The objective of this consensus is to update recommendations and provide expert opinion on aspects not addressed by current guidelines or with low grade evidence.
Materials and Methods
Selection of experts and working method.
For the preparation of this consensus, the GRUCINI-GETH-TC selected
sixteen experts from among its members based on their expertise in CMV
research and clinical practice. The Expert Panel included hematologists
involved in transplant programs in adults (JLP, LV, RD, AP, CM, IE,
MS-Ll, IG-C, RM, MR, RC, CS) or in pediatric patients (MG-V),
hematologists involved in cell therapy production (MG) and virologists
(EG, MAM, DN). The Expert Panel was assisted by a methodologist (AC)
who was involved in the field of evidence-based medicine and guideline
production as part of the GETH-TC secretary.
The Expert Panel agreed on key clinical areas and key questions within each clinical area, using the criterion of clinical uncertainty detected in the previous survey conducted by the GETH-TC in 21 centers, accounting for 71% of the allo-HSCT performed in Spain.[15,16] In addition, a specific survey was performed in Spanish transplant centers in 2022 on CMV DNAemia monitoring and management during LMV prophylaxis (see Summary Report, Supplementary material).
Specific questions were assigned to two experts and the methodologist, who conducted a literature search aimed at identifying trials and retrospective studies. Each group prepared a response proposal, which was reviewed by all the experts, and those reaching at least 90% consensus were accepted. A recommendation level was assigned using the grading system of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)[17] (Supplementary material Table 1). Those recommendations made by the group that are considered new or that have changed previous recommendations are highlighted in bold letters in the text.
The Expert Panel agreed on key clinical areas and key questions within each clinical area, using the criterion of clinical uncertainty detected in the previous survey conducted by the GETH-TC in 21 centers, accounting for 71% of the allo-HSCT performed in Spain.[15,16] In addition, a specific survey was performed in Spanish transplant centers in 2022 on CMV DNAemia monitoring and management during LMV prophylaxis (see Summary Report, Supplementary material).
Specific questions were assigned to two experts and the methodologist, who conducted a literature search aimed at identifying trials and retrospective studies. Each group prepared a response proposal, which was reviewed by all the experts, and those reaching at least 90% consensus were accepted. A recommendation level was assigned using the grading system of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID)[17] (Supplementary material Table 1). Those recommendations made by the group that are considered new or that have changed previous recommendations are highlighted in bold letters in the text.
Results
Virological Monitoring.
1. Question 1: Should CMV DNAemia be monitored in hematological patients treated with CAR-T therapies, biologic therapies, or small-molecule therapies (BTK and JAK inhibitors) before or after allo-HSCT?
CMV DNAemia is common (up to 45% in CMV-seropositive patients) in the CAR-T therapy setting within the first 90 days after infusion of CAR-T cells.[18,3,4] Although CMV DNAemia in these patients has been associated occasionally with end-organ CMV disease[19] and lower overall survival,[3,4] most episodes usually resolve without the need for antiviral treatment; however, CMV monitoring is suggested for high-risk patients (high-risk CAR-HEMATOTOX score) as well as those displaying CMV DNAemia before CAR-T infusion and those under corticosteroids therapy for cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS),[20] starting at baseline and up to day 60 after CAR-T infusion (BIIu).
The JAK inhibitor, ruxolitinib, has received FDA and EMA approval as first-line treatment for steroid-refractory acute and chronic graft versus host disease (GVHD). Different studies have described CMV reactivation during ruxolitinib use in this setting.[21-23] However, given the strong association between acute GVHD and CMV reactivation,[24] only some studies have suggested that ruxolitinib treatment is a significant adverse prognostic factor for the complete response of first CMV reactivation. This was analyzed separately for each reactivation as a competing risk with death in a cause-specific Cox model of survival after the first GVHD occurrence, with the onset of ruxolitinib therapy coded as a time-dependent covariate.23
Therefore, the group considers that, at present, there is insufficient evidence to suggest the need to routinely monitor CMV DNA burden in patients treated with new therapies, including BTK inhibitors[25] and JAK inhibitors (BIIu).[26]
2. Question 2: What is the optimal frequency and duration of monitoring in the allo-HSCT setting?
Following recent guidelines, we recommend that all CMV allo-HSCT patients, regardless of donor and/or recipient CMV serostatus, should be monitored at least once a week starting in the first two weeks after infusion until day +100 post-allo-HSCT (AII).[11-13] After day +100, high-risk patients, including cord blood transplant (CBT) recipients, patients who start PET during the first 100 days, those who received extended letermovir prophylaxis beyond day +100, and those with moderate to severe acute or chronic graft-versus-host disease (GVHD) or treatment with high-dose corticosteroids, should be monitored with the same frequency until immunosuppression withdrawal (AII).[11,12]
Patients under LMV prophylaxis should be monitored following the same schedule as above (AI). Due to the mechanism of action of LMV, fragmented viral DNA can accumulate in the blood compartment in the absence of true CMV replication.[27,28] Current data support the idea that most episodes of CMV DNAemia occurring during LMV prophylaxis resolve without treatment, probably reflecting abortive CMV infections.[29,30] The most convenient CMV DNA threshold level or kinetics to guide pre-emptive antiviral therapy (PET) administration during CMV prophylaxis remains to be defined6. In the meantime, a relatively high threshold (i.e., 1,500 IU/mL in plasma; 10,000 IU/mL in whole blood) can safely be used to prompt PET inception (BII).
3. Question 3: When should early treatment be started? It should be a high or low level of DNAemia / viral doubling time.
The CMV loading threshold that determines PET initiation varies widely in transplant centers, typically between 1,000 and 10,000 IU/mL in whole blood or 100 to 1,500 IU/mL in plasma.[15] In most centers, the PET threshold is not adjusted to the patient's risk of CMV disease.[31] The CMV viral load threshold in blood to initiate PET should be established at each center, depending on the analytical characteristics of the qPCR and the matrix used. There is no clinical evidence, in terms of mortality incidence, that supports recommending the use of high or low thresholds for PET. Nevertheless, a recent systematic review of randomized and observational studies from 2013 to 2023 demonstrated that antiviral preemptive therapy started at CMV viral load thresholds between 2 and 3 log10 IU/mL was associated with similar CMV disease rates. Thus, viral thresholds in this range appear to effectively protect patients not receiving prophylaxis (BIIr).[32] Indeed, there is some evidence associating PET with higher mortality, suggesting that toxicity related with available anti-CMV drugs could be a matter of concern in this setting.[33]
Use of dt to start PET. Using the CMV DNA doubling time (dt) as a parameter for guiding PET is a recent suggestion. Using CMV load kinetics through the first two consecutive positive qPCR determinations to calculate the dt (spaced no more than 10 days apart and with load increments not less than 0.5 log10), it was determined that, in patients not receiving CMV prophylaxis, dt ≤2 days predicted the need to administer PET with a sensitivity of 100% when the established threshold for PET is 1,500 IU/mL (around 1,000 copies/mL).[34] This strategy results in shorter PET times, without a higher incidence of recurrent DNAemia.[35] The dt calculated from the CMV loads provided by different qPCRs is similar, given their collinearity for low load intervals, contrary to the magnitude of the loads.[36] The use of dt therefore allows direct comparison of results obtained in centers that use similar or different qPCRs. Therefore, the group recommends it dt use (BIII), in addition to qPCR CMV viral load, in the context of clinical trials, in order to generate evidence.
4. Question 4: What is the value of CMV DNA load quantitation for diagnosing CMV disease, especially CMV pneumonia and gastrointestinal disease?
Diagnosis of proven CMV pneumonia and gastrointestinal (GI) disease requires histopathological and virological evidence (observation of cytopathogenic effect/conventional culture/detection of viral proteins by immunohistochemistry -IHC- in biopsy material).[37] Detection of viral DNA in bronchoalveolar lavage (BAL) is not diagnostic, since it may simply reflect asymptomatic shedding.[37] The absence of CMV DNA in BAL has a negative predictive value close to 100%.[11,38,39] Although the probability of CMV pneumonia rises in parallel with increased viral load in BAL, especially in patients with a high pre-test probability, a diagnostic threshold has not been reached. A threshold value of 500 IU/mL has been suggested to discriminate between disease (higher values) and asymptomatic shedding (lower values).[38] In a subsequent study, it was confirmed that the presence of CMV loads greater than this threshold is frequent in the BAL of patients with a low probability of CMV pneumonia.[39] The lack of homogeneous BAL collection protocols and variability in the analytical characteristics of qPCRs make it extremely difficult to establish a universal diagnostic CMV burden threshold.
As in BAL samples, CMV DNA detection in feces or intestinal biopsies is not diagnostic. However, CMV-PCR shows the same sensitivity (100%), specificity (98%), and positive (93%) and negative predictive value (100%) as CMV-IHC in the G-I tract.[40] Nevertheless, the potential value of quantifying CMV load in intestinal biopsies requires further validation.
Immune Monitoring.
5. Question 5: Specific CMV immune monitoring: in which patients and for what purpose?
Systematic monitoring of the specific T-cell immune response against CMV could be useful to identify patients at risk for primary, recurrent or clinically refractory CMV DNAemia who are amenable to treatment with specific T lymphocyte-adoptive T cell transfer and end-organ disease.[41–43] The best marker of protection against these clinical events is the number of CD8+ and/or CD4+ T lymphocytes that express interferon gamma (IFNγ) after being stimulated in vitro with CMV antigens (particularly pp65 and IE-1).[41–43] Various protection thresholds have been proposed but not clinically validated. These cells can be quantified by flow cytometry with intracellular cytokine staining (ICS), ELISpot (CMV Tspot/CMV T-Track) or enzyme immunoassay (Quantiferon® CMV). The clinical value of quantifying specific T lymphocytes against CMV has been proven in a few non-randomized prospective intervention studies.[44,45] Systematic immunological monitoring of allo-HSCT patients is not currently standard practice, and this is unlikely to change until its clinical value is proven in randomized trials.[29] However, in particular cases (i.e., recipients with prior CMV DNAemia, those with GvHD and/or under corticosteroids, or after ending LMV prophylaxis), the lack of specific anti-CMV T cells could be used to support continuous CMV monitoring over time. The group therefore recommends monitoring CMV immunity whenever possible in order to generate real-world evidence.
CMV Infection Control Strategies.
6. Question 6: Can we tailor the singular efficacy of LMV in CMV prophylaxis?
Although end-organ CMV disease can generally be reduced with PET, CMV DNAemia itself has been associated with increased non-relapse mortality in allo-HSCT receptors, suggesting deleterious indirect effects.[33] Several agents have been challenged as prophylaxis, but most did not demonstrate efficacy or were associated with an unacceptable toxicity.[46] Foscarnet (FOS) prophylaxis has been used in patients in uncontrolled trials only and its prolonged use as prophylaxis is limited by IV administration and toxicities.[47,48] Maribavir (MBV) failed to demonstrate a significant benefit on the incidence of DNAemia, CMV disease, or need of PET at week 24 and had no statistically significant effect in reducing mortality.[49] Finally, brincidofovir (BCDV) showed no significant difference in the incidence of clinically significant CMV infection (csCMV-I) at week 24 and was associated with increased GI toxicity.[50]
Only LMV reduced csCMV-I and all-cause mortality with a good safety profile.[51] Based on the results of the randomized phase 3 trial of letermovir prophylaxis, different guidelines have assigned it the highest level of recommendation (A-I).[11-13] Looking for patient subgroups that could most benefit, no significant differences were observed in the incidence of CMV DNAemia/pp65 antigenemia between the high-risk (related or unrelated donor with HLA mismatch, haploidentical donor, cord blood transplant, T-depletion, ATG or alemtuzumab use, GVHD grade ≥2) and low-risk groups (HLA-matched related or unrelated donor). A trend was observed towards higher incidence of CMV DNAemia in the haploidentical HSCT group, with no impact on mortality or CMV end-organ disease.51 A meta-analysis published in 2018 confirmed LMV as the best option in terms of efficacy and safety.[52]
Single-center reports found that haploidentical HSCT with posttransplant cyclophosphamide (PTCy) resulted in either increased or comparable DNAemia incidence compared to historical comparisons of HLA-matched HCT.[53,54] In a recent retrospective registry-based study performed by the GETH-TC, multivariate analysis showed that the risk of DNAemia was significantly higher in haploidentical HSCT PTCy patients [HR (95%) 2.17 (1.52–3.10); p<0.001] and in unrelated donor HSCT patients [HR (95%) 1.49 (1.05–2.10); p<0.03] than when using an HLA-identical family donor16. Recently, however, PTCy itself (regardless of donor source or HLA match) has been considered a risk factor for DNAemia incidence.55 In this study of the Center for International Blood and Marrow Transplantation Research (CIBMTR) comparing patients receiving haploHSCT with PTCy (n=757), matched related (MR) with PTCy (n=403), or MR with calcineurin inhibitor-based prophylaxis (CNI) (n=1605), cumulative incidences of DNAemia by day 180 were 42%, 37%, and 23%, respectively (P=0,001), without differences in end-organ CMV disease incidence.[55]
Based on this information (and only if universal prophylaxis with LMV is restricted), our recommendation would be to use LMV in higher-risk patients (BII), including:
7. Question 7: When should LMV prophylaxis be withdrawn?
Implementation of LMV in clinical practice has raised new questions, including those referring to the optimal duration. The pivotal trial observed a clear clinical benefit in all patients receiving LMV up to day +100 post-transplant, uniformly and independently of other characteristics and risk factors. However, it also showed a clear 12% increase in csCMV-I between discontinuation of LMV at day +100 and week 24. This increase in late events due to CMV after day +100 occurs preferentially in high-risk patients, particularly those with GVHD and on treatment with corticosteroids. These patients could potentially benefit from maintaining LMV prophylaxis beyond day +100.[51]
Recently, Russo et al. published the results of a phase III clinical trial to evaluate the efficacy and safety of LMV in prophylaxis maintained up to day +200 (NCT03930615).[56] After completing the first 100 days of prophylaxis, high-risk patients were randomized to continue receiving LMV versus placebo (ratio 2:1). The rate of csCMV-I between weeks 14 and 28 was reduced from 18.9% in the placebo group to 2.8% in the LMV arm (p<0.0005), with a safety profile and similar adverse effects in the two arms.[56] A 10% increase in csCMV-I has been also noted after LMV withdrawal, however, which warrants further CMV monitoring in high-risk patients after LMV stop.
Based on these results, we recommend continuing LMV prophylaxis until day +100 in all eligible patients, extended to at least until day +200 during active GVHD treated with corticosteroids (>0.5 mg/kg/day) (AI). In this setting, immunological monitoring could eventually prove useful to guide optimal duration of LMV prophylaxis (BII).
8. Question 8: How should breakthrough DNAemia episodes during CMV prophylaxis be managed?
A proportion of patients (7.4%) will present breakthrough DNAemia requiring PET while on prophylaxis with LMV51 and risk factors been identified, including cumulative corticosteroid dose, PTCy use, and D-/R+ CMV serostatus.[57,58] As has been previously discussed, the most convenient CMV-DNAemia level to guide PET treatment initiation during LMV prophylaxis is not yet clearly defined. Nonetheless, our recommendation is to use a higher CMV DNAemia threshold than is used to guide PET in patients who do not receive prophylaxis.6 The group recommends not to treat a single positive PCR to avoid unnecessary antiviral therapy in self-resolving “blips” (the presence of CMV DNA at any level in a single plasma specimen, preceded and succeeded by a negative PCR specimen, 7 days apart)(BII).[59,60] In cases of breakthrough CMV DNAemia, we advocate performing molecular CMV mutational studies when possible. However, given that CMV DNAemia may be an expression of abortive infection due to the mechanism of action of letermovir, as discussed before, we and others recommend confirming active viral replication using virus isolation, DNAse technique, or by checking CMV-RNAemia before performing mutational studies.[61] Although the frequency of CMV mutations conferring resistance to LMV is low,[51] identifying UL56 gene mutations (V236M, C325W) may be helpful in avoiding extended LMV prophylaxis, switching to PET strategy and selecting the most adequate agent.[62]
9. Question 9: Is secondary prophylaxis recommended in patients with recurrent CMV-DNAemia?
A subset of patients will develop recurrent CMV-DNAemia, requiring several rounds of antiviral therapy. These patients are usually high (D-/R+), or high-intermediate (D+/R+) serological risk, receiving corticosteroids as GVHD treatment, and in the first six months post-HSCT.59,60 In these cases, it would be clinically justified to perform secondary prophylaxis after CMV DNAemia clearance of the second episode of reactivation and maintain it until corticosteroids withdrawal or evidence of immune reconstitution.[29] As noted above, protective levels have been proposed but not yet clinically validated.[44]
Given the experience of real-life data of secondary prophylaxis,63-66 LMV could be the treatment of choice in this situation, provided there is no LMV-resistant mutation and negative DNAemia before LMV onset (BII).[51,67–69] Secondary prophylaxis with LMV after initial failure of primary prophylaxis could be an option in cases of defective absorption suspicion in recipients with diarrhea, provided that CMV mutations conferring resistance to LMV can be reasonably excluded (BIII).
10. Question 10: Is PET still an option as a primary strategy for CMV infection/disease?
As mentioned above, the clinical superiority of prophylaxis with LMV over PET strategies has been demonstrated in phase III trial and several real-life studies. In countries where universal prophylaxis with LMV is not feasible, however, PET is the recommended strategy to prevent CMV disease, and the latter method is also used after LMV prophylaxis failure.
Intravenous ganciclovir (GCV) (AI) and oral valganciclovir (VGCV) are the most frequently used agents, with myelotoxicity and nephrotoxicity being the toxicity limitation.[11] A randomized clinical trial showed that FOS is as effective as GCV,[70] and therefore has the same recommendation level (AI). Since it presents less myelotoxicity than GCV, its use is recommended in patients with neutropenia or thrombocytopenia.
Recently a multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT compared maribavir 400 mg twice daily or valganciclovir for 8 weeks with 12 weeks of follow-up in 547 patients.[71] Although noninferiority of MBV to VGCV for the primary endpoint was not achieved based on the prespecified noninferiority margin, MBV demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Although. MBV did not granted FDA/EMA indication as first line CMV PET, given its safety profile, the consensus recommend to considered it as an alternative in patients who develop neutropenia (BI).
11. Question 11: When to stop antiviral therapy in PET strategies?
ECIL and ASTCT guidelines recommend stopping PET upon negative PCR result after a minimum 15 days of treatment.[11,12] A recent small study suggests that PET can be stopped after the first negative PCR regardless of the duration of treatment up to that time point, without increasing the risk of recurrence and limiting drug-related toxicities as far as possible.[72] More studies are needed to change present guidelines, that the consensus support (AII).
Pharmacological Resistance.
12. Question 12: When to suspect and how to confirm CMV resistance to antivirals?
Definitions of CMV infection refractory (clinical) or resistant (genetic) to antivirals for use in clinical trials were proposed by Chemaly et al.[73] Nonetheless, the refractory definition should probably be wider in the clinical setting, including patients with long-lasting positive DNAemia of < 1 log or positive DNAemia after more than 21 days of PET onset.
Refractory CMV infection has a higher incidence than resistant in HSCT recipients, with rates varying between 29% to 39% and 1.7% to 14.5%, respectively.[74] This substantial difference is likely driven by poor host immunity in response to active viral replication, leading to refractory infection despite antiviral therapy and frequent underdiagnosis due to scarce diagnostic units for clinically useful time-results.[75]
Risk factors for the relatively common refractoriness and infrequent antiviral genetic resistance are summarized in Supplementary material Table 2.[73]
Systematic studies in patients treated with allo-HSCT have shown an increasing incidence of genetic resistance, more frequently mutations in UL97 and much less frequently in UL54.[76,77] The canonical mutations M460V/I, H520Q, C592G, A594V, L595S appear in 80% of cases and are associated with resistance only to GCV; therefore, diagnostic genotyping should include codon ranges of at least 440–640. Generally, mutations in the UL54 polymerase gene are preceded by mutations in the UL97 gene, increasing the level of resistance to GCV and conferring cross-resistance to FOS and cidofovir (CDV). This fact reinforces the importance of early virological study since the evolution of resistance and/or multi-resistance increases gradually and progressively with time of exposure to the antiviral drug.[78] For this reason, genetic resistance study is recommended when there is clinical suspicion.[11] Confirmation of resistance to antivirals is done by genotypic and phenotypic methods (see Supplementary material Table 3).[79,80] In recent years, next generation sequencing (NGS) enabled the study of the entire spectrum of genetic diversity and can also detect mutations in virus populations of only 5%, which may play an important role in the evolution of virus resistance.[81,82] Based on these data, our recommendation is to perform mutational analysis if no negative DNAemia is achieved after three weeks of optimal antiviral treatment or if it increases after two weeks of treatment (BII).
13. Question 13: How should refractory or resistant CMV infection be managed?
Management of patients with refractory or genetically resistant CMV infection requires the use of an anti-CMV drug not resistant to the detected mutation, following the recommendations of the consensus group supported by ECIL-7 Guidelines.[11]
Until now initial treatment for a csCMV-I has usually been done with GCV or VGCV, and when refractoriness or (more commonly) severe pancytopenia appears, the drug of choice is FOS (AIIu) or CDV at 5 mg/kg/week if renal function is maintained (BIIu). Recently, oral MBV at a dose of 400 mg every 12 hours has been authorized and will be considered a new standard, at least in patients with hematological or renal toxicity (AI).[83] The combination of GCV and FOS at half doses can be used as second or third line (CIIu). Provided there is no clinical alloreactivity (active GVHD), immunosuppression should be reduced, including steroids (BIII). Leflunomide and artesunate can also be considered for third line treatment (CIII). Until now, there is no evidence that allows the use of LMV or BCDV as rescue treatments for refractory CMV infection.
Cell Therapy in CMV Infection.
14. Question 14: When and in whom should adoptive transfer of virus-specific T lymphocytes be used?
Adoptive transfer of virus-specific T cells (VSTs) has demonstrated safety and efficacy in treating virus-associated diseases and malignancies in HSCT, including CMV, adenovirus, BK virus, human herpesvirus,6 and Epstein-Barr virus.[84] This has led to the recent approval of the first allogeneic anti-viral T cell product (tabelecleucel) for the treatment of EBV+ post-transplant lymphoproliferative disease.[85]
There are two main strategies for obtaining CMV-specific lymphocytes: direct magnetic selection using CMV tetramers/streptamers[86] or ex-vivo expansion of VSTs prior to infusion.[87] Both approaches have proven effective, but a direct comparison between them has not been made.
Currently, two phase III trials are employing adoptive cell therapy for CMV. In a prophylactic phase III study (EudraCT No. 2021-005105-27), posoleucel, a third-party multivirus-specific T cell therapy, was being evaluated for its potential to prevent CMV and other viral reactivations in high-risk HSCT patients, following promising results in the phase II trial.[88] However, the company (AlloVir) announced in December 2023 that they were discontinuing the phase III trial because pre-planned analyses showed it was unlikely to meet their primary endpoints. These results raise questions about the applicability of VSTs in the prophylactic context. In the treatment setting, the TRACE study (EudraCT No. 2018-000853-29) is a phase III trial testing a single infusion of allogeneic multi-specific VSTs generated using the CliniMACS Prodigy system and IFN-gamma magnetic capture for refractory viral infections after HSCT, including CMV. However, the trial is facing recruitment challenges, partly due to logistical complexities and time requirements for cellular product production. Nonetheless, this trial is anticipated to provide valuable insights into the treatment of CMV. An alternative approach, currently in development in academic centers and showing promise in phase 2 trials, involves establishing banks of third-party donor cryopreserved CMV-specific VSTs covering the most common HLAs. This ready-to-infuse off-the-shelf allogeneic therapy is expected to emerge as the cellular therapy solution for pharmacologically resistant/refractory CMV infection, with clinical trials warranted.
Concerning the clinical context of administration of CMV-CTLs, the consensus recommends to considered their use in the following patients (BII): a) with CMV organic disease resistant to first-line antiviral treatment; b) with resistant or refractory CMV DNAemia in two prior lines of treatment; c) with one or more documented genetic mutations associated with resistance to GCV or FOS, d) with recurrent (> 2 episodes) or persistent (> 6 weeks) CMV DNAemia, or e) with recurrent CMV-DNAemia with a low number of specific T lymphocytes against CMV identifying patients who are candidates for secondary prophylaxis or alternatively cell therapy.[29] By contrast, the use of cell therapy is limited in patients receiving high dose corticosteroid (≥ 1 mg/Kg/day), ATG or alemtuzumab (DII).
15. Question 15: Which antiviral drug combinations are available and/or under development?
The availability of drugs with different mechanisms of action against CMV makes their combination attractive in refractory cases. Expert guidelines generally discourage the use of drug combinations, which are limited to GCV plus FOS suggested as second or third-line therapy with low levels of evidence.11 However, various drug combinations active against CMV have recently been explored in in vitro models.82 Studies of the in vitro effect of MBV showed additive interactions with FOS, CDV, LMV, and GW275175X in wild-type and mutant CMV strains, exhibiting great antagonism with GCV and strong synergy with sirolimus. In turn, LMV and sirolimus combined also showed an additive effect in vitro in terms of anti-CMV activity in epithelial cells. Although many combinations remain to be explored, these observations may be useful for designing future clinical studies in both prophylaxis and treatment.
The biological and clinical activity of the anti-CMV alternative agents is summarized in Supplementary material Table 4.
16. Question 16: Are there differences in CMV infection management in pediatric patients?
Management of CMV infection is similar in pediatric and adult patients treated with HSCT, with the main differences deriving from the use of VGCV and LMV.
Valganciclovir. VGCV, a valine and GCV ester derivative, serves as an alternative to oral and intravenous administration for CMV prophylaxis and treatment. In adults, a daily dose of 900 mg provides GCV exposure equivalent to intravenous administration at 5 mg/kg. Limited data on VGCV use in children have been published, and no consensus on pediatric dosing has been established. Studies in pediatric transplant recipients emphasize the inadequacy of dosing algorithms based solely on body surface area, highlighting the importance of incorporating renal function, assessed by estimated creatinine clearance (CrCLS).[89] Age-independent bioavailability and predominant renal elimination of VGCV support the use of algorithms incorporating CrCLS in pediatric patients, achieving comparable GCV exposures to adults.[90] FDA approval for preventing CMV disease in high-risk pediatric transplant patients is based on a dosing algorithm with a maximum dose of 900 mg if CrCLS exceeds 150 mL/min/1.73 m². The requirement to take VGCV with food led to the development of an oral suspension (50 mg/mL), bioequivalent to tablets, benefiting pediatric patients unable to swallow.[91] The suspension is well-tolerated, with mostly mild or moderate gastrointestinal adverse events. A study on CMV mutations in pediatric patients using VGCV for prophylaxis indicated a low incidence of resistance-associated mutations, with no clinical consequences from resistant viruses.[92]
Letermovir. Recent results from a registry-based study of the Infectious Diseases Working Group of the Italian Association of Pediatric Hematology-Oncology (AIEOP),93 a single center study[94] and the phase 2b open-label, single-arm clinical trial MK 8228-030 (NCT03940586)[95] have confirmed that pharmacokinetics, efficacy, safety, and tolerability of LMV in pediatric patients from birth to less than 18 years of age at risk of developing CMV infection and/or disease following HSCT are similar to adults. Administration of adult letermovir doses in this adolescent cohort resulted in exposures within adult clinical program margins and was associated with safety and efficacy similar to adults.[95]
Maribavir. In pediatric patients, a new clinical trial, SHP620-302: “A phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study to evaluate the efficacy and safety of MBV compared with VGCV for the treatment of CMV Infection in HSCT Recipients” to assess safety and effectiveness in children is ongoing.
1. Question 1: Should CMV DNAemia be monitored in hematological patients treated with CAR-T therapies, biologic therapies, or small-molecule therapies (BTK and JAK inhibitors) before or after allo-HSCT?
CMV DNAemia is common (up to 45% in CMV-seropositive patients) in the CAR-T therapy setting within the first 90 days after infusion of CAR-T cells.[18,3,4] Although CMV DNAemia in these patients has been associated occasionally with end-organ CMV disease[19] and lower overall survival,[3,4] most episodes usually resolve without the need for antiviral treatment; however, CMV monitoring is suggested for high-risk patients (high-risk CAR-HEMATOTOX score) as well as those displaying CMV DNAemia before CAR-T infusion and those under corticosteroids therapy for cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS),[20] starting at baseline and up to day 60 after CAR-T infusion (BIIu).
The JAK inhibitor, ruxolitinib, has received FDA and EMA approval as first-line treatment for steroid-refractory acute and chronic graft versus host disease (GVHD). Different studies have described CMV reactivation during ruxolitinib use in this setting.[21-23] However, given the strong association between acute GVHD and CMV reactivation,[24] only some studies have suggested that ruxolitinib treatment is a significant adverse prognostic factor for the complete response of first CMV reactivation. This was analyzed separately for each reactivation as a competing risk with death in a cause-specific Cox model of survival after the first GVHD occurrence, with the onset of ruxolitinib therapy coded as a time-dependent covariate.23
Therefore, the group considers that, at present, there is insufficient evidence to suggest the need to routinely monitor CMV DNA burden in patients treated with new therapies, including BTK inhibitors[25] and JAK inhibitors (BIIu).[26]
2. Question 2: What is the optimal frequency and duration of monitoring in the allo-HSCT setting?
Following recent guidelines, we recommend that all CMV allo-HSCT patients, regardless of donor and/or recipient CMV serostatus, should be monitored at least once a week starting in the first two weeks after infusion until day +100 post-allo-HSCT (AII).[11-13] After day +100, high-risk patients, including cord blood transplant (CBT) recipients, patients who start PET during the first 100 days, those who received extended letermovir prophylaxis beyond day +100, and those with moderate to severe acute or chronic graft-versus-host disease (GVHD) or treatment with high-dose corticosteroids, should be monitored with the same frequency until immunosuppression withdrawal (AII).[11,12]
Patients under LMV prophylaxis should be monitored following the same schedule as above (AI). Due to the mechanism of action of LMV, fragmented viral DNA can accumulate in the blood compartment in the absence of true CMV replication.[27,28] Current data support the idea that most episodes of CMV DNAemia occurring during LMV prophylaxis resolve without treatment, probably reflecting abortive CMV infections.[29,30] The most convenient CMV DNA threshold level or kinetics to guide pre-emptive antiviral therapy (PET) administration during CMV prophylaxis remains to be defined6. In the meantime, a relatively high threshold (i.e., 1,500 IU/mL in plasma; 10,000 IU/mL in whole blood) can safely be used to prompt PET inception (BII).
3. Question 3: When should early treatment be started? It should be a high or low level of DNAemia / viral doubling time.
The CMV loading threshold that determines PET initiation varies widely in transplant centers, typically between 1,000 and 10,000 IU/mL in whole blood or 100 to 1,500 IU/mL in plasma.[15] In most centers, the PET threshold is not adjusted to the patient's risk of CMV disease.[31] The CMV viral load threshold in blood to initiate PET should be established at each center, depending on the analytical characteristics of the qPCR and the matrix used. There is no clinical evidence, in terms of mortality incidence, that supports recommending the use of high or low thresholds for PET. Nevertheless, a recent systematic review of randomized and observational studies from 2013 to 2023 demonstrated that antiviral preemptive therapy started at CMV viral load thresholds between 2 and 3 log10 IU/mL was associated with similar CMV disease rates. Thus, viral thresholds in this range appear to effectively protect patients not receiving prophylaxis (BIIr).[32] Indeed, there is some evidence associating PET with higher mortality, suggesting that toxicity related with available anti-CMV drugs could be a matter of concern in this setting.[33]
Use of dt to start PET. Using the CMV DNA doubling time (dt) as a parameter for guiding PET is a recent suggestion. Using CMV load kinetics through the first two consecutive positive qPCR determinations to calculate the dt (spaced no more than 10 days apart and with load increments not less than 0.5 log10), it was determined that, in patients not receiving CMV prophylaxis, dt ≤2 days predicted the need to administer PET with a sensitivity of 100% when the established threshold for PET is 1,500 IU/mL (around 1,000 copies/mL).[34] This strategy results in shorter PET times, without a higher incidence of recurrent DNAemia.[35] The dt calculated from the CMV loads provided by different qPCRs is similar, given their collinearity for low load intervals, contrary to the magnitude of the loads.[36] The use of dt therefore allows direct comparison of results obtained in centers that use similar or different qPCRs. Therefore, the group recommends it dt use (BIII), in addition to qPCR CMV viral load, in the context of clinical trials, in order to generate evidence.
4. Question 4: What is the value of CMV DNA load quantitation for diagnosing CMV disease, especially CMV pneumonia and gastrointestinal disease?
Diagnosis of proven CMV pneumonia and gastrointestinal (GI) disease requires histopathological and virological evidence (observation of cytopathogenic effect/conventional culture/detection of viral proteins by immunohistochemistry -IHC- in biopsy material).[37] Detection of viral DNA in bronchoalveolar lavage (BAL) is not diagnostic, since it may simply reflect asymptomatic shedding.[37] The absence of CMV DNA in BAL has a negative predictive value close to 100%.[11,38,39] Although the probability of CMV pneumonia rises in parallel with increased viral load in BAL, especially in patients with a high pre-test probability, a diagnostic threshold has not been reached. A threshold value of 500 IU/mL has been suggested to discriminate between disease (higher values) and asymptomatic shedding (lower values).[38] In a subsequent study, it was confirmed that the presence of CMV loads greater than this threshold is frequent in the BAL of patients with a low probability of CMV pneumonia.[39] The lack of homogeneous BAL collection protocols and variability in the analytical characteristics of qPCRs make it extremely difficult to establish a universal diagnostic CMV burden threshold.
As in BAL samples, CMV DNA detection in feces or intestinal biopsies is not diagnostic. However, CMV-PCR shows the same sensitivity (100%), specificity (98%), and positive (93%) and negative predictive value (100%) as CMV-IHC in the G-I tract.[40] Nevertheless, the potential value of quantifying CMV load in intestinal biopsies requires further validation.
Immune Monitoring.
5. Question 5: Specific CMV immune monitoring: in which patients and for what purpose?
Systematic monitoring of the specific T-cell immune response against CMV could be useful to identify patients at risk for primary, recurrent or clinically refractory CMV DNAemia who are amenable to treatment with specific T lymphocyte-adoptive T cell transfer and end-organ disease.[41–43] The best marker of protection against these clinical events is the number of CD8+ and/or CD4+ T lymphocytes that express interferon gamma (IFNγ) after being stimulated in vitro with CMV antigens (particularly pp65 and IE-1).[41–43] Various protection thresholds have been proposed but not clinically validated. These cells can be quantified by flow cytometry with intracellular cytokine staining (ICS), ELISpot (CMV Tspot/CMV T-Track) or enzyme immunoassay (Quantiferon® CMV). The clinical value of quantifying specific T lymphocytes against CMV has been proven in a few non-randomized prospective intervention studies.[44,45] Systematic immunological monitoring of allo-HSCT patients is not currently standard practice, and this is unlikely to change until its clinical value is proven in randomized trials.[29] However, in particular cases (i.e., recipients with prior CMV DNAemia, those with GvHD and/or under corticosteroids, or after ending LMV prophylaxis), the lack of specific anti-CMV T cells could be used to support continuous CMV monitoring over time. The group therefore recommends monitoring CMV immunity whenever possible in order to generate real-world evidence.
CMV Infection Control Strategies.
6. Question 6: Can we tailor the singular efficacy of LMV in CMV prophylaxis?
Although end-organ CMV disease can generally be reduced with PET, CMV DNAemia itself has been associated with increased non-relapse mortality in allo-HSCT receptors, suggesting deleterious indirect effects.[33] Several agents have been challenged as prophylaxis, but most did not demonstrate efficacy or were associated with an unacceptable toxicity.[46] Foscarnet (FOS) prophylaxis has been used in patients in uncontrolled trials only and its prolonged use as prophylaxis is limited by IV administration and toxicities.[47,48] Maribavir (MBV) failed to demonstrate a significant benefit on the incidence of DNAemia, CMV disease, or need of PET at week 24 and had no statistically significant effect in reducing mortality.[49] Finally, brincidofovir (BCDV) showed no significant difference in the incidence of clinically significant CMV infection (csCMV-I) at week 24 and was associated with increased GI toxicity.[50]
Only LMV reduced csCMV-I and all-cause mortality with a good safety profile.[51] Based on the results of the randomized phase 3 trial of letermovir prophylaxis, different guidelines have assigned it the highest level of recommendation (A-I).[11-13] Looking for patient subgroups that could most benefit, no significant differences were observed in the incidence of CMV DNAemia/pp65 antigenemia between the high-risk (related or unrelated donor with HLA mismatch, haploidentical donor, cord blood transplant, T-depletion, ATG or alemtuzumab use, GVHD grade ≥2) and low-risk groups (HLA-matched related or unrelated donor). A trend was observed towards higher incidence of CMV DNAemia in the haploidentical HSCT group, with no impact on mortality or CMV end-organ disease.51 A meta-analysis published in 2018 confirmed LMV as the best option in terms of efficacy and safety.[52]
Single-center reports found that haploidentical HSCT with posttransplant cyclophosphamide (PTCy) resulted in either increased or comparable DNAemia incidence compared to historical comparisons of HLA-matched HCT.[53,54] In a recent retrospective registry-based study performed by the GETH-TC, multivariate analysis showed that the risk of DNAemia was significantly higher in haploidentical HSCT PTCy patients [HR (95%) 2.17 (1.52–3.10); p<0.001] and in unrelated donor HSCT patients [HR (95%) 1.49 (1.05–2.10); p<0.03] than when using an HLA-identical family donor16. Recently, however, PTCy itself (regardless of donor source or HLA match) has been considered a risk factor for DNAemia incidence.55 In this study of the Center for International Blood and Marrow Transplantation Research (CIBMTR) comparing patients receiving haploHSCT with PTCy (n=757), matched related (MR) with PTCy (n=403), or MR with calcineurin inhibitor-based prophylaxis (CNI) (n=1605), cumulative incidences of DNAemia by day 180 were 42%, 37%, and 23%, respectively (P=0,001), without differences in end-organ CMV disease incidence.[55]
Based on this information (and only if universal prophylaxis with LMV is restricted), our recommendation would be to use LMV in higher-risk patients (BII), including:
1. Seropositive recipients allografted from
seronegative CMV related or unrelated donor;
2. HSCT with at least one D/R HLA mismatch at the A, B or DR loci;
3. HSCT using PTCy;
4. CBT, and
5. Ex vivo T cell depletion.
2. HSCT with at least one D/R HLA mismatch at the A, B or DR loci;
3. HSCT using PTCy;
4. CBT, and
5. Ex vivo T cell depletion.
7. Question 7: When should LMV prophylaxis be withdrawn?
Implementation of LMV in clinical practice has raised new questions, including those referring to the optimal duration. The pivotal trial observed a clear clinical benefit in all patients receiving LMV up to day +100 post-transplant, uniformly and independently of other characteristics and risk factors. However, it also showed a clear 12% increase in csCMV-I between discontinuation of LMV at day +100 and week 24. This increase in late events due to CMV after day +100 occurs preferentially in high-risk patients, particularly those with GVHD and on treatment with corticosteroids. These patients could potentially benefit from maintaining LMV prophylaxis beyond day +100.[51]
Recently, Russo et al. published the results of a phase III clinical trial to evaluate the efficacy and safety of LMV in prophylaxis maintained up to day +200 (NCT03930615).[56] After completing the first 100 days of prophylaxis, high-risk patients were randomized to continue receiving LMV versus placebo (ratio 2:1). The rate of csCMV-I between weeks 14 and 28 was reduced from 18.9% in the placebo group to 2.8% in the LMV arm (p<0.0005), with a safety profile and similar adverse effects in the two arms.[56] A 10% increase in csCMV-I has been also noted after LMV withdrawal, however, which warrants further CMV monitoring in high-risk patients after LMV stop.
Based on these results, we recommend continuing LMV prophylaxis until day +100 in all eligible patients, extended to at least until day +200 during active GVHD treated with corticosteroids (>0.5 mg/kg/day) (AI). In this setting, immunological monitoring could eventually prove useful to guide optimal duration of LMV prophylaxis (BII).
8. Question 8: How should breakthrough DNAemia episodes during CMV prophylaxis be managed?
A proportion of patients (7.4%) will present breakthrough DNAemia requiring PET while on prophylaxis with LMV51 and risk factors been identified, including cumulative corticosteroid dose, PTCy use, and D-/R+ CMV serostatus.[57,58] As has been previously discussed, the most convenient CMV-DNAemia level to guide PET treatment initiation during LMV prophylaxis is not yet clearly defined. Nonetheless, our recommendation is to use a higher CMV DNAemia threshold than is used to guide PET in patients who do not receive prophylaxis.6 The group recommends not to treat a single positive PCR to avoid unnecessary antiviral therapy in self-resolving “blips” (the presence of CMV DNA at any level in a single plasma specimen, preceded and succeeded by a negative PCR specimen, 7 days apart)(BII).[59,60] In cases of breakthrough CMV DNAemia, we advocate performing molecular CMV mutational studies when possible. However, given that CMV DNAemia may be an expression of abortive infection due to the mechanism of action of letermovir, as discussed before, we and others recommend confirming active viral replication using virus isolation, DNAse technique, or by checking CMV-RNAemia before performing mutational studies.[61] Although the frequency of CMV mutations conferring resistance to LMV is low,[51] identifying UL56 gene mutations (V236M, C325W) may be helpful in avoiding extended LMV prophylaxis, switching to PET strategy and selecting the most adequate agent.[62]
9. Question 9: Is secondary prophylaxis recommended in patients with recurrent CMV-DNAemia?
A subset of patients will develop recurrent CMV-DNAemia, requiring several rounds of antiviral therapy. These patients are usually high (D-/R+), or high-intermediate (D+/R+) serological risk, receiving corticosteroids as GVHD treatment, and in the first six months post-HSCT.59,60 In these cases, it would be clinically justified to perform secondary prophylaxis after CMV DNAemia clearance of the second episode of reactivation and maintain it until corticosteroids withdrawal or evidence of immune reconstitution.[29] As noted above, protective levels have been proposed but not yet clinically validated.[44]
Given the experience of real-life data of secondary prophylaxis,63-66 LMV could be the treatment of choice in this situation, provided there is no LMV-resistant mutation and negative DNAemia before LMV onset (BII).[51,67–69] Secondary prophylaxis with LMV after initial failure of primary prophylaxis could be an option in cases of defective absorption suspicion in recipients with diarrhea, provided that CMV mutations conferring resistance to LMV can be reasonably excluded (BIII).
10. Question 10: Is PET still an option as a primary strategy for CMV infection/disease?
As mentioned above, the clinical superiority of prophylaxis with LMV over PET strategies has been demonstrated in phase III trial and several real-life studies. In countries where universal prophylaxis with LMV is not feasible, however, PET is the recommended strategy to prevent CMV disease, and the latter method is also used after LMV prophylaxis failure.
Intravenous ganciclovir (GCV) (AI) and oral valganciclovir (VGCV) are the most frequently used agents, with myelotoxicity and nephrotoxicity being the toxicity limitation.[11] A randomized clinical trial showed that FOS is as effective as GCV,[70] and therefore has the same recommendation level (AI). Since it presents less myelotoxicity than GCV, its use is recommended in patients with neutropenia or thrombocytopenia.
Recently a multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT compared maribavir 400 mg twice daily or valganciclovir for 8 weeks with 12 weeks of follow-up in 547 patients.[71] Although noninferiority of MBV to VGCV for the primary endpoint was not achieved based on the prespecified noninferiority margin, MBV demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Although. MBV did not granted FDA/EMA indication as first line CMV PET, given its safety profile, the consensus recommend to considered it as an alternative in patients who develop neutropenia (BI).
11. Question 11: When to stop antiviral therapy in PET strategies?
ECIL and ASTCT guidelines recommend stopping PET upon negative PCR result after a minimum 15 days of treatment.[11,12] A recent small study suggests that PET can be stopped after the first negative PCR regardless of the duration of treatment up to that time point, without increasing the risk of recurrence and limiting drug-related toxicities as far as possible.[72] More studies are needed to change present guidelines, that the consensus support (AII).
Pharmacological Resistance.
12. Question 12: When to suspect and how to confirm CMV resistance to antivirals?
Definitions of CMV infection refractory (clinical) or resistant (genetic) to antivirals for use in clinical trials were proposed by Chemaly et al.[73] Nonetheless, the refractory definition should probably be wider in the clinical setting, including patients with long-lasting positive DNAemia of < 1 log or positive DNAemia after more than 21 days of PET onset.
Refractory CMV infection has a higher incidence than resistant in HSCT recipients, with rates varying between 29% to 39% and 1.7% to 14.5%, respectively.[74] This substantial difference is likely driven by poor host immunity in response to active viral replication, leading to refractory infection despite antiviral therapy and frequent underdiagnosis due to scarce diagnostic units for clinically useful time-results.[75]
Risk factors for the relatively common refractoriness and infrequent antiviral genetic resistance are summarized in Supplementary material Table 2.[73]
Systematic studies in patients treated with allo-HSCT have shown an increasing incidence of genetic resistance, more frequently mutations in UL97 and much less frequently in UL54.[76,77] The canonical mutations M460V/I, H520Q, C592G, A594V, L595S appear in 80% of cases and are associated with resistance only to GCV; therefore, diagnostic genotyping should include codon ranges of at least 440–640. Generally, mutations in the UL54 polymerase gene are preceded by mutations in the UL97 gene, increasing the level of resistance to GCV and conferring cross-resistance to FOS and cidofovir (CDV). This fact reinforces the importance of early virological study since the evolution of resistance and/or multi-resistance increases gradually and progressively with time of exposure to the antiviral drug.[78] For this reason, genetic resistance study is recommended when there is clinical suspicion.[11] Confirmation of resistance to antivirals is done by genotypic and phenotypic methods (see Supplementary material Table 3).[79,80] In recent years, next generation sequencing (NGS) enabled the study of the entire spectrum of genetic diversity and can also detect mutations in virus populations of only 5%, which may play an important role in the evolution of virus resistance.[81,82] Based on these data, our recommendation is to perform mutational analysis if no negative DNAemia is achieved after three weeks of optimal antiviral treatment or if it increases after two weeks of treatment (BII).
13. Question 13: How should refractory or resistant CMV infection be managed?
Management of patients with refractory or genetically resistant CMV infection requires the use of an anti-CMV drug not resistant to the detected mutation, following the recommendations of the consensus group supported by ECIL-7 Guidelines.[11]
Until now initial treatment for a csCMV-I has usually been done with GCV or VGCV, and when refractoriness or (more commonly) severe pancytopenia appears, the drug of choice is FOS (AIIu) or CDV at 5 mg/kg/week if renal function is maintained (BIIu). Recently, oral MBV at a dose of 400 mg every 12 hours has been authorized and will be considered a new standard, at least in patients with hematological or renal toxicity (AI).[83] The combination of GCV and FOS at half doses can be used as second or third line (CIIu). Provided there is no clinical alloreactivity (active GVHD), immunosuppression should be reduced, including steroids (BIII). Leflunomide and artesunate can also be considered for third line treatment (CIII). Until now, there is no evidence that allows the use of LMV or BCDV as rescue treatments for refractory CMV infection.
Cell Therapy in CMV Infection.
14. Question 14: When and in whom should adoptive transfer of virus-specific T lymphocytes be used?
Adoptive transfer of virus-specific T cells (VSTs) has demonstrated safety and efficacy in treating virus-associated diseases and malignancies in HSCT, including CMV, adenovirus, BK virus, human herpesvirus,6 and Epstein-Barr virus.[84] This has led to the recent approval of the first allogeneic anti-viral T cell product (tabelecleucel) for the treatment of EBV+ post-transplant lymphoproliferative disease.[85]
There are two main strategies for obtaining CMV-specific lymphocytes: direct magnetic selection using CMV tetramers/streptamers[86] or ex-vivo expansion of VSTs prior to infusion.[87] Both approaches have proven effective, but a direct comparison between them has not been made.
Currently, two phase III trials are employing adoptive cell therapy for CMV. In a prophylactic phase III study (EudraCT No. 2021-005105-27), posoleucel, a third-party multivirus-specific T cell therapy, was being evaluated for its potential to prevent CMV and other viral reactivations in high-risk HSCT patients, following promising results in the phase II trial.[88] However, the company (AlloVir) announced in December 2023 that they were discontinuing the phase III trial because pre-planned analyses showed it was unlikely to meet their primary endpoints. These results raise questions about the applicability of VSTs in the prophylactic context. In the treatment setting, the TRACE study (EudraCT No. 2018-000853-29) is a phase III trial testing a single infusion of allogeneic multi-specific VSTs generated using the CliniMACS Prodigy system and IFN-gamma magnetic capture for refractory viral infections after HSCT, including CMV. However, the trial is facing recruitment challenges, partly due to logistical complexities and time requirements for cellular product production. Nonetheless, this trial is anticipated to provide valuable insights into the treatment of CMV. An alternative approach, currently in development in academic centers and showing promise in phase 2 trials, involves establishing banks of third-party donor cryopreserved CMV-specific VSTs covering the most common HLAs. This ready-to-infuse off-the-shelf allogeneic therapy is expected to emerge as the cellular therapy solution for pharmacologically resistant/refractory CMV infection, with clinical trials warranted.
Concerning the clinical context of administration of CMV-CTLs, the consensus recommends to considered their use in the following patients (BII): a) with CMV organic disease resistant to first-line antiviral treatment; b) with resistant or refractory CMV DNAemia in two prior lines of treatment; c) with one or more documented genetic mutations associated with resistance to GCV or FOS, d) with recurrent (> 2 episodes) or persistent (> 6 weeks) CMV DNAemia, or e) with recurrent CMV-DNAemia with a low number of specific T lymphocytes against CMV identifying patients who are candidates for secondary prophylaxis or alternatively cell therapy.[29] By contrast, the use of cell therapy is limited in patients receiving high dose corticosteroid (≥ 1 mg/Kg/day), ATG or alemtuzumab (DII).
15. Question 15: Which antiviral drug combinations are available and/or under development?
The availability of drugs with different mechanisms of action against CMV makes their combination attractive in refractory cases. Expert guidelines generally discourage the use of drug combinations, which are limited to GCV plus FOS suggested as second or third-line therapy with low levels of evidence.11 However, various drug combinations active against CMV have recently been explored in in vitro models.82 Studies of the in vitro effect of MBV showed additive interactions with FOS, CDV, LMV, and GW275175X in wild-type and mutant CMV strains, exhibiting great antagonism with GCV and strong synergy with sirolimus. In turn, LMV and sirolimus combined also showed an additive effect in vitro in terms of anti-CMV activity in epithelial cells. Although many combinations remain to be explored, these observations may be useful for designing future clinical studies in both prophylaxis and treatment.
The biological and clinical activity of the anti-CMV alternative agents is summarized in Supplementary material Table 4.
16. Question 16: Are there differences in CMV infection management in pediatric patients?
Management of CMV infection is similar in pediatric and adult patients treated with HSCT, with the main differences deriving from the use of VGCV and LMV.
Valganciclovir. VGCV, a valine and GCV ester derivative, serves as an alternative to oral and intravenous administration for CMV prophylaxis and treatment. In adults, a daily dose of 900 mg provides GCV exposure equivalent to intravenous administration at 5 mg/kg. Limited data on VGCV use in children have been published, and no consensus on pediatric dosing has been established. Studies in pediatric transplant recipients emphasize the inadequacy of dosing algorithms based solely on body surface area, highlighting the importance of incorporating renal function, assessed by estimated creatinine clearance (CrCLS).[89] Age-independent bioavailability and predominant renal elimination of VGCV support the use of algorithms incorporating CrCLS in pediatric patients, achieving comparable GCV exposures to adults.[90] FDA approval for preventing CMV disease in high-risk pediatric transplant patients is based on a dosing algorithm with a maximum dose of 900 mg if CrCLS exceeds 150 mL/min/1.73 m². The requirement to take VGCV with food led to the development of an oral suspension (50 mg/mL), bioequivalent to tablets, benefiting pediatric patients unable to swallow.[91] The suspension is well-tolerated, with mostly mild or moderate gastrointestinal adverse events. A study on CMV mutations in pediatric patients using VGCV for prophylaxis indicated a low incidence of resistance-associated mutations, with no clinical consequences from resistant viruses.[92]
Letermovir. Recent results from a registry-based study of the Infectious Diseases Working Group of the Italian Association of Pediatric Hematology-Oncology (AIEOP),93 a single center study[94] and the phase 2b open-label, single-arm clinical trial MK 8228-030 (NCT03940586)[95] have confirmed that pharmacokinetics, efficacy, safety, and tolerability of LMV in pediatric patients from birth to less than 18 years of age at risk of developing CMV infection and/or disease following HSCT are similar to adults. Administration of adult letermovir doses in this adolescent cohort resulted in exposures within adult clinical program margins and was associated with safety and efficacy similar to adults.[95]
Maribavir. In pediatric patients, a new clinical trial, SHP620-302: “A phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study to evaluate the efficacy and safety of MBV compared with VGCV for the treatment of CMV Infection in HSCT Recipients” to assess safety and effectiveness in children is ongoing.
Discussion and Summary of Recommendations.
Advances in CMV monitoring
and management have revolutionized approaches to infection control in
transplant settings. From virological and immune monitoring to tailored
prophylactic strategies and novel therapeutic interventions, ongoing
research endeavors aim to optimize patient outcomes and mitigate the
impact of CMV-related morbidity and mortality. Continued collaboration
and multidisciplinary efforts are essential to address unanswered
questions and refine existing guidelines, ultimately improving the
standard of care for patients undergoing allo-HSCT. A summary of
recommendations agreed by the consensus is detailed in Table 1.
This consensus highlights areas in need of further research to optimize CMV management. CMV DNAemia monitoring in patients undergoing CAR-T therapy remains contentious due to varying clinical outcomes and the potential for spontaneous resolution. In the allo-HSCT setting, the consensus recommends regular monitoring of CMV DNAemia in the patient when either the patient or donor is CMV seropositive, including those with GVHD or under letermovir prophylaxis. The emergence of CMV DNAemia during letermovir prophylaxis presents challenges in interpretation, with the ongoing debate surrounding the need and threshold for PET inception. The utilization of CMV DNA doubling time (DT) has emerged as a promising tool to guide PET initiation, ensuring timely intervention without compromising patient outcomes.
Assessment of CMV-specific T-cell immunity might identify patients at risk of CMV DNAemia and help guide therapeutic interventions. While systematic immunological monitoring is not yet standard practice, it may be warranted in specific clinical scenarios, such as recipients with prior CMV DNAemia or those with GVHD. Further research is needed to validate the clinical utility of immune monitoring and establish standardized protocols.
LMV has emerged as a cornerstone in CMV prophylaxis, demonstrating efficacy and safety in reducing CMV infection and mortality post-HSCT. Nonetheless, personalized prophylactic strategies can be informed by identifying risk factors such as the use of posttransplant cyclophosphamide, the real significance of breakthrough DNAemia, and the use of CMV-specific T-cell immunological monitoring. Careful consideration of antiviral drug selection is essential in cases of breakthrough CMV DNAemia during prophylaxis, with emphasis on avoiding unnecessary toxicity and assessing for potential LMV resistance mutations. Furthermore, implementing secondary prophylaxis with LMV may be warranted in patients with recurrent CMV DNAemia, provided that careful monitoring for resistance mutations is also carried out.
The emergence of CMV resistance to antiviral therapy poses challenges in clinical management, underscoring the importance of promptly identifying and selecting alternative agents. Mutational analysis is recommended for cases of refractory CMV infection. However, in this context, antiviral pharmacological combinations lack support from clinical trials, and access to adoptive transfer of virus-specific T lymphocytes is limited in most centers. Currently, available data are derived from heterogeneous studies conducted in different clinical contexts; therefore, optimal dosing and administration schedules for VSTs are not known. Nonetheless, clinical responses have been achieved even with doses as low as 4.1 x 103/kg.[96] It should also be taken into account that efficacy partly depends on in vivo expansion and that memory cells have a greater potential for expansion than terminally differentiated T cells;[97] therefore, selecting this subset may improve the efficiency of the product. To date, most trials exploring the use of adoptively transferred viral-specific T cells have been in second or later lines of therapy after the failure of antiviral drugs.
Despite issues of feasibility and the potential for failure due to viral recognition through a non-shared HLA allele in the HLA-disparate setting, HSCT donor-derived viral-specific T cells have demonstrated benefit for refractory infections as well as for prophylaxis and first-line treatment. Infusion of third-party derived partially HLA-matched VSTs has a demonstrated benefit in the refractory setting but could be considered as a first-line therapy or even prophylactically in high-risk patients with predicted intolerance to antiviral medications due to organ dysfunction. The preliminary feasibility, safety, and efficacy of allogeneic, off-the-shelf, multi-virus-specific T-cell therapy has been demonstrated for use as first-line therapy[98] and as prophylaxis.[99] As a next step, further research is needed to elucidate optimal treatment strategies and mitigate the risk of resistance development.
In pediatric patients, valganciclovir and letermovir are promising options for CMV prophylaxis and treatment, with ongoing studies evaluating safety and efficacy. Pediatric-specific dosing algorithms and clinical trials are essential to ensure optimized management strategies tailored to this patient population.
 |
|
This consensus highlights areas in need of further research to optimize CMV management. CMV DNAemia monitoring in patients undergoing CAR-T therapy remains contentious due to varying clinical outcomes and the potential for spontaneous resolution. In the allo-HSCT setting, the consensus recommends regular monitoring of CMV DNAemia in the patient when either the patient or donor is CMV seropositive, including those with GVHD or under letermovir prophylaxis. The emergence of CMV DNAemia during letermovir prophylaxis presents challenges in interpretation, with the ongoing debate surrounding the need and threshold for PET inception. The utilization of CMV DNA doubling time (DT) has emerged as a promising tool to guide PET initiation, ensuring timely intervention without compromising patient outcomes.
Assessment of CMV-specific T-cell immunity might identify patients at risk of CMV DNAemia and help guide therapeutic interventions. While systematic immunological monitoring is not yet standard practice, it may be warranted in specific clinical scenarios, such as recipients with prior CMV DNAemia or those with GVHD. Further research is needed to validate the clinical utility of immune monitoring and establish standardized protocols.
LMV has emerged as a cornerstone in CMV prophylaxis, demonstrating efficacy and safety in reducing CMV infection and mortality post-HSCT. Nonetheless, personalized prophylactic strategies can be informed by identifying risk factors such as the use of posttransplant cyclophosphamide, the real significance of breakthrough DNAemia, and the use of CMV-specific T-cell immunological monitoring. Careful consideration of antiviral drug selection is essential in cases of breakthrough CMV DNAemia during prophylaxis, with emphasis on avoiding unnecessary toxicity and assessing for potential LMV resistance mutations. Furthermore, implementing secondary prophylaxis with LMV may be warranted in patients with recurrent CMV DNAemia, provided that careful monitoring for resistance mutations is also carried out.
The emergence of CMV resistance to antiviral therapy poses challenges in clinical management, underscoring the importance of promptly identifying and selecting alternative agents. Mutational analysis is recommended for cases of refractory CMV infection. However, in this context, antiviral pharmacological combinations lack support from clinical trials, and access to adoptive transfer of virus-specific T lymphocytes is limited in most centers. Currently, available data are derived from heterogeneous studies conducted in different clinical contexts; therefore, optimal dosing and administration schedules for VSTs are not known. Nonetheless, clinical responses have been achieved even with doses as low as 4.1 x 103/kg.[96] It should also be taken into account that efficacy partly depends on in vivo expansion and that memory cells have a greater potential for expansion than terminally differentiated T cells;[97] therefore, selecting this subset may improve the efficiency of the product. To date, most trials exploring the use of adoptively transferred viral-specific T cells have been in second or later lines of therapy after the failure of antiviral drugs.
Despite issues of feasibility and the potential for failure due to viral recognition through a non-shared HLA allele in the HLA-disparate setting, HSCT donor-derived viral-specific T cells have demonstrated benefit for refractory infections as well as for prophylaxis and first-line treatment. Infusion of third-party derived partially HLA-matched VSTs has a demonstrated benefit in the refractory setting but could be considered as a first-line therapy or even prophylactically in high-risk patients with predicted intolerance to antiviral medications due to organ dysfunction. The preliminary feasibility, safety, and efficacy of allogeneic, off-the-shelf, multi-virus-specific T-cell therapy has been demonstrated for use as first-line therapy[98] and as prophylaxis.[99] As a next step, further research is needed to elucidate optimal treatment strategies and mitigate the risk of resistance development.
In pediatric patients, valganciclovir and letermovir are promising options for CMV prophylaxis and treatment, with ongoing studies evaluating safety and efficacy. Pediatric-specific dosing algorithms and clinical trials are essential to ensure optimized management strategies tailored to this patient population.
Acknowledgments
The
study was performed in collaboration with the Spanish Group of
Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC).
Author Contributions
Each
author identified, reviewed, and summarized the literature and their
own experience on the assigned key questions and approved the final
version of the manuscript. CS, JLP, and DN drafted the manuscript.
References
- Schmidt-Hieber M, Labopin M, Beelen D, et al. CMV serostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation: A report from the Acute Leukemia Working Party of EBMT. Blood. 2013;122(19):3359-3364. https://doi.org/10.1182/blood-2013-05-499830 PMid:24037724
- Solano de la Asuncion C, Giménez E, Hernández-Boluda JC, et al. Immunobiology of cytomegalovirus infection in patients with haematological malignancies undergoing treatment with small molecule inhibitors. Br J Haematol. 2023;200(6):e58-e61. https://doi.org/10.1111/bjh.18655 PMid:36652997
- árquez-Algaba E, Iacoboni G, Pernas B, et al. Impact of Cytomegalovirus Replication in Patients with Aggressive B Cell Lymphoma Treated with Chimeric Antigen Receptor T Cell Therapy. Transplant Cell Ther. 2022;28(12):851.e1-851.e8. https://doi.org/10.1016/j.jtct.2022.09.007 PMid:36221995
- Chen G, Herr M, Nowak J, et al. Cytomegalovirus reactivation after CD19 CAR T-cell therapy is clinically significant. Haematologica. 2023;108(2):615-620. https://doi.org/10.3324/haematol.2022.281719 PMid:36263844 PMCid:PMC9890024
- 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;3026(15):1-9. https://doi.org/10.1016/S2352-3026(15)00289-6 PMid:26947200
- Einsele H, Ljungman P, Boeckh M. How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation. Blood. 2020;135(19):1619-1629. https://doi.org/10.1182/blood.2019000956 PMid:32202631 PMCid:PMC7484743
- Ljungman P, Tridello G, Piñana JL, et al. Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry. Front Immunol. 2023;14(March):1-11. https://doi.org/10.3389/fimmu.2023.1125824 PMid:36960069 PMCid:PMC10028143
- 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. https://doi.org/10.1182/blood-2003-10-3616 PMid:14644993
- Cesaro S, Ljungman P, Tridello G, et al. New trends in the management of cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a survey of the Infectious Diseases Working Pary of EBMT. Bone Marrow Transplant. 2022;(July). https://doi.org/10.21203/rs.3.rs-1818073/v1
- Dadwal SS. Update on prevention of cytomegalovirus in hematopoietic cell transplantation. Curr Opin Infect Dis. 2019;32(1):63-68. https://doi.org/10.1097/QCO.0000000000000517 PMid:30543548
- Ljungman P, de la Camara R, Robin C, et al. 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. https://doi.org/10.1016/S1473-3099(19)30107-0 PMid:31153807
- Girmenia C, Lazzarotto T, Bonifazi F, et al. Assessment and prevention of cytomegalovirus infection in allogeneic hematopoietic stem cell transplant and in solid organ transplant: A multidisciplinary consensus conference by the Italian GITMO, SITO, and AMCLI societies. Clin Transplant. 2019;33(10):e13666. https://doi.org/10.1111/ctr.13666 PMid:31310687
- Hakki M, Aitken SL, Danziger-Isakov L, et al. American Society for Transplantation and Cellular Therapy Series: #3-Prevention of Cytomegalovirus Infection and Disease After Hematopoietic Cell Transplantation. Transplant Cell Ther. 2021;27(9):707-719. https://doi.org/10.1016/j.jtct.2021.05.001 PMid:34452721
- Yong MK, Shigle TL, Kim YJ, Carpenter PA, Chemaly RF, Papanicolaou GA. American Society for Transplantation and Cellular Therapy Series: #4 - Cytomegalovirus treatment and management of resistant or refractory infections after hematopoietic cell transplantation: ASTCT Guidelines on CMV treatment. Transplant Cell Ther. 2021;27(12):957-967. https://doi.org/10.1016/j.jtct.2021.09.010 PMid:34560310
- Solano C, de la Camara R, Vazquez L, Lopez J, Gimenez E, Navarro D. Cytomegalovirus Infection Management in Allogeneic Stem Cell Transplant Recipients: a National Survey in Spain. J Clin Microbiol. 2015;53(8):2741-2744. https://doi.org/10.1128/JCM.01057-15 PMid:26063857 PMCid:PMC4508446
- Solano C, Vazquez L, Gimenez E, et al. Cytomegalovirus DNAemia and risk of mortality in allogeneic hematopoietic stem cell transplantation: Analysis from the Spanish Hematopoietic Transplantation and Cell Therapy Group. Am J Transplant. 2020; Online ahe.
- Ullmann AJ, Cornely OA, Donnelly JP, et al. ESCMID guideline for the diagnosis and management of Candida diseases 2012: Developing European guidelines in clinical microbiology and infectious diseases. Clin Microbiol Infect. 2012;18(SUPPL.7):1-8. https://doi.org/10.1111/1469-0691.12037 PMid:23137133
- Solano de la Asunción C, Hernani R, Albert E, et al. Cytomegalovirus DNAemia in haematological patients undergoing CD19-directed chimeric antigen receptor T-cell therapy: should it be systematically monitored? Clin Microbiol Infect. 2023;29(8):1093-1095. https://doi.org/10.1016/j.cmi.2023.05.010 PMid:37182642
- Kampouri E, Little JS, Rejeski K, Manuel O, Hammond SP, Hill JA. Infections after chimeric antigen receptor (CAR)-T-cell therapy for hematologic malignancies. Transpl Infect Dis. 2023;25(S1):1-17. https://doi.org/10.1111/tid.14157 PMid:37787373
- Rejeski K, Wang Y, Albanyan O, et al. The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL. Am J Hematol. 2023;98(11):1699-1710. https://doi.org/10.1002/ajh.27056 PMid:37584447
- Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2021;385(3):228-238. https://doi.org/10.1056/NEJMoa2033122 PMid:34260836
- Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020;382(19):1800-1810. https://doi.org/10.1056/NEJMoa1917635 PMid:32320566
- Lebon D, Dujardin A, Caulier A, et al. Ruxolitinib-induced reactivation of cytomegalovirus and Epstein-Barr virus in graft-versus-host disease. Leuk Res. 2023;125(December 2022). https://doi.org/10.1016/j.leukres.2022.107005 PMid:36580876
- Akahoshi Y, Kimura SI, Inamoto Y, et al. Effect of Cytomegalovirus Reactivation with or Without Acute Graft-Versus-Host Disease on the Risk of Nonrelapse Mortality. Clin Infect Dis. 2021;73(3):E620-E628. https://doi.org/10.1093/cid/ciaa1871 PMid:33341890
- Solano de la Asunción C, Terol MJ, Saus A, et al. Cytomegalovirus-specific T-cell immunity and DNAemia in patients with chronic lymphocytic leukaemia undergoing treatment with ibrutinib. Br J Haematol. 2021;195(4):637-641. https://doi.org/10.1111/bjh.17732 PMid:34402042
- de la Asunción CS, Giménez E, Hernández-Boluda JC, et al. Assessment of the potential value of plasma Torque Teno virus DNA load monitoring to predict cytomegalovirus DNAemia in patients with hematological malignancies treated with small molecule inhibitors: A proof-of-concept study. J Med Virol. 2023;95(7):e28933. https://doi.org/10.1002/jmv.28933 PMid:37403897
- Cassaniti I, Colombo AA, Bernasconi P, et al. Positive HCMV DNAemia in stem cell recipients undergoing letermovir prophylaxis is expression of abortive infection. Am J Transplant. 2021;21(4):1622-1628. https://doi.org/10.1111/ajt.16450 PMid:33320429
- Weinberger S, Steininger C. Reliable quantification of Cytomegalovirus DNAemia in Letermovir treated patients. Antiviral Res. 2022;201(January):105299. https://doi.org/10.1016/j.antiviral.2022.105299 PMid:35354065
- Giménez E, Guerreiro M, Torres I, et al. Features of cytomegalovirus DNAemia and virus-specific T-cell responses in allogeneic hematopoietic stem-cell transplant recipients during prophylaxis with letermovir. Transpl Infect Dis. Published online February 7, 2023. https://doi.org/10.1111/tid.14021 PMid:36748748
- Solano C, Giménez E, Albert E, Piñana JL, Navarro D. Immunovirology of cytomegalovirus infection in allogeneic stem cell transplant recipients undergoing prophylaxis with letermovir: A narrative review. J Med Virol. 2023;95(8):e29005. https://doi.org/10.1002/jmv.29005 PMid:37526411
- Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113(23):5711-5719. https://doi.org/10.1182/blood-2008-10-143560 PMid:19299333 PMCid:PMC2700312
- Sadowska-Klasa A, Leisenring WM, Limaye AP, Boeckh M. Cytomegalovirus Viral Load Threshold to Guide Preemptive Therapy in Hematopoietic Cell Transplant Recipients: Correlation With Cytomegalovirus Disease. J Infect Dis. 2024;229(5):1435-1439. https://doi.org/10.1093/infdis/jiad386 PMid:37682870
- Giménez E, Torres I, Albert E, et al. Cytomegalovirus ( CMV ) infection and risk of mortality in allogeneic hematopoietic stem cell transplantation (Allo - HSCT): A systematic review, meta-analysis, and meta-regression analysis. Am J Transpl. 2019;19(March):2479-2494. https://doi.org/10.1111/ajt.15515 PMid:31247126
- Gimenez E, Munoz-Cobo B, Solano C, Amat P, Navarro D. Early kinetics of plasma cytomegalovirus DNA load in allogeneic stem cell transplant recipients in the era of highly sensitive real-time PCR assays: does it have any clinical value? J Clin Microbiol. 2014;52(2):654-656. https://doi.org/10.1128/JCM.02571-13 PMid:24478505 PMCid:PMC3911364
- Solano C, Gimenez E, Pinana JL, et al. Preemptive antiviral therapy for CMV infection in allogeneic stem cell transplant recipients guided by the viral doubling time in the blood. Bone Marrow Transplant. 2016;51(5):718-721. https://doi.org/10.1038/bmt.2015.303 PMid:26642339
- Vinuesa V, Gimenez E, Solano C, Gimeno C, Navarro D. Would Kinetic Analyses of Plasma Cytomegalovirus DNA Load Help to Reach Consensus Criteria for Triggering the Initiation of Preemptive Antiviral Therapy in Transplant Recipients? Clin Infect Dis. 2016;63(11):1533-1535. https://doi.org/10.1093/cid/ciw608 PMid:27578818
- Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017;64(1):87-91. https://doi.org/10.1093/cid/ciw668 PMid:27682069
- Boeckh M, Stevens-Ayers T, Travi G, et al. Cytomegalovirus (CMV) DNA Quantitation in Bronchoalveolar Lavage Fluid From Hematopoietic Stem Cell Transplant Recipients With CMV Pneumonia. J Infect Dis. 2017;215(10):1514-1522. https://doi.org/10.1093/infdis/jix048 PMid:28181657 PMCid:PMC5461426
- Pinana JL, Gimenez E, Gomez MD, et al. Pulmonary cytomegalovirus (CMV) DNA shedding in allogeneic hematopoietic stem cell transplant recipients: Implications for the diagnosis of CMV pneumonia. J Infect. 2019;78(5):393-401. https://doi.org/10.1016/j.jinf.2019.02.009 PMid:30797790 PMCid:PMC7126576
- Suárez-Lledó M, Marcos MÁ, Cuatrecasas M, et al. Quantitative PCR Is Faster, More Objective, and More Reliable Than Immunohistochemistry for the Diagnosis of Cytomegalovirus Gastrointestinal Disease in Allogeneic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2019;25(11):2281-2286. https://doi.org/10.1016/j.bbmt.2019.07.016 PMid:31325586
- Romero
PP, Blanco P, Giménez E, Solano C, Navarro D. An update on the
management and prevention of cytomegalovirus infection following
allogeneic hematopoietic stem cell transplantation. Future Virol.
2015;10(2). https://doi.org/10.2217/fvl.14.102
- Meesing A, Razonable RR. Pharmacologic and immunologic management of cytomegalovirus infection after solid organ and hematopoietic stem cell transplantation. Expert Rev Clin Pharmacol. 2018;11(8):773-788. https://doi.org/10.1080/17512433.2018.1501557 PMid:30009675
- Khanna R. Immune Monitoring of Infectious Complications in Transplant Patients: an Important Step towards Improved Clinical Management. J Clin Microbiol. 2018;56(4). https://doi.org/10.1128/JCM.02009-17 PMid:29343541 PMCid:PMC5869832
- Navarro D, Amat P, de la Camara 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. https://doi.org/10.1093/ofid/ofw107 PMid:27419179 PMCid:PMC4943548
- Avetisyan G, Aschan J, Hagglund H, Ringden O, Ljungman P. Evaluation of intervention strategy based on CMV-specific immune responses after allogeneic SCT. Bone Marrow Transplant. 2007;40(9):865-869. https://doi.org/10.1038/sj.bmt.1705825 PMid:17724444
- 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. https://doi.org/10.1182/bloodadvances.2018016493 PMid:30154125 PMCid:PMC6113617
- 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.
- 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. https://doi.org/10.1038/sj.bmt.1702450 PMid:10918402
- Marty FM, Ljungman P, Papanicolaou GA, et al. 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. https://doi.org/10.1016/S1473-3099(11)70024-X PMid:21414843
- Marty FM, Winston DJ, Chemaly RF, et al. 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. https://doi.org/10.1016/j.bbmt.2018.09.038 PMid:30292744 PMCid:PMC8196624
- 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. https://doi.org/10.1056/NEJMoa1706640 PMid:29211658
- Gagelmann N, Ljungman P, Styczynski J, Kroger N. Comparative Efficacy and Safety of Different Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant. 2018;24(10):2101-2109. https://doi.org/10.1016/j.bbmt.2018.05.017 PMid:29777868
- Goldsmith SR, Slade M, DiPersio JF, et al. Cytomegalovirus viremia, disease, and impact on relapse in T-cell replete peripheral blood haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide. Haematologica. 2016;101(11):e465-e468. https://doi.org/10.3324/haematol.2016.149880 PMid:27443287 PMCid:PMC5394884
- Huntley D, Giménez E, Pascual MJ, et al. Incidence, features, and outcomes of cytomegalovirus DNAemia in unmanipulated haploidentical allogeneic hematopoietic stem cell transplantation with post-transplantation cyclophosphamide. Transpl Infect Dis. 2020;22(1):1-9. https://doi.org/10.1111/tid.13206 PMid:31677215
- Goldsmith SR, Abid MB, Auletta JJ, et al. Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis. Blood. 2021;137(23):3291-3305. https://doi.org/10.1182/blood.2020009362 PMid:33657221 PMCid:PMC8351903
- Russo D, Schmitt M, Pilorge S, et al. Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2024;11(2):e127-e135. https://doi.org/10.1016/S2352-3026(23)00344-7 PMid:38142695
- Perchetti GA, Biernacki MA, Xie H, et al. Cytomegalovirus breakthrough and resistance during letermovir prophylaxis. Bone Marrow Transplant. 2023;58(4):430-436. https://doi.org/10.1038/s41409-023-01920-w PMid:36693927
- Mizuno K, Sakurai M, Kato J, et al. Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2022;24(6):1-9. https://doi.org/10.1111/tid.13904 PMid:35870130
- Huntley D, Talaya A, Giménez E, et al. Features of Cytomegalovirus DNAemia Blips in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Implications for Optimization of Preemptive Antiviral Therapy Strategies. Biol Blood Marrow Transplant. 2020;26(5):972-977. https://doi.org/10.1016/j.bbmt.2020.01.015 PMid:32007638
- Giménez E, Guerreiro M, Torres I, et al. Features of cytomegalovirus DNAemia and virus-specific T-cell responses in allogeneic hematopoietic stem-cell transplant recipients during prophylaxis with letermovir. Transpl Infect Dis. 2023;25(2):1-10. https://doi.org/10.1111/tid.14021 PMid:36748748
- Piccirilli G, Lanna F, Gabrielli L, et al. CMV-RNAemia as a new marker of active viral replication in transplant recipients. J Clin Microbiol. 2024;62(5):2-6. https://doi.org/10.1128/jcm.01630-23 PMid:38534109 PMCid:PMC11078005
- Chaer F El, Shah DP, Chemaly RF. How i treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood. 2016;128(23):2624-2636. https://doi.org/10.1182/blood-2016-06-688432 PMid:27760756 PMCid:PMC5146744
- Lin A, Maloy M, Su Y, et al. Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: Real-world experience. Transpl Infect Dis. 2019;21(6):e13187. https://doi.org/10.1111/tid.13187 PMid:31585500 PMCid:PMC8573720
- Su Y, Stern A, Karantoni E, et al. Impact of Letermovir Primary Cytomegalovirus Prophylaxis on 1-Year Mortality After Allogeneic Hematopoietic Cell Transplantation: A Retrospective Cohort Study. Clin Infect Dis. 2022;(January 2013):1-10. https://doi.org/10.1093/cid/ciab1064 PMid:34979021 PMCid:PMC9477449
- Anderson A, Raja M, Vazquez N, Morris M, Komanduri K, Camargo J. Clinical "real-world" experience with letermovir for prevention of cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients. Clin Transplant. 2020;34(7):1-8. https://doi.org/10.1111/ctr.13866 PMid:32242979
- Robin C, Thiebaut A, Alain S, et al. Letermovir for Secondary Prophylaxis of Cytomegalovirus Infection and Disease after Allogeneic Hematopoietic Cell Transplantation: Results from the French Compassionate Program. Biol Blood Marrow Transplant. 2020;26(5):978-984. https://doi.org/10.1016/j.bbmt.2020.01.027 PMid:32035273
- Chemaly RF, Ullmann AJ, Stoelben S, et al. Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. N Engl J Med. 2014;370(19):1781-1789. https://doi.org/10.1056/NEJMoa1309533 PMid:24806159
- El Helou G, Razonable RR. Letermovir for the prevention of cytomegalovirus infection and disease in transplant recipients: an evidence-based review. Infect Drug Resist. 2019;12:1481-1491. https://doi.org/10.2147/IDR.S180908 PMid:31239725 PMCid:PMC6556539
- Restelli U, Croce D, Pacelli V, Ciceri F, Girmenia C. Cost-effectiveness analysis of the use of letermovir for the prophylaxis of cytomegalovirus in adult cytomegalovirus seropositive recipients undergoing allogenic hematopoietic stem cell transplantation in Italy. Infect Drug Resist. 2019;12:1127-1138. https://doi.org/10.2147/IDR.S196282 PMid:31190905 PMCid:PMC6512572
- Reusser P, Einsele H, Lee J, et al. Randomized multicenter trial of foscarnet versus ganciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell transplantation. Blood. 2002;99(4):1159-1164. https://doi.org/10.1182/blood.V99.4.1159 PMid:11830461
- Papanicolaou GA, Avery RK, Cordonnier C, et al. Treatment for First Cytomegalovirus Infection Post-Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir. Clin Infect Dis. 2024;78(3):562-572. https://doi.org/10.1093/cid/ciad709 PMid:38036487 PMCid:PMC10954327
- Solano C, Giménez E, Piñana JL, et al. When should preemptive antiviral therapy for active CMV infection be withdrawn from allogeneic stem cell transplant recipients? Bone Marrow Transplant. 2017;52(10):1448-1451. https://doi.org/10.1038/bmt.2017.109 PMid:28581458
- Chemaly RF, Chou S, Einsele H, et al. 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. https://doi.org/10.1093/cid/ciy696 PMid:30137245 PMCid:PMC7348585
- Khawaja F, Batista M V., El Haddad L, Chemaly RF. Resistant or refractory cytomegalovirus infections after hematopoietic cell transplantation: Diagnosis and management. Curr Opin Infect Dis. Published online 2019:565-574. https://doi.org/10.1097/QCO.0000000000000607 PMid:31567572
- Khawaja F, Spallone A, Kotton CN, Chemaly RF. Cytomegalovirus infection in transplant recipients: newly approved additions to our armamentarium. Clin Microbiol Infect. 2023;29(1):44-50. https://doi.org/10.1016/j.cmi.2022.07.001 PMid:35843567
- 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. https://doi.org/10.1093/infdis/jit475 PMid:23983215
- Fischer L, Imrich E, Sampaio KL, et al. Identification of resistance-associated HCMV UL97- and UL54-mutations and a UL97-polymporphism with impact on phenotypic drug-resistance. Antiviral Res. 2016;131:1-8. https://doi.org/10.1016/j.antiviral.2016.04.002 PMid:27058773
- Chou S. Approach to drug-resistant cytomegalovirus in transplant recipients. Curr Opin Infect Dis. 2015;28(4):293-299. https://doi.org/10.1097/QCO.0000000000000170 PMid:26098499 PMCid:PMC4522269
- Chou S. Advances in the genotypic diagnosis of cytomegalovirus antiviral drug resistance. Antiviral Res. 2020;176:104711. https://doi.org/10.1016/j.antiviral.2020.104711 PMid:31940472 PMCid:PMC7080590
- Lopez-Aladid R, Guiu A, Sanclemente G, et al. Detection of cytomegalovirus drug resistance mutations in solid organ transplant recipients with suspected resistance. J Clin Virol. 2017;90:57-63. https://doi.org/10.1016/j.jcv.2017.03.014 PMid:28359845
- Lopez-Aladid R, Guiu A, Mosquera MM, et al. Improvement in detecting cytomegalovirus drug resistance mutations in solid organ transplant recipients with suspected resistance using next-generation sequencing. PLoS One. 2019;14(7):e0219701. https://doi.org/10.1371/journal.pone.0219701 PMid:31318908 PMCid:PMC6638921
- Chou S, Ercolani RJ, Derakhchan K. Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus. Antiviral Res. 2018;157:128-133. https://doi.org/10.1016/j.antiviral.2018.07.013 PMid:30040968 PMCid:PMC6097806
- Avery RK, Alain S, Alexander BD, et al. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial. Clin Infect Dis. 2022;75(4):690-701. https://doi.org/10.1093/cid/ciab988 PMid:34864943 PMCid:PMC9464078
- Quach DH, Lulla P, Rooney CM. Banking on virus-specific T cells to fulfill the need for off-the-shelf cell therapies. Blood. 2023;141(8):877-885. https://doi.org/10.1182/blood.2022016202 PMid:36574622 PMCid:PMC10023738
- Mahadeo KM, Baiocchi R, Beitinjaneh A, et al. Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE ). Lancet Oncol. 2024;25(3):376-387. https://doi.org/10.1016/S1470-2045(23)00649-6 PMid:38309282
- Roex MCJ, van Balen P, Germeroth L, et al. Generation and infusion of multi-antigen-specific T cells to prevent complications early after T-cell depleted allogeneic stem cell transplantation-a phase I/II study. Leukemia. 2020;34(3):831-844. https://doi.org/10.1038/s41375-019-0600-z PMid:31624377
- Prockop SE, Hasan A, Doubrovina E, et al. Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant. J Clin Invest. 2023;133(10). https://doi.org/10.1172/JCI165476 PMid:36951958 PMCid:PMC10178844
- Pfeiffer T, Tzannou I, Wu M, et al. Posoleucel, an Allogeneic, Off-the-Shelf Multivirus-Specific T-Cell Therapy, for the Treatment of Refractory Viral Infections in the Post-HCT Setting. Clin Cancer Res. 2023;29(2):3240330. https://doi.org/10.1158/1078-0432.CCR-22-2415 PMid:36628536 PMCid:PMC9843433
- Pescovitz MD, Ettenger RB, Strife CF, et al. Pharmacokinetics of oral valganciclovir solution and intravenous ganciclovir in pediatric renal and liver transplant recipients. Transpl Infect Dis. 2010;12(3):195-203. https://doi.org/10.1111/j.1399-3062.2009.00478.x PMid:20002356
- Vaudry W, Ettenger R, Jara P, et al. Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients. Am J Transplant. 2009;9(3):636-643. https://doi.org/10.1111/j.1600-6143.2008.02528.x PMid:19260840
- Pescovitz MD, Jain A, Robson R, Mulgaonkar S, Freeman R, Bouw MR. Establishing pharmacokinetic bioequivalence of valganciclovir oral solution versus the tablet formulation. Transplant Proc. 2007;39(10):3111-3116. https://doi.org/10.1016/j.transproceed.2007.10.007 PMid:18089334
- Martin M, Goyette N, Ives J, Boivin G. Incidence and characterization of cytomegalovirus resistance mutations among pediatric solid organ transplant patients who received valganciclovir prophylaxis. J Clin Virol. 2010;47(4):321-324. https://doi.org/10.1016/j.jcv.2010.01.009 PMid:20138805
- Galaverna F, Baccelli F, Zama D, et al. Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP). Bone Marrow Transplant. 2024;59(4):505-512. https://doi.org/10.1038/s41409-024-02209-2 PMid:38272999
- César T, Le MP, Klifa R, et al. Letermovir for CMV Prophylaxis in Very High-Risk Pediatric Hematopoietic Stem Cell Transplantation Recipients for Inborn Errors of Immunity. J Clin Immunol. 2024;44(1). https://doi.org/10.1007/s10875-023-01617-1 PMid:38117473
- Groll AH, Schulte JH, Antmen AB, et al. Pharmacokinetics, Safety, and Efficacy of Letermovir for Cytomegalovirus Prophylaxis in Adolescent Hematopoietic Cell Transplantation Recipients. Pediatr Infect Dis J. 2024;43(3):203-208. https://doi.org/10.1097/INF.0000000000004208 PMid:38241643
- Feucht J, Opherk K, Lang P, et al. Adoptive T-cell therapy with hexon-specific Th1 cells as a treatment of refractory adenovirus infection after HSCT. Blood. 2015;125(12):1986-1994. https://doi.org/10.1182/blood-2014-06-573725 PMid:25617426
- Scheinberg P, Melenhorst JJ, Brenchley JM, et al. The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor. Blood. 2009;114(24):5071-5080. https://doi.org/10.1182/blood-2009-04-214684 PMid:19776383 PMCid:PMC2788980
- Gottlieb D, Jiang W, Avdic S, et al. Administration of Third-Party Virus-Specific T-Cells (VST) at the Time of Initial Therapy for Infection after Haemopoietic Stem Cell Transplant Is Safe and Associated with Favourable Clinical Outcomes (the REACT-Quickly trial). Blood. 2019;134(Supplement_1):251. https://doi.org/10.1182/blood-2019-125166
- Gottlieb DJ, Clancy LE, Withers B, et al. Prophylactic antigen-specific T-cells targeting seven viral and fungal pathogens after allogeneic haemopoietic stem cell transplant. Clin Transl Immunol. 2021;10(3):1-18. https://doi.org/10.1002/cti2.1249 PMid:33747509 PMCid:PMC7960021
Supplementary Files
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SURVEY REPORT: Challenges in CMV Prophylaxis for allo-HSCT Recipients in Spain: Key Findings from the GETH-TC 2022 Survey.
Rationale for the Survey
Despite continuous progress in the field of allogeneic hematopoietic stem cell transplantation (allo-HSCT), cytomegalovirus (CMV) infection continues to significantly impact the morbidity and mortality associated with this procedure, placing a substantial burden on healthcare resources. Traditional management strategies, particularly periodic monitoring of CMV viremia and preemptive treatment (PET), may need changing following the recent approval of Letermovir (LMV), the first drug authorized for primary prophylaxis in CMV seropositive recipients.
LMV approval was granted in Spain in August 2021, though this was restricted to high-risk patient groups. In response to this shift, the Spanish Group of Hematopoietic Transplantation and Cellular Therapy (GETH-TC) conducted a survey in January 2022 to assess the speed of LMV prophylaxis implementation in the country and explore variations in critical aspects of its management between different centers. In this summary, we highlight the most significant findings.
Participating centers
A total of 17 adult allo-HSCT units participated in the survey (Figure 1). The median annual number of allo-HSCT procedures per center over the last 5 years was 47 (17–120).
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Implementation of Letermovir prophylaxis in real clinical practice
As of January 2022, 14 of the 17 participating centers had already initiated the use of LMV (Figure 2). The remaining three centers were scheduled to begin its implementation within the next three months.
At the time of the survey, 46% of allo-HSCT patients in the participating centers met the LMV funding criteria established by the AEMPS (Spanish Agency of Medicines and Medical Devices), with a range from 5 to 85% across different centers.
LMV was used as primary prophylaxis in 10 patients not initially considered at high risk, later identified as such based on other risk factors at the investigator's discretion and after compassionate use requests. Similarly, six cases involved the use of LMV as extended or secondary prophylaxis, with patient selection guided by clinical criteria without relying on specific immune response studies for decision-making.
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Standardization of LMV Use in GETH-TC Centers
Only 59% of the participating centers (n=10) had a specific protocol for viremia monitoring and initiation of preemptive treatment (PET) when using LMV. In addition, significant variability in the definition of breakthrough infection was observed among these centers, with markedly divergent thresholds (Figure 3). It is notable that only two centers employed different threshold values based on the patient's baseline risk and incorporated the viremia doubling time into the decision-making process.
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Availability of additional CMV-related techniques
In total, 82% of participating centers indicated having access to CMV antiviral resistance testing. However, in four of them (30%) samples had to be sent to external centers, leading to delays in obtaining results. Only 35% of studies routinely incorporated specific immunity against CMV screening and note that in two of these centers the test was unavailable on-site.
Viewpoint on the need for a national protocol to standardize LMV management.
There was unanimous consensus among participating centers of the need to create consensus guidelines and recommendations as a key aspect in the immediate future.
Conclusions
Following its approval, the implementation of LMV in GETH-TC centers has been rapid, although with varying rates and noticeable variability in the percentage of treated patients and usage beyond official recommendations. This situation introduces new challenges, requiring adjustments to traditional monitoring strategies and new criteria for precise differentiation between "blip" and breakthrough infection. It was also observed that a significant proportion of GETH-TC centers face obstacles in accessing important complementary tests, such as viral resistance studies, in a timely manner. This clinical guide has been updated in response to the unanimous consensus among all participating centers of the need to adopt standardized guidelines, with the primary goal of improving allo-HSCT outcomes in our environment.
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