Cytomegalovirus (CMV) reactivation remains one of the most common and life-threatening infectious complications following allogeneic hematopoietic stem cell transplantation, despite novel diagnostic technologies, several novel prophylactic agents, and further improvements in preemptive therapy and treatment of established CMV disease. Treatment decisions for CMV reactivation are becoming increasingly difficult and must take into account whether the patient has received antiviral prophylaxis, the patient’s individual risk profile for CMV disease, CMV-specific T-cell reconstitution, CMV viral load, and the potential drug resistance detected at the time of initiation of antiviral therapy. Thus, we increasingly use personalized treatment strategies for the recipient of an allograft with CMV reactivation based on prior use of anti-CMV prophylaxis, viral load, the assessment of CMV-specific T-cell immunity, and the molecular assessment of resistance to antiviral drugs.

Cytomegalovirus (CMV) is a latent virus that belongs to the family of herpesviruses and is one of the common viral pathogens that can reactivate after hematopoietic stem cell transplant (HCT) during the time of T-cell deficiency or dysfunction. It reactivates in ∼60% to 70% of CMV-seropositive patients, and primary infection affects 20% to 30% of CMV-seronegative recipients transplanted from CMV-seropositive donors. Uncontrolled CMV reactivations can lead to a life-threatening multiorgan CMV disease, such as pneumonia, gastroenteritis, or retinitis.1-5  CMV-seropositive patients undergoing allogeneic HCT (allo-HCT) have an overall higher mortality posttransplant compared with CMV-seronegative patients, especially when undergoing an allograft from an unrelated or mismatched donor.1-9  The risk of prolonged and recurrent reactivation, as well as mortality, may be even higher if the donor is CMV seronegative.8,10-12 

A correlation between T-cell deficiency and dysfunction, especially CD4 deficiency and CMV reactivation, has been seen in patients with HIV infection and following solid organ transplantation.13  In HCT patients, a low lymphocyte count and CD4+ T-cell count <50 per microliter at 3 months posttransplant are risk factors for the development of late CMV disease.14  Hakki et al15  also showed that low CD4 T-cell counts (<100 per microliter) and low CD8 T-cell counts (<50 per microliter) at this time point are associated with poor CMV-specific immunity.

Several new developments, such as novel sensitive and rapid diagnostic assays, definition of risk factors, and highly active anti-CMV agents for preemptive therapy, have contributed to reduce the incidence of CMV disease and CMV-related complications posttransplantation8,14,16-25 ; novel agents, such as maribavir, may further expand the armamentarium that is available for preemptive therapy.26 

However, CMV reactivation remains one of the most common and life-threatening infectious complications following allo-HCT, and reactivation in the era of routine use of prophylaxis poses novel complexities.5,7,19 

In the past 5 years, there have been 2900 publications on the treatment of CMV infection and 70 publications on the management of CMV reactivation following allo-HCT. These numbers pose a challenge to even the most efficient stem cell transplant physician who needs to critically digest the available information, as well as highlights the continued complexities in the management of CMV reactivation following allo-HCT.5,24,27,28 

The development of highly effective antiviral agents against CMV and the availability of novel and sensitive assays for the detection and quantification of the virus have resulted in the emergence of 2 main strategies to prevent CMV-related outcomes among allograft recipients: antiviral prophylaxis and preemptive therapy based on sensitive detection techniques.

Preemptive antiviral treatment is triggered by early detection of CMV reactivation, before clinical manifestations of CMV disease occur, and it has reduced the incidence of CMV disease.14,17  Preemptive antiviral therapy is based on surveillance by quantitative polymerase chain reaction (PCR) assays, which allows the initiation of preemptive therapy above a certain detection threshold,18,29  depending on the risk of CMV disease in a specific patient.19 

The introduction of the international standard has improved the interlaboratory variability of PCR assays,30  but significant differences remain that continue to pose challenges in comparing results between laboratories.31  With this strategy, the risk of early-onset CMV disease (before 100 days posttransplant) is <3%, but patients continue to be at risk for late-onset CMV disease and CMV-related complications,1,21,25,32-36  even in the current era,12  and resistant/refractory CMV infection remains a problem in a significant proportion of patients.5 

Anti-CMV prophylaxis

Several studies12,37-41  demonstrated that CMV reactivation posttransplant was associated with an increased risk for overall and all-cause mortality, independent of the use of preemptive therapy. Importantly, the risk increased with increasing viral load.42  Therefore, prevention of viral replication, rather than surveillance-based preemptive therapy, might be beneficial for a seropositive patient following allo-HCT.12,43,44  In the 1980s and 1990s, anti-CMV prophylaxis with high-dose acyclovir or valacyclovir was studied and shown to have some effect on CMV reactivation45,46 ; however, it is not widely used because its efficacy in preventing CMV disease is limited.47 

For decades, highly effective agents to control CMV infection have been limited to drugs with significant toxicity (ie, ganciclovir, foscarnet, and cidofovir). Ganciclovir is associated with hematotoxicity and thus, an increased incidence of secondary bacterial and fungal infections,48-52  IV foscarnet is associated with electrolyte disturbances and severe nephrotoxicity,53-56  and cidofovir is associated with nephrotoxicity, hematotoxicity, and ocular toxicity.45  Ganciclovir is the only drug that has been evaluated as prophylaxis in randomized trials14,49,57 ; however, it did not result in improved overall survival because of severe neutropenia and secondary bacterial and fungal infections.58,59 

The results from relatively small uncontrolled trials provide support for prophylaxis with valganciclovir or foscarnet only in very high-risk patients.60,61 

Valganciclovir prophylaxis was not shown to provide improved protection from CMV disease compared with PCR-guided preemptive therapy for the prevention of late-onset CMV disease.62  Thus, until recently, most centers have not used antiviral prophylaxis; instead, they have relied on preemptive therapy as the management strategy.47  This has changed recently with the introduction of letermovir.

Letermovir prophylaxis

Letermovir inhibits the human CMV (HCMV) terminase complex, which is a novel mechanism of action. It was studied in 2 randomized placebo-controlled studies for CMV prophylaxis, including in 686 patients following allo-HCT.21,22  The introduction of letermovir is an important advance because it is not myelotoxic or nephrotoxic, and does not require dose adjustments based on renal and mild to moderate hepatic dysfunction.63  Furthermore, letermovir is available in oral and IV formulations, allowing early administration posttransplant and during phases when patients are acutely ill or unable to take oral medication. Dose adjustments are required in patients receiving graft-versus-host disease (GvHD) prophylaxis with cyclosporine.63,64 

In a phase 3 trial, prophylaxis with letermovir significantly reduced the rate of clinically significant CMV infection defined as development of CMV disease or the need for administration of preemptive anti-CMV therapy. In addition, all-cause mortality was reduced by week 24 following allo-HCT; however, statistical significance was lost by week 48. The reduction in clinically significant CMV infection and all-cause mortality was especially pronounced in patients at high risk for CMV reactivation (eg, patients undergoing an HCT from a haploidentical or mismatched donor or those receiving anti-thymocyte globulin [ATG] for GvHD prophylaxis).21,22  In a post hoc analysis, it was shown that letermovir also reduced all-cause mortality at week 48 after allo-HCT in patients who developed clinically significant CMV infection.3  Since its approval, there has been increased use of letermovir prophylaxis in allograft recipients posttransplant, especially in patients at high risk for CMV reactivation and disease. The results of the phase 3 trial, as well as clinical postlicensing experience, indicate that the use of letermovir delays viral reactivation to the time after discontinuation of prophylaxis in patients with continued immunosuppression. The impact of this late reactivation, how patients at risk are best identified, and how it should be best managed are being studied.

Unfortunately, 2 other novel antiviral agents (maribavir, brincidofovir) and a DNA vaccine (ASP113) failed to improve the CMV-related outcomes in phase 3 prophylaxis trials,25,32,65  although phase 2 trials of the DNA vaccine,66  maribavir,67  and brincidofovir68  had demonstrated significantly fewer CMV events and lower antiviral activity. Early trials of a CMV peptide and modified vaccinia Ankara vaccines showed promising results in initial randomized trials69,70  and are being evaluated further.

A 37-year-old woman was diagnosed with a high-risk multiple myeloma [t(t4;14) and 17p del]; following 4 cycles of induction therapy and tandem high-dose melphalan therapy with autologous HCT, she exhibited progressive myeloma at 9 months posttransplant. A male CMV-seronegative donor with a 9/10 HLA match was identified for this CMV-seropositive patient. Following reinduction and conditioning therapy with fludarabine/treosulfan plus ATG and a peripheral blood stem cell transplant, she received cyclosporine and methotrexate for GvHD prophylaxis. Antiviral prophylaxis in this high-risk patient included acyclovir prophylaxis for herpes simplex virus (HSV)/varicella zoster virus (VZV) infection and letermovir (240 mg/d; reduced dose because the patient received cyclosporine) beginning on day +9. She was monitored weekly for CMV reactivation but did not experience a documented CMV infection. The patient achieved a partial response for her multiple myeloma, and donor lymphocyte infusion plus lenalidomide was started. The patient stopped letermovir prophylaxis on day +80 when anti-myeloma therapy was started. The ongoing viral screening revealed CMV reactivation on day +94 with a viral load of 18 900 IU/mL. Because letermovir prophylaxis has not been shown to induce cross-resistance to other anti-CMV agents in a patient with full hematopoietic reconstitution, we started preemptive therapy with valganciclovir in an outpatient setting. After 4 weeks of antiviral therapy, the patient finally cleared the CMV infection (Figure 1).

Figure 1.

Case 1: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 37-year-old woman with high-risk multiple myeloma.

Figure 1.

Case 1: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 37-year-old woman with high-risk multiple myeloma.

Close modal

An allograft recipient at high-risk for CMV disease benefits the most from antiviral prophylaxis. In the phase 3 trial of CMV prophylaxis with letermovir,22  very few patients developed CMV reactivation with quantifiable viral load; among those was 1 patient with a mutation (UL56 V236M) that confers letermovir resistance. Despite the fact that only a few breakthrough infections during prophylaxis with letermovir were reported, we monitor patients on letermovir prophylaxis for CMV reactivation. However, it should be recognized that, probably as a result of the mechanism of action of letermovir, low-grade DNAemia does not indicate letermovir failure. Rapid breakthrough infection was reported in some patients who received letermovir for secondary prophylaxis or when used for treatment of CMV reactivation with high viral loads.71  Mutations in codons 231 to 369 of the UL56 gene have been described in these patients with letermovir-resistant CMV infection.72  All patients who developed CMV reactivation during or following letermovir prophylaxis responded to preemptive antiviral therapy and did not demonstrate induction of cross-resistance to other antiviral drugs following letermovir prophylaxis.

A 62-year-old man with acute lymphoblastic leukemia in remission received a 10/10 HLA-matched T-cell–replete peripheral blood stem cell transplant following reduced-intensity conditioning with melphalan, fludarabine, and total-body irradiation (300 cGy). The patient was CMV seropositive, and the donor was seronegative. He received low-dose acyclovir for prevention of HSV and VZV. Neutrophil engraftment occurred at day 14, and oral letermovir was started on day 28. Weekly PCR surveillance was performed. On day 34 after HCT, the patient showed a CMV plasma viral load of 240 IU/mL. Because the patient did not have acute GvHD, and thus, did not receive systemic steroids, letermovir prophylaxis was continued. The viral load was 70 IU/mL on day 38, and subsequent weekly viral load tests were negative until day 100, when letermovir was discontinued. Subsequent weekly PCR surveillance showed several low-level viral load results ranging from 42 to 88 IU/mL between days 112 and 140, which were not treated (Figure 2).

Figure 2.

Case 2: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 62-year-old man with ALL in remission.

Figure 2.

Case 2: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 62-year-old man with ALL in remission.

Close modal

Subclinical reactivation on antiviral prophylaxis is not uncommon. Indeed, several studies performed with ganciclovir and valganciclovir prophylaxis showed subclinical reactivation rates of 20% to 40%.15  Most episodes resolved without changing the antiviral prophylaxis regimen. Similar results have recently been observed with letermovir prophylaxis. We start letermovir in low-risk patients after neutrophil engraftment and when they can take oral medication, but no later than day 28. We continue weekly PCR surveillance in letermovir recipients and treat breakthrough infections at levels similar to those used in the phase 3 randomized controlled trial22  (Figure 3). The patient illustrates that low-level reactivation can resolve on continued letermovir prophylaxis without further intervention in a low-risk situation. We would have treated a viral load of 220 IU/mL if the patient had received corticosteroids at a dose ≥1 mg/kg or met other high-risk criteria (Figure 3). Earlier data from the ganciclovir era showed that subclinical reactivation that occurred during prophylaxis improved CMV-specific T-cell immune reconstitution.15  Whether such an effect also occurs in recipients of letermovir prophylaxis is being studied. Our patients had a few episodes of low-level reactivation after discontinuation of letermovir at day 100, which did not require preemptive treatment.

Figure 3.

Viral load thresholds for starting preemptive therapy. Adapted from CMV Prevention: Prophylaxis, Surveillance, and Preemptive Therapy in Hematopoietic Stem Cell Transplant Recipients Guidelines.111 

Figure 3.

Viral load thresholds for starting preemptive therapy. Adapted from CMV Prevention: Prophylaxis, Surveillance, and Preemptive Therapy in Hematopoietic Stem Cell Transplant Recipients Guidelines.111 

Close modal

Because antiviral prophylaxis, especially with letermovir, is not yet available at all centers performing allo-HCT and is often not used in low-risk patients, we discuss the management of patients after allo-HCT who received prophylaxis with valganciclovir or those who did not receive antiviral prophylaxis.

A 52-year-old woman HCMV-seropositive patient with a Philadelphia-positive B-cell acute lymphoblastic leukemia entered a complete remission following induction therapy and received a 9/10 matched cord blood transplant. Because this patient is at extremely high risk for CMV disease, she received oral valganciclovir prophylaxis beginning on day 24 posttransplant (starting with 2 × 900 mg/d, which was reduced to 2 × 450 mg/d because of poor graft function). This strategy had been shown to be effective in previous studies in high-risk patients.14,60  On day 74, the patient developed a CMV reactivation with a viral load of 13 650 IU/mL. The patient was switched to IV foscarnet (2 × 60 mg/kg of body weight), which was stopped after 14 days because of impaired renal function. Resistance testing revealed a C592G UL97 mutation not associated with high-level resistance to ganciclovir; thus, IV ganciclovir was restarted at full dose, and a CMV-specific T-cell product from a 9/10 HLA-matched CMV-seropositive third-party donor was generated using the cytokine catch assay and transfused to the patient. The patient had cleared the viral infection 14 days later, ganciclovir therapy was stopped, and the weekly blood samples obtained from the patient remained negative for CMV in all subsequent analyses (Figure 4).

Figure 4.

Case 3: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 52-year-old woman with Philadelphia-positive ALL in CR.

Figure 4.

Case 3: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 52-year-old woman with Philadelphia-positive ALL in CR.

Close modal

When CMV reactivation with a high viral load is detected following long-term antiviral prophylaxis or preemptive therapy with valganciclovir (>6 weeks of antiviral drug exposure) in a patient who carries a high risk for CMV disease, a drug-resistant CMV infection must be suspected.5,73-77  Additionally, the reduction in the dose of valganciclovir might have further increased the risk of ganciclovir resistance. The bioavailability of valganciclovir is variable.78 

Therefore, therapeutic drug monitoring is used routinely in Stockholm to avoid underdosing, as well as overdosing.79  In addition, dose reductions in (val)ganciclovir because of hematotoxicity should be avoided; the full dose of the drug should be maintained by adding growth factor support.27,80,81  Because resistance testing revealed a C592G UL97 mutation, which is associated only with low-level resistance, the patient was retreated with high-dose IV ganciclovir when the renal function deteriorated during foscarnet therapy. Because the patient had impaired renal function, which would potentially limit the use of all available antiviral agents at that time, as well as had an infection with already low-level ganciclovir resistance, we decided to restart therapy with IV ganciclovir and to add a CMV-specific T-cell product from a CMV-seropositive third-party donor (the stem cell donor was CMV seronegative). Transfer of CMV-specific T-cell products containing CMV-specific CD4+ and CD8+ T cells selected from CMV-seropositive donors by cytokine catch assay has been demonstrated to be safe and successful in controlling drug-resistant CMV infection in a small number of CMV-seropositive recipients of a cord blood transplant,82-86  whereas infusions of CMV-specific T-cell products from third-party donors containing highly purified CD8+ CMV-specific T cells selected by streptamer technology failed to clear drug-resistant CMV infection.87  An alternative approach in this patient (that would have been done in Seattle) is to use high-dose ganciclovir (7.5-10 mg/kg twice daily, adjusted for renal function) with granulocyte colony-stimulating factor (G-CSF) support, given the low-level resistance mutation.24,76,77  Other successful alternative pharmacological therapies for allograft recipients with resistant and refractory CMV infection include artesunate and leflunomide, which were reported in small patient cohorts.8,24,88-92  The most interesting new pharmacological treatment for refractory CMV infection is maribavir; in doses ≥400 mg twice daily, it was shown to be active against refractory and resistant CMV infection in a large randomized double-blind phase 2 trial in patients following hematopoietic or solid organ transplantation.93 

The role of letermovir in routine clinical use will have to be established. It has not yet been introduced in all countries; because of cost issues, some centers have decided only to give it to selected primarily high-risk patients. No data exist regarding letermovir use in children, and the optimal duration of prophylaxis also needs to be properly studied. Therefore, we will also discuss the management of patients with CMV reactivation not receiving antiviral prophylaxis.

A 55-year-old HCMV-seropositive man was diagnosed with acute myeloid leukemia and achieved a complete response following 2 cycles of induction therapy. An HLA-identical HCMV-seropositive brother was identified as a donor, and an allo-HCT was performed following reduced-intensity conditioning. The patient received acyclovir prophylaxis for HSV/VZV infection. No anti-CMV prophylaxis was introduced. On day +20 the patient developed grade 1 skin GvHD, which resolved without any treatment. The patient underwent weekly monitoring using quantitative real-time PCR. In addition, CMV-specific T-cell numbers were monitored every 2 weeks, using a home-made streptamer assay, as part of a clinical study. At day 90 posttransplant, a CMV load of 1280 IU/mL was noted, and immune monitoring at that time revealed the presence of CD8+ CMV-specific T cells in the peripheral blood, as determined by streptamer assay.

With the rather low viral load in a patient at low risk for CMV disease (CMV-seropositive HLA-identical sibling donor, no severe GvHD, no ATG used for conditioning) with a documented CMV-specific T-cell response, we decided not to use preemptive treatment; instead, we continued to monitor viral load and CMV-specific T-cell responses. The next 2 analyses showed a decrease in the viral load to 840 IU/mL and then to 472.50 IU/mL and a persisting CMV-specific T-cell response. Without any anti-CMV therapy, the patient finally cleared the CMV infection, and the continued monitoring (routinely performed at the Würzburg Center until day 180 in a patient with a CMV reactivation early posttransplant) did not reveal any further CMV reactivations (Figure 5).

Figure 5.

Case 4: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 55-year-old man with AML in CR.

Figure 5.

Case 4: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 55-year-old man with AML in CR.

Close modal

Monitoring of CD8+ and/or CD4+ CMV-specific T cells can be performed using different techniques (eg, streptamers, pentamers, and other MHC multimers) or CMV-specific (more recently CMV-specific peptide) T-cell responses (cytotoxic activity against CMV-infected targets, T-cell proliferation, cytokine production [eg, by enzyme-linked immunospot assay or flow cytometry]).15,94-96  Commercial tests are now also available to monitor CMV-specific and even polyfunctional (interferon-γ, tumor necrosis factor-α) CMV-specific T cells following allo-HCT.97-105  If a patient has a documented CMV-specific T-cell response at the time of detection of virus reactivation with a low or medium viral load, we continue monitoring the viral load and delay antiviral chemotherapy until the viral load increases or the CMV-specific T-cell response diminishes or completely disappears.5,106 

In patients at low risk for CMV disease (R+/D+, donor HLA-identical sibling, no severe GvHD) with a CMV reactivation and a low to medium viral load, we continue monitoring for an increase in viral load but do not start preemptive therapy.107-109  In Würzburg, we believe that monitoring for CMV-specific T-cell responses can further inform treatment decisions95,105 ; thus, we believe the documented CMV-specific CD8+ T-cell response further reduced the risk for the development of CMV disease in this patient. This strategy has not been tested in a randomized trial, and we have to caution that, in rare cases at the Fred Hutchinson Cancer Research Center, CMV disease has been seen in patients with a documented CMV-directed T-cell response, indicating that not all of the T-cell responses detected are protective.

A 28-year-old man was diagnosed with high-risk acute myeloid leukemia. Following 2 cycles of induction therapy he entered a complete remission and, following myeloablative conditioning, received a transplant from a fully matched unrelated donor. GvHD prophylaxis included ATG and cyclosporine/methotrexate. The patient was CMV seropositive and received a transplant from a CMV-seropositive donor. Acyclovir prophylaxis for HSV/VZV infection was administered. On day +26, the patient developed grade 3 acute GvHD involving the skin and the intestinal tract. The patient received high-dose corticosteroid therapy (methylprednisolone, 2 mg/kg of body weight) and additional ruxolitinib for insufficient control of intestinal GvHD following tapering of the steroids.

On day 48, viral load monitoring showed a high CMV viral load (35 700 IU/mL) and, because of poor marrow function, the patient received foscarnet (2 × 60 mg/kg of body weight). Following 2 weeks of therapy the viral load was reduced to 12 600 IU/mL, and foscarnet therapy was continued. Because of deterioration of renal function, ganciclovir (2 × 5 mg/kg) was started, with 1 week of G-CSF for ongoing poor marrow function. With further decreasing viral load and improvement of intestinal GvHD, the patient was discharged and therapy was switched to oral valganciclovir until CMV infection was cleared. In Stockholm, the treatment would have been guided by therapeutic drug monitoring of ganciclovir, and the dose would have been adjusted accordingly. Monitoring for CMV infection was continued weekly until day +180. Another episode of CMV reactivation required treatment with valganciclovir for another 14 days until clearance of the virus infection (Figure 6).

Figure 6.

Case 5: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 28-year-old man with high-risk AML in CR.

Figure 6.

Case 5: engraftment, viral reactivation, antiviral prophylaxis, treatment, and other relevant clinical data of a 28-year-old man with high-risk AML in CR.

Close modal

Although no formal comparative study between IV ganciclovir and valganciclovir has been performed, many centers routinely use valganciclovir as first-line preemptive therapy. For patients not able to take an oral drug, IV ganciclovir or foscarnet is commonly used. A clinical trial performed by the Infectious Disease Working Party of the European Blood and Marrow Transplantation Society56  showed similar efficacy, but different toxicities, for preemptive therapy using IV ganciclovir or foscarnet. Thus, in patients with poor marrow function, we prefer preemptive therapy with foscarnet, whereas in patients with deterioration of renal function we would switch to IV ganciclovir. If both neutropenia and renal insufficiency are present, one can consider ganciclovir or valganciclovir with preemptive G-CSF support.80,81  We tend to administer preemptive therapy for CMV infection until viral clearance for ≥14 days14,44,110  in patients failing both ganciclovir and foscarnet because of poor efficacy or unacceptable toxicity. Cidofovir is 1 possible option.

The increased use of anti-CMV prophylaxis, quantitative PCR assays, assays to define the CMV-specific T-cell response posttransplant, and novel techniques to detect resistance to antiviral drugs, as well as a better understanding of risk factors for CMV disease, make the identification of the optimal therapy for a patient with CMV reactivation following allo-HCT challenging. Therefore, we increasingly use personalized treatment strategies when we approach allograft recipients with a documented CMV reactivation.

We consider the following factors when making decisions about how to treat CMV reactivation in a patient who underwent allo-HCT:

  1. Did the patient receive anti-CMV prophylaxis when CMV reactivation was detected or prior to the reactivation? If so, which agent and for how long?

  2. Did high-level CMV reactivation occur during/following antiviral prophylaxis? If so, screening for antiviral resistance might be indicated.

  3. Is the patient at high risk for CMV disease (cord blood transplant, haploidentical HCT, ATG for seroprophylaxis, graft from an HLA-mismatched unrelated donor)?

  4. CMV load/kinetics

  5. CMV-specific T-cell reconstitution

  6. Comorbidities (eg, foscarnet for patients with poor marrow function or ganciclovir for patients with impaired renal function)

The treatment strategies used in our patients (Table 1) are based on these considerations; however, not all of them have been confirmed in randomized controlled trials. For instance, although CMV-specific T-cell immunity correlates with protection from high-level reactivation in observational studies, our strategy to use it to withhold preemptive therapy (Case 3) should be systematically evaluated, optimally in a randomized trial. Also, the viral load thresholds that we used to start preemptive therapy while on letermovir prophylaxis (Figure 3) have been developed by synthesizing the data on subclinical reactivation in recipients of antiviral prophylaxis with letermovir and ganciclovir/valganciclovir,20,74  but they may need to be adjusted as more experience with letermovir emerges.

The authors thank Rachel Blazevic for assistance with the figures.

This work was supported by Deutsche Forschungsgemeinschaft with the research group FOR 2830, Advanced Concepts in Cellular Immune Control of Cytomegalovirus (project P09; H.E.), and the Collaborative Research Centre (Transregio CRC 221, A03). M.B. was supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (K24HL093294-02) and the NIH National Institute of Allergy and Infectious Diseases (AI-2014028).

Contribution: All authors submitted case presentations and discussions, and were involved in the writing of the manuscript.

Conflict-of-interest disclosure: P.L. reports personal fees from AiCuris and grants from Astellas, Oxford Immunotech, Takeda (Shire), and MSD outside of the submitted work. M.B. reports grants and personal fees from Merck, Takeda/Shire, Gilead Sciences, and VirBio; grants from Astellas and Chimerix; personal fees, including options to acquire equity from Helocyte and EvrysBio; and personal fees from GlaxoSmithKline, Moderna, and AlloVir, outside of the submitted work. H.E. declares no competing financial interests.

Correspondence: Hermann Einsele, Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacher Str 6, 97080 Würzburg, Germany; e-mail: [email protected].

1.
Zaia
JA
,
Gallez-Hawkins
GM
,
Tegtmeier
BR
, et al
.
Late cytomegalovirus disease in marrow transplantation is predicted by virus load in plasma
.
J Infect Dis
.
1997
;
176
(
3
):
782
-
785
.
2.
Teira
P
,
Battiwalla
M
,
Ramanathan
M
, et al
.
Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis
.
Blood
.
2016
;
127
(
20
):
2427
-
2438
.
3.
Ljungman
P
,
Schmitt
M
,
Marty
FM
, et al
.
A mortality analysis of letermovir prophylaxis for cytomegalovirus (CMV) in CMV-seropositive recipients of allogeneic hematopoietic-cell transplantation [published online ahead of print 8 Jun 2019]
.
Clin Infect Dis
.
doi:10.1093/cid/ciz490
.
4.
Fuji
S
,
Einsele
H
,
Kapp
M
.
Cytomegalovirus disease in hematopoietic stem cell transplant patients: current and future therapeutic options
.
Curr Opin Infect Dis
.
2017
;
30
(
4
):
372
-
376
.
5.
Chemaly
RF
,
Chou
S
,
Einsele
H
, et al;
Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum
.
Definitions of resistant and refractory cytomegalovirus infection and disease in transplant recipients for use in clinical trials
.
Clin Infect Dis
.
2019
;
68
(
8
):
1420
-
1426
.
6.
Zhou
W
,
Longmate
J
,
Lacey
SF
, et al
.
Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients
.
Blood
.
2009
;
113
(
25
):
6465
-
6476
.
7.
Einsele
H
,
Mielke
S
,
Grigoleit
GU
.
Diagnosis and treatment of cytomegalovirus 2013
.
Curr Opin Hematol
.
2014
;
21
(
6
):
470
-
475
.
8.
Boeckh
M
,
Murphy
WJ
,
Peggs
KS
.
Recent advances in cytomegalovirus: an update on pharmacologic and cellular therapies
.
Biol Blood Marrow Transplant
.
2015
;
21
(
1
):
24
-
29
.
9.
Schmidt-Hieber
M
,
Tridello
G
,
Ljungman
P
, et al
.
The prognostic impact of the cytomegalovirus serostatus in patients with chronic hematological malignancies after allogeneic hematopoietic stem cell transplantation: a report from the Infectious Diseases Working Party of EBMT
.
Ann Hematol
.
2019
;
98
(
7
):
1755
-
1763
.
10.
Boeckh
M
,
Nichols
WG
.
The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy
.
Blood
.
2004
;
103
(
6
):
2003
-
2008
.
11.
Ariza-Heredia
EJ
,
Nesher
L
,
Chemaly
RF
.
Cytomegalovirus diseases after hematopoietic stem cell transplantation: a mini-review
.
Cancer Lett
.
2014
;
342
(
1
):
1
-
8
.
12.
Green
ML
,
Leisenring
W
,
Xie
H
, et al
.
Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study
.
Lancet Haematol
.
2016
;
3
(
3
):
e119
-
e127
.
13.
Sester
M
,
Sester
U
,
Gärtner
B
, et al
.
Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation
.
Transplantation
.
2001
;
71
(
9
):
1287
-
1294
.
14.
Boeckh
M
,
Gooley
TA
,
Myerson
D
,
Cunningham
T
,
Schoch
G
,
Bowden
RA
.
Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study
.
Blood
.
1996
;
88
(
10
):
4063
-
4071
.
15.
Hakki
M
,
Riddell
SR
,
Storek
J
, et al
.
Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation
.
Blood
.
2003
;
102
(
8
):
3060
-
3067
.
16.
Einsele
H
,
Ehninger
G
,
Steidle
M
, et al
.
Polymerase chain reaction to evaluate antiviral therapy for cytomegalovirus disease
.
Lancet
.
1991
;
338
(
8776
):
1170
-
1172
.
17.
Einsele
H
,
Ehninger
G
,
Hebart
H
, et al
.
Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation
.
Blood
.
1995
;
86
(
7
):
2815
-
2820
.
18.
Marty
FM
,
Rubin
RH
.
The prevention of infection post-transplant: the role of prophylaxis, preemptive and empiric therapy
.
Transpl Int
.
2006
;
19
(
1
):
2
-
11
.
19.
Boeckh
M
,
Ljungman
P
.
How we treat cytomegalovirus in hematopoietic cell transplant recipients
.
Blood
.
2009
;
113
(
23
):
5711
-
5719
.
20.
Marty
FM
,
Boeckh
M
.
Maribavir and human cytomegalovirus-what happened in the clinical trials and why might the drug have failed?
Curr Opin Virol
.
2011
;
1
(
6
):
555
-
562
.
21.
Chemaly
RF
,
Ullmann
AJ
,
Ehninger
G
.
CMV prophylaxis in hematopoietic-cell transplantation
.
N Engl J Med
.
2014
;
371
(
6
):
576
-
577
.
22.
Marty
FM
,
Ljungman
P
,
Chemaly
RF
, et al
.
Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation
.
N Engl J Med
.
2017
;
377
(
25
):
2433
-
2444
.
23.
Camargo
JF
,
Komanduri
KV
.
Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation
.
Hematol Oncol Stem Cell Ther
.
2017
;
10
(
4
):
233
-
238
.
24.
Chemaly
RF
,
Hill
JA
,
Voigt
S
,
Peggs
KS
.
In vitro comparison of currently available and investigational antiviral agents against pathogenic human double-stranded DNA viruses: A systematic literature review
.
Antiviral Res
.
2019
;
163
:
50
-
58
.
25.
Marty
FM
,
Winston
DJ
,
Chemaly
RF
, et al;
SUPPRESS Trial Clinical Study Group
.
A randomized, double-blind, placebo-controlled phase 3 trial of oral brincidofovir for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplantation
.
Biol Blood Marrow Transplant
.
2019
;
25
(
2
):
369
-
381
.
26.
Maertens
J
,
Cordonnier
C
,
Jaksch
P
, et al
.
Maribavir for preemptive treatment of cytomegalovirus reactivation
.
N Engl J Med
.
2019
;
381
(
12
):
1136
-
1147
.
27.
El Chaer
F
,
Shah
DP
,
Chemaly
RF
.
How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients
.
Blood
.
2016
;
128
(
23
):
2624
-
2636
.
28.
Griffiths
P
.
New vaccines and antiviral drugs for cytomegalovirus
.
J Clin Virol
.
2019
;
116
:
58
-
61
.
29.
Chen
SJ
,
Chen
YC
.
Potential application of TALENs against murine cytomegalovirus latent infections
.
Viruses
.
2019
;
11
(
5
):
E414
.
30.
Rubin
RH
.
Preemptive therapy in immunocompromised hosts
.
N Engl J Med
.
1991
;
324
(
15
):
1057
-
1059
.
31.
Hirsch
HH
,
Martino
R
,
Ward
KN
,
Boeckh
M
,
Einsele
H
,
Ljungman
P
.
Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus
.
Clin Infect Dis
.
2013
;
56
(
2
):
258
-
266
.
32.
Preiksaitis
JK
,
Hayden
RT
,
Tong
Y
, et al
.
Are we there yet? Impact of the First International Standard for Cytomegalovirus DNA on the harmonization of results reported on plasma samples
.
Clin Infect Dis
.
2016
;
63
(
5
):
583
-
589
.
33.
Marty
FM
,
Ljungman
P
,
Papanicolaou
GA
, et al;
Maribavir 1263-300 Clinical Study Group
.
Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial
.
Lancet Infect Dis
.
2011
;
11
(
4
):
284
-
292
.
34.
Krause
H
,
Hebart
H
,
Jahn
G
,
Müller
CA
,
Einsele
H
.
Screening for CMV-specific T cell proliferation to identify patients at risk of developing late onset CMV disease
.
Bone Marrow Transplant
.
1997
;
19
(
11
):
1111
-
1116
.
35.
Broers
AE
,
van Der Holt
R
,
van Esser
JW
, et al
.
Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation
.
Blood
.
2000
;
95
(
7
):
2240
-
2245
.
36.
Craddock
C
,
Grigg
AP
.
T-cell depletion does not necessarily compromise donor stem cell engraftment in patients receiving reduced-intensity conditioning regimens
.
Bone Marrow Transplant
.
2003
;
31
(
12
):
1177
-
author reply 1179
.
37.
Boeckh
M
,
Leisenring
W
,
Riddell
SR
, et al
.
Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity
.
Blood
.
2003
;
101
(
2
):
407
-
414
.
38.
Miller
W
,
Flynn
P
,
McCullough
J
, et al
.
Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-v-host disease
.
Blood
.
1986
;
67
(
4
):
1162
-
1167
.
39.
Koskinen
P
,
Lemstrøm
K
,
Mattila
S
,
Häyry
P
,
Nieminen
MS
.
Cytomegalovirus infection associated accelerated heart allograft arteriosclerosis may impair the late function of the graft
.
Clin Transplant
.
1996
;
10
(
6 Pt 1
):
487
-
493
.
40.
Nichols
WG
,
Corey
L
,
Gooley
T
,
Davis
C
,
Boeckh
M
.
High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection
.
J Infect Dis
.
2002
;
185
(
3
):
273
-
282
.
41.
Larsson
K
,
Aschan
J
,
Remberger
M
,
Ringdén
O
,
Winiarski
J
,
Ljungman
P
.
Reduced risk for extensive chronic graft-versus-host disease in patients receiving transplants with human leukocyte antigen-identical sibling donors given polymerase chain reaction-based preemptive therapy against cytomegalovirus
.
Transplantation
.
2004
;
77
(
4
):
526
-
531
.
42.
Cantoni
N
,
Hirsch
HH
,
Khanna
N
, et al
.
Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2010
;
16
(
9
):
1309
-
1314
.
43.
Chan
ST
,
Logan
AC
.
The clinical impact of cytomegalovirus infection following allogeneic hematopoietic cell transplantation: why the quest for meaningful prophylaxis still matters
.
Blood Rev
.
2017
;
31
(
3
):
173
-
183
.
44.
Tomblyn
M
,
Young
JA
,
Haagenson
MD
, et al;
CIBMTR Infection and Immune Reconstitution Working Committee
.
Decreased infections in recipients of unrelated donor hematopoietic cell transplantation from donors with an activating KIR genotype
.
Biol Blood Marrow Transplant
.
2010
;
16
(
8
):
1155
-
1161
.
45.
Prentice
HG
,
Gluckman
E
,
Powles
RL
, et al;
European Acyclovir for CMV Prophylaxis Study Group
.
Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic bone marrow transplantation
.
Lancet
.
1994
;
343
(
8900
):
749
-
753
.
46.
Ljungman
P
,
de La Camara
R
,
Milpied
N
, et al;
Valacyclovir International Bone Marrow Transplant Study Group
.
Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants
.
Blood
.
2002
;
99
(
8
):
3050
-
3056
.
47.
Ljungman
P
,
de la Camara
R
,
Robin
C
, et al;
2017 European Conference on Infections in Leukaemia group
.
Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7)
.
Lancet Infect Dis
.
2019
;
19
(
8
):
e260
-
e272
.
48.
Pollack
M
,
Heugel
J
,
Xie
H
, et al
.
An international comparison of current strategies to prevent herpesvirus and fungal infections in hematopoietic cell transplant recipients
.
Biol Blood Marrow Transplant
.
2011
;
17
(
5
):
664
-
673
.
49.
Goodrich
JM
,
Mori
M
,
Gleaves
CA
, et al
.
Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation
.
N Engl J Med
.
1991
;
325
(
23
):
1601
-
1607
.
50.
Winston
DJ
,
Ho
WG
,
Bartoni
K
, et al
.
Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial
.
Ann Intern Med
.
1993
;
118
(
3
):
179
-
184
.
51.
Salzberger
B
,
Bowden
RA
,
Hackman
RC
,
Davis
C
,
Boeckh
M
.
Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome
.
Blood
.
1997
;
90
(
6
):
2502
-
2508
.
52.
Einsele
H
,
Hebart
H
,
Kauffmann-Schneider
C
, et al
.
Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection
.
Bone Marrow Transplant
.
2000
;
25
(
7
):
757
-
763
.
53.
Nakamae
H
,
Storer
B
,
Sandmaier
BM
, et al
.
Cytopenias after day 28 in allogeneic hematopoietic cell transplantation: impact of recipient/donor factors, transplant conditions and myelotoxic drugs
.
Haematologica
.
2011
;
96
(
12
):
1838
-
1845
.
54.
Reusser
P
,
Gambertoglio
JG
,
Lilleby
K
,
Meyers
JD
.
Phase I-II trial of foscarnet for prevention of cytomegalovirus infection in autologous and allogeneic marrow transplant recipients
.
J Infect Dis
.
1992
;
166
(
3
):
473
-
479
.
55.
Bacigalupo
A
,
Tedone
E
,
Van Lint
MT
, et al
.
CMV prophylaxis with foscarnet in allogeneic bone marrow transplant recipients at high risk of developing CMV infections
.
Bone Marrow Transplant
.
1994
;
13
(
6
):
783
-
788
.
56.
Bregante
S
,
Bertilson
S
,
Tedone
E
, et al
.
Foscarnet prophylaxis of cytomegalovirus infections in patients undergoing allogeneic bone marrow transplantation (BMT): a dose-finding study
.
Bone Marrow Transplant
.
2000
;
26
(
1
):
23
-
29
.
57.
Reusser
P
,
Einsele
H
,
Lee
J
, et al;
Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation
.
Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation
.
Blood
.
2002
;
99
(
4
):
1159
-
1164
.
58.
Robin
C
,
Hémery
F
,
Dindorf
C
, et al
.
Economic burden of preemptive treatment of CMV infection after allogeneic stem cell transplantation: a retrospective study of 208 consecutive patients
.
BMC Infect Dis
.
2017
;
17
(
1
):
747
.
59.
Yong
MK
,
Ananda-Rajah
M
,
Cameron
PU
, et al
.
Cytomegalovirus reactivation is associated with increased risk of late-onset invasive fungal disease after allogeneic hematopoietic stem cell transplantation: a multicenter study in the current era of viral load monitoring
.
Biol Blood Marrow Transplant
.
2017
;
23
(
11
):
1961
-
1967
.
60.
Montesinos
P
,
Sanz
J
,
Cantero
S
, et al
.
Incidence, risk factors, and outcome of cytomegalovirus infection and disease in patients receiving prophylaxis with oral valganciclovir or intravenous ganciclovir after umbilical cord blood transplantation
.
Biol Blood Marrow Transplant
.
2009
;
15
(
6
):
730
-
740
.
61.
Milano
F
,
Pergam
SA
,
Xie
H
, et al
.
Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients
.
Blood
.
2011
;
118
(
20
):
5689
-
5696
.
62.
Boeckh
M
,
Nichols
WG
,
Chemaly
RF
, et al
.
Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a randomized trial
.
Ann Intern Med
.
2015
;
162
(
1
):
1
-
10
.
63.
Chen
K
,
Cheng
MP
,
Hammond
SP
,
Einsele
H
,
Marty
FM
.
Antiviral prophylaxis for cytomegalovirus infection in allogeneic hematopoietic cell transplantation
.
Blood Adv
.
2018
;
2
(
16
):
2159
-
2175
.
64.
Kropeit
D
,
von Richter
O
,
Stobernack
HP
,
Rübsamen-Schaeff
H
,
Zimmermann
H
.
Pharmacokinetics and safety of letermovir coadministered with cyclosporine a or tacrolimus in healthy subjects
.
Clin Pharmacol Drug Dev
.
2018
;
7
(
1
):
9
-
21
.
65.
Maertens
J
,
Bermúdez
A
,
Logan
A
, et al
.
A randomised, placebo-controlled phase 3 study to evaluate the efficacy and safety of ASP0113, a first-in-class, DNA-based vaccine in CMV-seropositive allogeneic haematopoietic cell transplant recipients
. In:
45th Annual Meeting of the European Society for Blood and Marrow Transplantation, Frankfurt am Main, Germany 24-27 March 2019
,
abstract OS6
.
66.
Kharfan-Dabaja
MA
,
Boeckh
M
,
Wilck
MB
, et al
.
A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial
.
Lancet Infect Dis
.
2012
;
12
(
4
):
290
-
299
.
67.
Nakamura
R
,
La Rosa
C
,
Longmate
J
, et al
.
Viraemia, immunogenicity, and survival outcomes of cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic haemopoietic stem-cell transplantation: randomised phase 1b trial
.
Lancet Haematol
.
2016
;
3
(
2
):
e87
-
e98
.
68.
Winston
DJ
,
Young
JA
,
Pullarkat
V
, et al
.
Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients: a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study
.
Blood
.
2008
;
111
(
11
):
5403
-
5410
.
69.
Marty
FM
,
Winston
DJ
,
Rowley
SD
, et al;
CMX001-201 Clinical Study Group
.
CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation
.
N Engl J Med
.
2013
;
369
(
13
):
1227
-
1236
.
70.
Jung
S
,
Michel
M
,
Stamminger
T
,
Michel
D
.
Fast breakthrough of resistant cytomegalovirus during secondary letermovir prophylaxis in a hematopoietic stem cell transplant recipient
.
BMC Infect Dis
.
2019
;
19
(
1
):
388
.
71.
Goldner
T
,
Hempel
C
,
Ruebsamen-Schaeff
H
,
Zimmermann
H
,
Lischka
P
.
Geno- and phenotypic characterization of human cytomegalovirus mutants selected in vitro after letermovir (AIC246) exposure
.
Antimicrob Agents Chemother
.
2014
;
58
(
1
):
610
-
613
.
72.
Boeckh
M
,
Gallez-Hawkins
GM
,
Myerson
D
,
Zaia
JA
,
Bowden
RA
.
Plasma polymerase chain reaction for cytomegalovirus DNA after allogeneic marrow transplantation: comparison with polymerase chain reaction using peripheral blood leukocytes, pp65 antigenemia, and viral culture
.
Transplantation
.
1997
;
64
(
1
):
108
-
113
.
73.
Erice
A
,
Chou
S
,
Biron
KK
,
Stanat
SC
,
Balfour
HH
Jr.
,
Jordan
MC
.
Progressive disease due to ganciclovir-resistant cytomegalovirus in immunocompromised patients
.
N Engl J Med
.
1989
;
320
(
5
):
289
-
293
.
74.
Gilbert
C
,
Roy
J
,
Belanger
R
, et al
.
Lack of emergence of cytomegalovirus UL97 mutations conferring ganciclovir (GCV) resistance following preemptive GCV therapy in allogeneic stem cell transplant recipients
.
Antimicrob Agents Chemother
.
2001
;
45
(
12
):
3669
-
3671
.
75.
Hantz
S
,
Garnier-Geoffroy
F
,
Mazeron
MC
, et al;
French CMV Resistance Survey Study Group
.
Drug-resistant cytomegalovirus in transplant recipients: a French cohort study
.
J Antimicrob Chemother
.
2010
;
65
(
12
):
2628
-
2640
.
76.
Allice
T
,
Busca
A
,
Locatelli
F
,
Falda
M
,
Pittaluga
F
,
Ghisetti
V
.
Valganciclovir as pre-emptive therapy for cytomegalovirus infection post-allogenic stem cell transplantation: implications for the emergence of drug-resistant cytomegalovirus
.
J Antimicrob Chemother
.
2009
;
63
(
3
):
600
-
608
.
77.
Shmueli
E
,
Or
R
,
Shapira
MY
, et al
.
High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation
.
J Infect Dis
.
2014
;
209
(
4
):
557
-
561
.
78.
Tängdén
T
,
Cojutti
PG
,
Roberts
JA
,
Pea
F
.
Valganciclovir pharmacokinetics in patients receiving oral prophylaxis following kidney transplantation and model-based predictions of optimal dosing regimens
.
Clin Pharmacokinet
.
2018
;
57
(
11
):
1399
-
1405
.
79.
Åsberg
A
,
Bjerre
A
,
Neely
M
.
New algorithm for valganciclovir dosing in pediatric solid organ transplant recipients
.
Pediatr Transplant
.
2014
;
18
(
1
):
103
-
111
.
80.
Kuritzkes
DR
,
Parenti
D
,
Ward
DJ
, et al
.
Filgrastim prevents severe neutropenia and reduces infective morbidity in patients with advanced HIV infection: results of a randomized, multicenter, controlled trial. G-CSF 930101 Study Group
.
AIDS
.
1998
;
12
(
1
):
65
-
74
.
81.
Dubreuil-Lemaire
ML
,
Gori
A
,
Vittecoq
D
, et al;
GCS 309 European Study Group
.
Lenograstim for the treatment of neutropenia in patients receiving ganciclovir for cytomegalovirus infection: a randomised, placebo-controlled trial in AIDS patients
.
Eur J Haematol
.
2000
;
65
(
5
):
337
-
343
.
82.
Feuchtinger
T
,
Opherk
K
,
Bethge
WA
, et al
.
Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation
.
Blood
.
2010
;
116
(
20
):
4360
-
4367
.
83.
Tzannou
I
,
Papadopoulou
A
,
Naik
S
, et al
.
Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, Epstein-Barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation
.
J Clin Oncol
.
2017
;
35
(
31
):
3547
-
3557
.
84.
Tzannou
I
,
Leen
AM
.
Preventing stem cell transplantation-associated viral infections using T-cell therapy
.
Immunotherapy
.
2015
;
7
(
7
):
793
-
810
.
85.
Papadopoulou
A
,
Gerdemann
U
,
Katari
UL
, et al
.
Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT
.
Sci Transl Med
.
2014
;
6
(
242
):
242ra83
.
86.
Rooney
CM
,
Leen
AM
,
Vera
JF
,
Heslop
HE
.
T lymphocytes targeting native receptors
.
Immunol Rev
.
2014
;
257
(
1
):
39
-
55
.
87.
Neuenhahn
M
,
Albrecht
J
,
Odendahl
M
, et al
.
Transfer of minimally manipulated CMV-specific T cells from stem cell or third-party donors to treat CMV infection after allo-HSCT
.
Leukemia
.
2017
;
31
(
10
):
2161
-
2171
.
88.
Wolf
DG
,
Shimoni
A
,
Resnick
IB
, et al
.
Human cytomegalovirus kinetics following institution of artesunate after hematopoietic stem cell transplantation
.
Antiviral Res
.
2011
;
90
(
3
):
183
-
186
.
89.
Stuehler
C
,
Stüssi
G
,
Halter
J
, et al
.
Combination therapy for multidrug-resistant cytomegalovirus disease
.
Transpl Infect Dis
.
2015
;
17
(
5
):
751
-
755
.
90.
Gokarn
A
,
Toshniwal
A
,
Pathak
A
, et al
.
Use of leflunomide for treatment of cytomegalovirus infection in recipients of allogeneic stem cell transplant
.
Biol Blood Marrow Transplant
.
2019
;
25
(
9
):
1832
-
1836
.
91.
El Chaer
F
,
Mori
N
,
Shah
D
, et al
.
Adjuvant and salvage therapy with leflunomide for recalcitrant cytomegalovirus infections in hematopoietic cell transplantation recipients: a case series
.
Antiviral Res
.
2016
;
135
:
91
-
96
.
92.
Avery
RK
,
Bolwell
BJ
,
Yen-Lieberman
B
, et al
.
Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection
.
Bone Marrow Transplant
.
2004
;
34
(
12
):
1071
-
1075
.
93.
Papanicolaou
GA
,
Silveira
FP
,
Langston
AA
, et al
.
Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: a randomized, dose-ranging, double-blind, phase 2 study
.
Clin Infect Dis
.
2019
;
68
(
8
):
1255
-
1264
.
94.
Reusser
P
,
Riddell
SR
,
Meyers
JD
,
Greenberg
PD
.
Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease
.
Blood
.
1991
;
78
(
5
):
1373
-
1380
.
95.
Hebart
H
,
Brugger
W
,
Grigoleit
U
, et al
.
Risk for cytomegalovirus disease in patients receiving polymerase chain reaction-based preemptive antiviral therapy after allogeneic stem cell transplantation depends on transplantation modality
.
Blood
.
2001
;
97
(
7
):
2183
-
2185
.
96.
Gratama
JW
,
Boeckh
M
,
Nakamura
R
, et al
.
Immune monitoring with iTAg MHC tetramers for prediction of recurrent or persistent cytomegalovirus infection or disease in allogeneic hematopoietic stem cell transplant recipients: a prospective multicenter study
.
Blood
.
2010
;
116
(
10
):
1655
-
1662
.
97.
Lee
SM
,
Kim
YJ
,
Yoo
KH
,
Sung
KW
,
Koo
HH
,
Kang
ES
.
Clinical usefulness of monitoring cytomegalovirus-specific immunity by QuantiFERON-CMV in pediatric allogeneic hematopoietic stem cell transplantation recipients
.
Ann Lab Med
.
2017
;
37
(
3
):
277
-
281
.
98.
Krawczyk
A
,
Ackermann
J
,
Goitowski
B
, et al
.
Assessing the risk of CMV reactivation and reconstitution of antiviral immune response post bone marrow transplantation by the QuantiFERON-CMV-assay and real time PCR
.
J Clin Virol
.
2018
;
99-100
:
61
-
66
.
99.
Paouri
B
,
Soldatou
A
,
Petrakou
E
, et al
.
QuantiFERON-Cytomegalovirus assay: a potentially useful tool in the evaluation of CMV-specific CD8+ T-cell reconstitution in pediatric hematopoietic stem cell transplant patients
.
Pediatr Transplant
.
2018
;
22
(
5
):
e13220
.
100.
Gliga
S
,
Korth
J
,
Krawczyk
A
, et al
.
T-Track-CMV and QuantiFERON-CMV assays for prediction of protection from CMV reactivation in kidney transplant recipients
.
J Clin Virol
.
2018
;
105
:
91
-
96
.
101.
Bono
P
,
Orlandi
A
,
Zoccoli
A
, et al
.
QuantiFERON CMV assay in allogenic stem cell transplant patients
.
J Clin Virol
.
2016
;
79
:
10
-
11
.
102.
Tey
SK
,
Kennedy
GA
,
Cromer
D
, et al
.
Clinical assessment of anti-viral CD8+ T cell immune monitoring using QuantiFERON-CMV assay to identify high risk allogeneic hematopoietic stem cell transplant patients with CMV infection complications
.
PLoS One
.
2013
;
8
(
10
):
e74744
.
103.
Chanouzas
D
,
Small
A
,
Borrows
R
,
Ball
S
.
Assessment of the T-SPOT.CMV interferon-γ release assay in renal transplant recipients: a single center cohort study
.
PLoS One
.
2018
;
13
(
3
):
e0193968
.
104.
Banas
B
,
Steubl
D
,
Renders
L
, et al
.
Clinical validation of a novel enzyme-linked immunosorbent spot assay-based in vitro diagnostic assay to monitor cytomegalovirus-specific cell-mediated immunity in kidney transplant recipients: a multicenter, longitudinal, prospective, observational study
.
Transpl Int
.
2018
;
31
(
4
):
436
-
450
.
105.
El Haddad
L
,
Ariza-Heredia
E
,
Shah
DP
, et al
.
The ability of a cytomegalovirus ELISPOT assay to predict outcome of low-level CMV reactivation in hematopoietic cell transplant recipients
.
J Infect Dis
.
2019
;
219
(
6
):
898
-
907
.
106.
Kumar
D
,
Mian
M
,
Singer
L
,
Humar
A
.
An interventional study using cell-mediated immunity to personalize therapy for cytomegalovirus infection after transplantation
.
Am J Transplant
.
2017
;
17
(
9
):
2468
-
2473
.
107.
Green
ML
,
Leisenring
W
,
Stachel
D
, et al
.
Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cytomegalovirus disease after hematopoietic cell transplantation
.
Biol Blood Marrow Transplant
.
2012
;
18
(
11
):
1687
-
1699
.
108.
Avetisyan
G
,
Aschan
J
,
Hägglund
H
,
Ringdén
O
,
Ljungman
P
.
Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT
.
Bone Marrow Transplant
.
2007
;
40
(
9
):
865
-
869
.
109.
Navarro
D
,
Amat
P
,
de la Cámara
R
, et al
.
Efficacy and safety of a preemptive antiviral therapy strategy based on combined virological and immunological monitoring for active cytomegalovirus infection in allogeneic stem cell transplant recipients
.
Open Forum Infect Dis
.
2016
;
3
(
2
):
ofw107
.
110.
Einsele
H
,
Reusser
P
,
Bornhäuser
M
, et al
.
Oral valganciclovir leads to higher exposure to ganciclovir than intravenous ganciclovir in patients following allogeneic stem cell transplantation
.
Blood
.
2006
;
107
(
7
):
3002
-
3008
.
111.
Flowers
MED
,
McDonald
G
,
Carpenter
P
, et al
.
Long-term follow-up after hematopoietic stem cell transplant. General guidelines for referring physicians. Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, version 29 July 2019
.
Sign in via your Institution