-cell therapy induces a remarkable response in B-acute lymphoid leukemia (B-ALL); however, relapse remains a major problem. In this regard, allo-SCT as a consolidation treatment after CAR-T cell therapy for B-ALL is recommended for pediatric and adult patients. Achieving complete remission (CR) with CAR-T cell therapy is considered a promising bridging therapy to allo-SCT. Novel CAR-T treatment techniques are being developed to change their role as a pre-transplant treatment.

Development of a Method of Measuring ß-D-Glucan and Its Use in Preemptive Therapy for Invasive Fungal Infections.

Invasive fungal infections (IFIs) are serious infections that develop in conjunction with neutropenia after chemotherapy for acute leukemia or with hematopoietic stem cell transplantation. Conventionally, empirical antifungal therapy was recommended to treat IFIs for patient safety despite a lack of evidence of fungal infections. However, many studies have indicated that antifungals were not necessary for over half of patients, and several detriments of empirical therapy were noted, e.g., antifungals caused adverse reactions, an increase in drug-resistant fungi was a possibility, and medical costs soared. ß-D-glucan (BDG) is a component of clinically important fungi such as Aspergillus and Candida. The G-test was developed in Japan as a way to measure BDG in serum using a coagulation factor from the blood of the horseshoe crab. Pre-emptive antifungal therapy based upon serodiagnosis with a BDG or galactomannan assay and CT imaging has been introduced. With pre-emptive antifungal therapy, the prognosis is equivalent to that with empirical therapy, and the dose of the antifungal has been successfully reduced. Measurement of BDG has been adopted widely as a method of diagnosing IFIs and is listed in the key guidelines for fungal infections and febrile neutropenia.

A biomarker-guided, prospective, phase 2 trial of pre-emptive graft-versus-host disease therapy using anti-thymocyte globulin.

BACKGROUND AIMS: Intensified immunosuppressive prophylaxis for graft-versus-host disease (GVHD) may be toxic and therefore warranted only in patients at high risk of developing GVHD. In patients who underwent allogeneic hematopoietic cell transplant at the authors' center, high serum soluble IL-2 receptor alpha (sIL-2Rα) and low IL-15 levels on day 7 post-transplant were found to predict a high risk of developing clinically significant GVHD (sGVHD), defined as grade 2-4 acute GVHD or moderate to severe chronic GVHD. METHODS: This was a prospective, phase 2 trial in which high-risk patients (serum sIL-2Rα >4500 ng/L or IL-15 <31 ng/L) received rabbit anti-thymocyte globulin (ATG) 3 mg/kg on day 8 post-transplant. Controls consisted of patients who had their sIL-2Rα/IL-15 levels measured but did not participate in the trial. A total of 68 trial patients and 143 controls were accrued to this study. The primary endpoint was incidence of sGVHD. RESULTS: There was a reduction in sGVHD in high-risk trial patients (received day 8 ATG) compared with high-risk controls (did not receive day 8 ATG) (sub-hazard ratio [SHR] = 0.48, P < 0.05). There was no significant difference between the groups in overall survival or relapse; however, there was a greater incidence of non-GVHD-associated non-relapse mortality in high-risk trial patients (SHR = 3.73, P < 0.05), mostly related to infections. This may be due in part to the biomarkers ineffectively stratifying GVHD risk. CONCLUSIONS: Pre-emptive ATG therapy is both feasible and effective at reducing sGVHD without increasing relapse. Further mitigation strategies are needed to reduce the risk of infection associated with intensified GVHD prophylaxis. This study was registered at ClinicalTrials.gov (NCT01994824).

Peripheral blood molecular measurable residual disease is sufficient to identify patients with acute myeloid leukaemia with imminent clinical relapse.

Longitudinal molecular measurable residual disease (MRD) sampling after completion of therapy serves as a refined tool for identification of imminent relapse of acute myeloid leukaemia (AML) among patients in long-term haematological complete remission. Tracking of increasing quantitative polymerase chain reaction MRD before cytomorphological reappearance of blasts may instigate individual management decisions and has paved the way for development of pre-emptive treatment strategies to substantially delay or perhaps even revert leukaemic regrowth. Traditionally, MRD monitoring is performed using repeated bone marrow aspirations, albeit the current European LeukemiaNet MRD recommendations acknowledge the use of peripheral blood as an alternative source for MRD assessment. Persistent MRD positivity in the bone marrow despite continuous morphological remission is frequent in both core binding factor leukaemias and nucleophosmin 1-mutated AML. In contrast, monthly assessment of MRD in peripheral blood superiorly separates patients with imminent haematological relapse from long-term remitters and may allow pre-emptive therapy of AML relapse.

Cytomegalovirus Prophylaxis versus Pre-emptive Strategy: Different CD4+ and CD8+ T Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation.

Reconstitution of T cells after transplantation is a determinant of the long-term success of the procedure, and the correlation with T cell recovery and cytomegalovirus reactivation and disease is well known. We evaluated 110 patients who underwent transplantation: 55 received pre-emptive antiviral treatment, and in the other 55 patients, prophylaxis with letermovir was employed. A progressive statistically significant difference in T cell reconstitution between the 2 groups was observed, starting from day +60 with faster recovery in the pre-emptive group. Moreover, a higher incidence of cytomegalovirus reactivation was observed in prophylactic group after discontinuation of letermovir, and subsequent antiviral treatment has been necessary. Our findings confirm, as previously reported, that cytomegalovirus reactivation is a potent stimulator of T cell function.

Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.

T cell mixed chimerism (MC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning for hematological malignancies may indicate engraftment failure or disease relapse. Immune modulation, such as donor lymphocyte infusion (DLI) or the rapid tapering-off or stopping of immunosuppressive treatment, can reverse MC to full donor chimerism (FDC). However, the development or aggravation of graft-versus-host disease (GvHD) and the related mortality remain major concerns with immune modulation. In this prospective, single-arm study (NCT03663751), we tested the efficacy and safety of low-dose decitabine (LD-DAC, 5 mg/m2 daily for 5 days and repeated every 6-8 weeks) without immune modulation in the treatment of patients with MC to prevent MC-associated relapse and/or graft failure. A total of 14 patients were enrolled. All the patients received myeloablative conditioning regimens, and MC was documented from day +30 to day +180 after allo-HSCT with a donor chimerism level ranging from 59 to 97% without detectable measurable residual disease (MRD). Eleven patients (78.6%) responded favorably to treatment, showing increased levels of donor chimerism (≥95%), while nine achieved FDC. All of these patients maintained their responses for a median of 11 months (3-22). The three patients who failed to respond favorably eventually either relapsed or experienced graft failure. All three were alive and in remission at the last follow-up after the second allo-HSCT. LD-DAC monotherapy was well tolerated and exerted limited hematological and nonhematological toxicities. New-onset GvHD symptoms were observed only in two patients. Overall, the estimated 2-year overall survival (OS) and event-free survival (EFS) after allo-HSCT were 90.9 ± 8.7% and 67.0 ± 13.7%, respectively. In conclusion, LD-DAC alone could reverse MC in most patients after allo-HSCT with myeloablative conditioning, while those who achieved FDC enjoyed long-term EFS without major complications. Further prospective studies with larger sample sizes are warranted to confirm the benefits of LD-DAC.

Cytomegalovirus (CMV) management in allogeneic hematopoietic cell transplantation: Pre-transplant predictors of survival, reactivation, and spontaneous clearance.

BACKGROUND: Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplant (alloHCT). METHOD: We analyzed 159 alloHCT recipients with 4409 quantitative CMV viral loads to determine pre-transplant predictors of CMV reactivation, clinically significant CMV infection (cs-CMVi, defined as CMV viral load >1000 IU/mL), CMV disease, kinetics of spontaneous clearance of CMV, and survival using a standardized pre-emptive therapy approach to identify at-risk groups to target prevention strategies. RESULTS: Cs-CMVi was most common in D-/R+ unrelated donor transplants (URD). Spontaneous CMV clearance occurred in 26% of patients who reached a viral load of 56-137 IU/mL, 6% at 138-250 IU/mL and in one patient >250 IU/mL. Median time between the first CMV reactivation (>56 IU/mL) and a viral load >250 IU/mL was 13 days, whereas the time from the first viral load >250 IU/mL to reach a vial load >1000 IU/mL was 4 days. Cs-CMVi was associated with a significant increase in non-relapse mortality (NRM) on multivariate analysis. CONCLUSIONS: Overall, this study indicates that D-/R+ URD recipients are at high-risk for cs-CMVi- and CMV-related mortality, and are potential candidates for targeted CMV prophylaxis. Spontaneous clearance of CMV beyond a viral load of 250 IU/mL is uncommon, suggesting that this could be used as an appropriate threshold to initiate pre-emptive therapy.