José Luis Piñana1#, Estela Giménez2#, Lourdes Vázquez3, María Ángeles Marcos4, Manuel Guerreiro5, Rafael Duarte6, Ariadna Pérez1, Carlos de Miguel6, Ildefonso Espigado7, Marta González-Vicent8, María Suarez-Lledó9, Irene García-Cadenas10, Rodrigo Martino10, Angel Cedillo11, Monserrat Rovira9, Rafael de la Cámara12, David Navarro3,13, Carlos Solano1,14*
on behalf of the Infectious Complications Subcommittee of the Spanish
Hematopoietic Stem Cell Transplantation and Cell Therapy Group
(GETH-TC).
1 Hematology Service, Hospital Clinico Universitario, INCLIVA Biomedical Research Institute, Valencia, Spain.
2 Microbiology Service, Hospital Clinico Universitario, INCLIVA Biomedical Research Institute, Valencia, Spain.
3 Hematology Department, University Hospital of Salamanca
(HUS/IBSAL), CIBERONC and Cancer Research Institute of Salamanca-IBMCC
(USAL-CSIC), Salamanca, Spain.
4 Microbiology Service, Hospital Clinic. Barcelona, Spain.
5 Hematology Service, Hospital Universitario y Politécnico La Fe. Health Research, Valencia, Spain.
6 Hematology Service, Hospital Universitario Puerta de Hierro, Madrid, Spain.
7 Hematology Service, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
8 Onco/Hematology and transplant Department, Hospital Niño Jesús, Madrid, Spain.
9 BMT Unit, Haematology Department, Institute of Haematology
and Oncology, IDIBAPS, Hospital Clinic, University of Barcelona,
Barcelona, Spain. Josep Carreras Leukaemia Research Foundation.
10 Hematology Service. Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
11 Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GETH-TC) Secretary, Madrid, Spain.
12 Hematology Service. Hospital Universitario de La Princesa, Madrid, Spain.
13 Department of Microbiology School of Medicine, University of Valencia, Valencia, Spain.
14 Department of Medicine, School of Medicine, University of Valencia, Valencia, Spain.
# Both authors contributed equally to this work.
Correspondence to: Carlos
Solano, Hematology Service, Hospital Clínico Universitario, INCLIVA
Biomedical Research Institute, Av. Blasco Ibáñez 17, 46010 Valencia,
Spain. Phone: 34(96)1973838; Fax: 34(96)31973839; E-mail:
carlos.solano@uv.es; ORCID: 0000-0003-3702-0817 X: @SolanoVercetC
Published: September 01, 2024
Received: June 10, 2024
Accepted: August 02, 2024
Mediterr J Hematol Infect Dis 2024, 16(1): e2024064 DOI
10.4084/MJHID.2024.064
This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0),
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
|
Abstract
Background: Cytomegalovirus
(CMV) infection is a common complication following allogeneic
hematopoietic stem cell transplantation (allo-HSCT) and in patients
receiving novel hematological therapies. Its impact on morbidity and
mortality necessitates effective management strategies. Despite recent
advances in diagnostics and treatment, unresolved questions persist
regarding monitoring and treatment, prompting the need for updated
recommendations.
Methods: A consensus was
reached among a panel of experts selected for their expertise in CMV
research and clinical practice. Key clinical areas and questions were
identified based on previous surveys and literature reviews.
Recommendations were formulated through consensus and graded using
established guidelines.
Results: Recommendations
were provided for virological monitoring, including the timing and
frequency of CMV DNAemia surveillance, especially during letermovir
(LMV) prophylaxis. We evaluated the role of CMV DNA load quantification
in diagnosing CMV disease, particularly pneumonia and gastrointestinal
involvement, along with the utility of specific CMV immune monitoring
in identifying at-risk patients. Strategies for tailoring LMV
prophylaxis, managing breakthrough DNAemia, and implementing secondary
prophylaxis in refractory cases were outlined. Additionally, criteria
for initiating early antiviral treatment based on viral load dynamics
were discussed.
Conclusion: The consensus
provides updated recommendations for managing CMV infection in
hematological patients, focusing on unresolved issues in monitoring,
prophylaxis, treatment, and resistance. These recommendations aim to
guide clinical practice and improve outcomes in this high-risk
population. Further research is warranted to validate these
recommendations and address ongoing challenges in CMV management with
emerging antiviral combinations, particularly in pediatric populations.
|
Introduction
Active
cytomegalovirus (CMV) infection occurs frequently after allogeneic
hematopoietic stem cell transplantation (allo-HSCT) and is associated
with increased morbidity and mortality.[1] Recently,
CMV DNAemia and disease have also been observed in patients with
hematological malignancies receiving molecular-targeting small
molecules[2] and in recipients of chimeric antigen receptor T-cell therapy (CAR-T)[3,4]
but their pathogenicity and clinical consequences remain to be
determined. In the allo-HSCT setting, between 60 and 70% of CMV
seropositive recipients (R) and between 20 and 30% of CMV seronegative
patients transplanted with CMV seropositive donors (D) will develop CMV
DNAemia after allo-HSCT in the absence of prophylaxis.[5]
CMV may cause end-organ disease, increasing morbidity and mortality,
which usually requires long-course antiviral treatment (at least 4
weeks) limited by common drug-related toxicities.[6]
CMV-seropositive patients treated with allo-HSCT may exhibit deeper
immunosuppression, which translates into lower overall survival
compared to CMV seronegative patients, in particular for unrelated
donors (URD) or D/R HLA mismatch1. This was also observed during the
coronavirus disease (COVID-19) pandemic when CMV-seropositive
recipients showed higher mortality than CMV-seronegative recipients.[7]
In CMV seropositive patients, the risk of prolonged and/or recurrent
reactivation, as well as mortality, is even higher when the donor is
CMV-seronegative.[5,8] Recent years
have seen advances in several areas, including the use of diagnostic
tools, monitoring of specific anti-CMV T-cell immunity and molecular
analyses of CMV mutations that translate into antiviral resistance,
identification of risk factors and direct and indirect effects, and
availability of new antiviral drugs for prophylaxis and/or treatment.[9]
All these advances have prompted significant changes in the management
and prophylactic strategies of this infection during the last five
years in the transplant setting.[10] Many of these are included in current guidelines and recommendations,[11-14]
although there are unanswered questions regarding the
management/monitoring of CMV infection in daily clinical practice,
including which groups of new hematological drugs need monitoring in
treated patients, the frequency and duration of CMV monitoring, the
utility of specific CMV T-cell monitoring, the significance of CMV
DNAemia and/or CMV resistant features during letermovir (LMV)
prophylaxis, and who could benefit from novel anti-CMV drugs and when.
These issues were highlighted by a national survey conducted by the
Infectious Complications Committee (GRUCINI) of the Spanish Group of
Hematopoietic Transplantation and Cellular Therapy (GETH-TC).[15]
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.
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:
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.
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.
![Table 1](https://www.mjhid.org/mjhid/article/download/5745/version/2848/4582/46170/Table%201.jpg) |
- Table 1. Consensus recommendations in key question topics.
|
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.
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Supplementary Files
![Supp Table1 1](https://www.mjhid.org/mjhid/article/download/5745/version/2848/4582/46166/Supp%20table%201.jpg)
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- Supplementary Table 1. Grading system for the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recommendations1.
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![Supp Table 2](https://www.mjhid.org/mjhid/article/download/5745/version/2848/4582/46159/Mini%20supp%20Table%202.jpg) |
- Supplementary Table 2. Risk factors for CMV resistance in HSCT recipients2.
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![Supp Table 3](https://www.mjhid.org/mjhid/article/download/5745/version/2848/4582/46160/Mini%20supp%20Table%203.jpg) |
- Supplementary
Table 3. Cytomegalovirus genes involved in resistance mutations3,4. GCV: ganciclovir, VGCV: valganciclovir; FOS: foscarnet, CDV: cidofovir; BCDV: brincidofovir; MBV: maribavir; LMV: letermovir.
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![Supp Table 4](https://www.mjhid.org/mjhid/article/download/5745/version/2848/4582/46169/Supp%20table%204.jpg) |
- Supplementary Table 4. Biological and clinical activity of anti-CMV alternative agents.
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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).
![supp Figure 1](Mini%20supp%20Figure%201.jpg) |
- Supplementary Figure 1. Geographical distribution of the participating centers. *Median number of allo-HSCT/year
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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.
![supp Figure 2](https://www.mjhid.org/mjhid/article/download/5745/version/2848/4582/46163/supp%20Figure%202.jpg) |
- Supplementary Figure 2. Implementation of LMV prophylaxis across the participating centers.
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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.
![supp Figure 3](https://www.mjhid.org/mjhid/article/download/5745/version/2848/4582/46164/supp%20Figure%203.jpg) |
- Supplementary Figure 3. Comparison
of expression of the markers analyzed
between all the 3 groups: Ph+ B-ALL (n=144), Ph-like ALLs (n= 19) and
B-ALLs negatives (n= 79). For this statistical analysis based on 3
groups the Kruskal-Wallis test was used.
|
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.
![supp Figure 4](https://www.mjhid.org/mjhid/article/download/5745/version/2848/4582/46165/supp%20Figure%204.jpg) |
- Supplementary Figure 4. Availability of additional CMV-related techniques in participant centers.
|