RESUMO
Despite the significant progress made, CMV infection is one of the most frequent infectious complications in transplant recipients. CMV infections that become refractory or resistant (R/R) to the available antiviral drugs constitute a clinical challenge and are associated with increased morbidity and mortality. Novel anti-CMV therapies have been recently developed and introduced in clinical practice, which may improve the treatment of these infections. In this review, we summarize the treatment options for R/R CMV infections in adult hematopoietic cell transplant and solid organ transplant recipients, with a special focus on newly available antiviral agents with anti-CMV activity, including maribavir and letermovir.
Assuntos
Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Farmacorresistência Viral , Transplantados , Humanos , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , Infecções por Citomegalovirus/etiologia , Antivirais/uso terapêutico , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Órgãos/efeitos adversos , Acetatos , Diclororribofuranosilbenzimidazol/análogos & derivados , QuinazolinasRESUMO
BACKGROUND: Cytomegalovirus infection (CMV) is a common complication after allogeneic hematopoietic stem cell transplantation (AHSCT). CMV infection increases transplantation costs; however, the extent of the financial burden may vary in different countries. This study aims to determine the clinical and economic impact of CMV infection in patients undergoing AHSCT in a middle-income country. METHODS: A total of 150 adult and pediatric patients post-AHSCT were included for analysis. In addition to incidence of CMV infections, data on graft versus host disease (GVHD) were also collected. Standard hospital charges for AHSCT and any additional transplantation-related expenditure within 12 months were also retrieved in 104 patients. RESULTS: CMV infection, acute GVHD and chronic GVHD occurred in 38.7%, 60.7%, and 22.0% of patients, respectively. Patients with CMV infections had higher readmission rates compared to those who did not (67.2% vs. 47.8%; p = 0.020). Additional expenditure was seen in HLA-haploidentical AHSCT and CMV infection (MYR11 712.25/USD2 504.49; p < 0.0001 and MYR5 807.24/USD1 241.79; p = 0.036), respectively. CONCLUSION: This single-center study demonstrated that patients who underwent HLA-haploidentical AHSCT and subsequently developed CMV infection had higher transplantation expenditures compared to those who had matched-related transplantation. Further studies should be conducted to evaluate if primary prophylaxis against CMV is cost-effective, especially in patients who undergo HLA-haploidentical AHSCT.
Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Humanos , Infecções por Citomegalovirus/economia , Infecções por Citomegalovirus/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/economia , Masculino , Feminino , Adulto , Seguimentos , Citomegalovirus/isolamento & purificação , Criança , Doença Enxerto-Hospedeiro/economia , Doença Enxerto-Hospedeiro/etiologia , Adolescente , Pessoa de Meia-Idade , Adulto Jovem , Prognóstico , Fatores de Risco , Pré-Escolar , Estudos Retrospectivos , Incidência , Condicionamento Pré-Transplante/efeitos adversosRESUMO
ABSTRACT: Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation recipients; however, data on CMV reactivation after chimeric antigen receptor (CAR) T-cell therapy are limited. We report the incidence and outcomes of 95 adult CMV-seropositive patients who received CAR T-cell therapy between February 2018 and February 2023. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV infection (cs-CMV). Thirty-one patients (33%) had evidence of CMV reactivation (any viremia), and 10 patients (11%) had cs-CMV. The median time from CAR T-cell infusion to CMV reactivation was 19 days (interquartile range [IQR], 9-31). The cumulative incidence of CMV (any viremia) was significantly higher among patients with grade 3 to 4 cytokine release syndrome (67 vs 28%; P = .01), and those who received corticosteroids (39 vs 21%; P = .03), anakinra (56 vs 28%; P = .02), or ≥2 immunosuppressants (41 vs 21%; P = .02). Receipt of corticosteroids (18 vs 0%; P = .004), tocilizumab (14 vs 0%; P = .04), anakinra (33 vs 7%; P = .008), and ≥2 immunosuppressants (20 vs 0%; P = .001) were all associated with cs-CMV. Receiving ≥2 immunosuppressants was associated with a twofold increase in CMV reactivation in multivariate analyses (adjusted odds ratio [aOR], 2.27; 95% confidence interval, 1.1-4.8; P = .03). Overall, the 1-year mortality was significantly higher in those with CMV reactivation (57% vs 23%; P = .001). Immunosuppression, particularly with corticosteroids, for the management of CAR T-cell toxicities, is a major risk factor for CMV reactivation.
Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Imunoterapia Adotiva , Ativação Viral , Humanos , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/imunologia , Masculino , Pessoa de Meia-Idade , Feminino , Citomegalovirus/fisiologia , Citomegalovirus/imunologia , Incidência , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Adulto , Receptores de Antígenos Quiméricos , IdosoAssuntos
Acetatos , Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Quinazolinas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/etiologia , Criança , Masculino , Feminino , Pré-Escolar , Acetatos/uso terapêutico , Quinazolinas/uso terapêutico , Adolescente , Citomegalovirus , Antivirais/uso terapêutico , Lactente , Aloenxertos , Transplante HomólogoRESUMO
The introduction of daratumumab has improved treatment outcomes for multiple myeloma (MM). However, infectious complications are a concern in patients receiving daratumumab. Although some reports have explored the association between daratumumab and cytomegalovirus (CMV) infection, most of these have focused on relapsed or refractory cases, and few describe patients with newly diagnosed MM (NDMM). In this study, we retrospectively analyzed CMV infections in 53 patients with NDMM who received daratumumab as induction therapy. CMV infection was defined as CMV antigenemia positivity. The median age at treatment initiation was 71 years (range, 50-82 years), and 50.9% of the patients were female. The median duration of daratumumab administration was 10.0 months (range, 0.3-63.8 months). Nine patients developed CMV infection, and the cumulative incidence rate at six months was 18.1% (95% confidence interval: 8.9-30.1%). One patient experienced CMV retinitis and required antiviral therapy, while the remaining eight patients did not require treatment and could be managed through observation. Few cases of CMV infection during daratumumab treatment for NDMM required treatment. However, the incidence of CMV infection was not negligible, suggesting that regular monitoring for CMV is worth considering to ensure more appropriate management during daratumumab treatment.
Assuntos
Anticorpos Monoclonais , Infecções por Citomegalovirus , Mieloma Múltiplo , Humanos , Idoso , Mieloma Múltiplo/tratamento farmacológico , Pessoa de Meia-Idade , Infecções por Citomegalovirus/etiologia , Feminino , Masculino , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Incidência , CitomegalovirusRESUMO
To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).
Assuntos
Antivirais , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Infecções por Citomegalovirus , Citomegalovirus , Quinazolinas , Ativação Viral , Humanos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Masculino , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/etiologia , Feminino , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/fisiologia , Adulto , Estudos Retrospectivos , Adolescente , Pessoa de Meia-Idade , Criança , Ativação Viral/efeitos dos fármacos , Antivirais/uso terapêutico , Quinazolinas/uso terapêutico , Quinazolinas/farmacologia , Pré-Escolar , Farmacorresistência Viral , Adulto Jovem , Lactente , Idoso , AcetatosRESUMO
INTRODUCTION: Cytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV prophylaxis, its utility can be compromised due to the risk of cytopenia. Letermovir, a novel agent approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients and high-risk kidney transplant recipients, exhibits reduced toxicity. This study aims to present the practical application of letermovir as both primary and secondary prophylaxis against CMV in heart transplant recipients (HTR). METHODS: In this observational, retrospective, single-center study, we included all consecutive adult HTRs from June 2020 to January 2022 who were administered letermovir for CMV prophylaxis. We documented instances of CMV breakthrough infections, side effects related to letermovir, changes in neutropenia following the switch from valganciclovir to letermovir, and any drug interactions with the immunosuppressive regimen. RESULTS: The study comprised 10 patients: two received primary prophylaxis with letermovir due to a high risk of CMV infection (donor-positive, recipient-negative serostatus), and eight received it as secondary prophylaxis following a CMV infection. The median duration of letermovir administration was 8 months (range 3-12 months). No CMV breakthrough infections were reported while on prophylaxis. However, three patients experienced CMV breakthrough infections after discontinuing letermovir prophylaxis (30%). No significant side effects were observed, although one patient reported digestive intolerance. Among the nine patients on tacrolimus, six needed reduced doses after switching to letermovir. CONCLUSION: This real-life study appears to support the effectiveness of letermovir prophylaxis in HTR. Nonetheless, the risk of CMV infection post-treatment cessation is notable. Further drug monitoring and research on the efficacy of letermovir for CMV prophylaxis in SOT patients is warranted.
Assuntos
Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Transplante de Coração , Humanos , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/etiologia , Transplante de Coração/efeitos adversos , Masculino , Estudos Retrospectivos , Antivirais/uso terapêutico , Feminino , Pessoa de Meia-Idade , Seguimentos , Citomegalovirus/isolamento & purificação , Adulto , Idoso , Prognóstico , Acetatos/uso terapêutico , Quinazolinas/uso terapêutico , Transplantados , Complicações Pós-Operatórias/prevenção & controle , Fatores de Risco , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/etiologiaRESUMO
BACKGROUND/AIM: Due to still unresolved questions regarding viruses as either a primary cause or a comorbidity in cancer, we examined a potential immune response to cytomegalovirus (CMV) in the renal cell carcinoma (RCC) setting using genomics and bioinformatics approaches. MATERIALS AND METHODS: Specifically, we assessed chemical complementarity scores (CSs) for solid tissue normal resident, T-cell receptor (TCR) complementarity determining region 3 (CDR3s) and CMV antigens and determined whether higher or lower CS groups were associated with a higher or lower survival probability. RESULTS: This was indeed the case, with all such analyses consistently indicating a lower overall and progression-free survival for the cases representing the higher TCR CDR3-CMV antigen chemical CSs. This basic result was obtained for two separate RCC datasets and multiple CMV antigens. CONCLUSION: The results raise the question, to what extent a systemic CMV infection may represent an important co-morbidity for RCC.
Assuntos
Carcinoma de Células Renais , Infecções por Citomegalovirus , Neoplasias Renais , Humanos , Carcinoma de Células Renais/complicações , Receptores de Antígenos de Linfócitos T alfa-beta , Infecções por Citomegalovirus/etiologia , Citomegalovirus , Neoplasias Renais/complicações , Receptores de Antígenos de Linfócitos TRESUMO
Cytomegalovirus (CMV) reactivation remains one of the major and life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Yet, there is still a lack of safe and effective ways to prevent CMV reactivation in allo-HSCT patients. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our transplant center between 2018 and 2022 to evaluate the efficacy of prophylactic CMV-specific intravenous immunoglobulin (CMV-IVIg) against CMV reactivation. After Propensity Score Matching, the CMV reactivation rate was significantly decreased in the CMV-IVIg group (HR, 2.952; 95% CI,1.492-5.841; P = .002) compared with the control group. Additionally, the time duration of CMV reactivation (P = .001) and bacterial infection rate (P = .013) were significantly lower in the CMV-IVIg group. Moreover, prophylactic CMV-IVIg was more effective in CMV seropositive patients who received ATG as part of GVHD prevention (HR, 8.225; 95% CI,1.809-37.39; P = .006). In conclusion, CMV-IVIg is considered an effective and safe way to prevent CMV reactivation in HSCT recipients, which may be related to the acceleration of immune reconstitution in the early stage after transplantation.
Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Humanos , Citomegalovirus , Imunoglobulinas Intravenosas/uso terapêutico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/tratamento farmacológico , Estudos Retrospectivos , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Anticorpos AntiviraisRESUMO
Cytomegalovirus (CMV) reactivation increases treatment-related mortality (TRM) after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed 141 adult acute leukemia (AL) patients suffered allo-HCT between 2017 and 2021, who developed CMV viremia post-HCT and treated with valganciclovir or foscarnet, to evaluate effectiveness and safety of both drugs. Viremia clearance rates (14 and 21 d post treatment) and toxicities were similar in two groups. However, valganciclovir was associated with a lower cumulative incidence of CMV recurrence within 180 days (16.7% vs. 35.7%, p=0.029) post CMV clearance. Finally, 2-year TRM was lower in valganciclovir group (9.7% ± 0.2% vs. 26.2% ± 0.3%, p = 0.026), result a superior 2-year overall survival (OS; 88.1% ± 5.2% vs. 64.4% ± 5.5%, p = 0.005) and leukemia-free survival (LFS; 82.0% ± 5.9% vs. 58.9% ± 5.6%, p = 0.009). Valganciclovir might decrease CMV viremia recurrence and led to better long-term outcome than foscarnet in adult AL patients developed CMV viremia post-HCT. Considering the inherent biases of retrospective study, well-designed trials are warranted to validate our conclusion.
Assuntos
Antivirais , Infecções por Citomegalovirus , Citomegalovirus , Foscarnet , Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Valganciclovir , Viremia , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Citomegalovirus/etiologia , Valganciclovir/uso terapêutico , Masculino , Feminino , Viremia/tratamento farmacológico , Adulto , Antivirais/uso terapêutico , Foscarnet/uso terapêutico , Pessoa de Meia-Idade , Citomegalovirus/efeitos dos fármacos , Estudos Retrospectivos , Adulto Jovem , Idoso , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Resultado do Tratamento , Leucemia/terapia , Leucemia/complicações , Leucemia/mortalidadeAssuntos
Antivirais , Infecções por Citomegalovirus , Vacinas contra Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Viremia , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/etiologia , Criança , Citomegalovirus/imunologia , Viremia/etiologia , Feminino , Masculino , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Pré-Escolar , Vacinas contra Citomegalovirus/imunologia , Adolescente , Lactente , Imunogenicidade da VacinaRESUMO
ABSTRACT: Preemptive therapy (PET) and letermovir prophylaxis are effective in preventing cytomegalovirus (CMV) disease within the first 100 days after allogeneic hematopoietic cell transplantation (HCT) but are associated with late-onset CMV disease. We retrospectively examined the clinical manifestations, risk factors, prevention algorithm, and outcome of late CMV disease in CMV seropositive day 100 survivors transplanted between 2001-2017 (PET cohort) and 2018-2021 (letermovir cohort). There were 203 episodes of late CMV disease among 2469 day 100 survivors, and the estimated cumulative incidence of first late CMV disease was 7.2% (95% confidence interval [CI], 6.2-8.3) with no difference between the PET (7.4%; 95% CI, 6.4-8.6) and the letermovir group (5.4%; 95% CI, 3.2-8.3). Thirty-seven patients (1.5%) had a second episode of CMV disease. In multivariable Cox regression models, posttransplant cyclophosphamide was associated with an increased risk of gastrointestinal CMV disease. CMV viremia or disease detected before day 100, corticosteroid treatment after day 100 at dose ≥1 mg/kg, acute and chronic graft-versus-host disease, lymphopenia, HLA-mismatched related donor status, were also associated with late CMV disease. HLA-mismatched donor status and late use of corticosteroids (≥1 mg/kg) were risk factors for late CMV disease recurrence. Late CMV disease occurred most frequently in a setting of prolonged low-level untreated viremia and was independently associated with death by 2 years after HCT. In summary, late CMV disease continues to occur in the present era. Improved prevention strategies for late CMV disease are needed.
Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Fatores de Risco , Estudos Retrospectivos , Antivirais/uso terapêutico , Idoso , Citomegalovirus , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Adolescente , Incidência , Adulto JovemRESUMO
Objective: Cytomegalovirus (CMV) reactivation is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Introduction of letermovir (LMV) seems to improve post-transplant outcomes, but delayed-onset CMV reactivation still remains a challenge. In this study, we report on our first experience with LMV prophylaxis in 93 CMV-seropositive adult patients receiving HSCT in our center. Materials and Methods: We retrospectively analyzed the data of 93 adult CMV-seropositive recipients receiving LMV as CMV prophylaxis after HSCT for hematological malignancies between 2019 and 2023. The starting LMV dose was 480 mg daily, reduced to 240 mg daily for those receiving cyclosporin A co-administration. CMV DNA in the blood was measured by real-time polymerase chain reaction weekly for the first 2 months after transplantation, then every other week until the end of immunosuppressive treatment. LMV was continued to day +100 or to CMV reactivation. Results: The median recipient age at the time of transplant was 51 (range: 20-71) years. All patients received grafts from peripheral blood, mostly for acute myeloid leukemia (60%). The median time from transplantation to LMV initiation was 3 (range: 0-24) days. While 55% of patients were transplanted from matched related donors, 32% had unrelated donors and 13% underwent haploidentical HSCT. Four patients (4%) had CMV "blips" while on LMV, but the drug was continued and repeated assays were negative. Only 2 patients (2%) experienced CMV reactivation while on LMV, on days 48 and 34 after HSCT, respectively. Seven patients (7%) developed late-onset CMV reactivation after a median of 124 days after HSCT (range: 118-152 days) and they were successfully treated with ganciclovir. CMV disease was not observed. Grade III-IV acute graft-versus-host disease occurred in 6 patients (6%) during LMV treatment. LMV treatment was free of side effects. Conclusion: LMV prophylaxis was effective in preventing CMV reactivation with a favorable safety profile. CMV reactivation occurred mostly after LMV discontinuation; thus, extending the duration of prophylaxis beyond 100 days could be beneficial.
Assuntos
Acetatos , Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Quinazolinas , Adulto , Humanos , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Citomegalovirus , Antivirais/efeitos adversos , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
BACKGROUND: Magnesium (Mg) is an essential element that is required as a cofactor for many cellular reactions, including immunologic pathways. The aim of this study was to investigate the potential impact of serum Mg levels on allogeneic hematopoietic stem cell transplantation (alloHSCT) outcomes. METHODS: Medical records of 340 alloHSCT recipients (median age: 45 [18-71] years; M/F: 210/130) were reviewed for this retrospective study. Serum Mg levels on days -28, -7, 0, +7, +14, +21, +30, +60, and +90 were included in the analysis. RESULTS: Serum Mg+14 levels predicted nonrelapse mortality (NRM) (P = .025) and had a significant impact on the development of mucositis (P = .027), fungal infection (P = .006), engraftment syndrome (P < .001), sinusoidal obstruction syndrome (SOS) (P = .001), cytomegalovirus (CMV) reactivation (P = .039), and acute graft vs host disease (GvHD) (P < .001). Based on the optimal threshold of serum Mg+14 level (1.33 mg/dL; area under the curve: 0.581 [0.515-0.648]; P = .018), the study group was divided into 2 subgroups as low- and high-Mg+14. The incidence of acute GvHD (P = .002), SOS (P = .013), engraftment syndrome (P = .013), CMV reactivation (P = .001), and Epstein Barr virus reactivation (P = .005) was significantly lower in low-Mg+14 group. The probability of overall survival (OS) was significantly better (P = .002), whereas NRM was lower in the low-Mg+14 group (P = .001). CONCLUSION: Hypomagnesemia seems to provide a considerable advantage for the post-transplant outcome, which may confirm its potential role in the immunologic microenvironment and adaptive immunity.
Assuntos
Infecções por Citomegalovirus , Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Pessoa de Meia-Idade , Infecções por Citomegalovirus/etiologia , Citomegalovirus/fisiologia , Infecções por Vírus Epstein-Barr/complicações , Estudos Retrospectivos , Magnésio , Herpesvirus Humano 4 , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/complicaçõesRESUMO
INTRODUCTION: Cytomegalovirus (CMV) infection remains a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While conventional antiviral agents such as ganciclovir can be used for CMV prophylaxis, toxicities such as myelosuppression are a major concern. AREA COVERED: This work aimed to summarize the latest information and practical issues regarding a new anti-CMV agent, letermovir (LET). EXPERT OPINION: LET inhibits CMV replication by binding to components of the DNA terminase complex. A phase 3 trial in allo-HSCT recipients showed a reduced incidence of clinically significant CMV infection in the LET group. In 2017, this agent was first approved for CMV prophylaxis in adult CMV-seropositive allo-HSCT recipients in the United States, and is now used worldwide. While LET has an excellent toxicity profile, there are issues to be aware of, such as interactions with other drug classes (e.g. immunosuppressants and antifungals) and reactivation of CMV infection following LET cessation. While LET is the current standard of care for CMV prophylaxis, there are no established protocols for preemptive treatment of asymptomatic CMV viremia or for treatment of developed CMV disease. Further research is needed to maximize the benefits of LET, including the discovery of biomarkers.
Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Quinazolinas , Adulto , Humanos , Acetatos/uso terapêutico , Antivirais/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Ensaios Clínicos Fase III como AssuntoRESUMO
INTRODUCTION: This study aimed to characterize patient risk groups and prognostic profiles to optimize clinical decision-making and guide appropriate medical cytomegalovirus (CMV) management among patients with allogeneic hematopoietic stem cell transplant (HSCT). METHODS: Between 8/2021 and 2/2022, a 3-round modified Delphi study was conducted to generate consensus among 10 international experts in HSCT and infectious diseases. Experts were asked about treatment and prognoses for patients in 7 distinct clinical scenarios. Furthermore, experts were asked to risk-stratify patients by pre-/post-transplant characteristics. Consensus around opting for/against a treatment was observed if ≥75% or <25% of experts reported ≥50% likelihood to recommend or if treatments were ranked inside/outside the top 2 options and ≥75% of experts were within 1 SD of mean ranks. RESULTS: Experts agreed on several unmet needs in CMV disease management post-HSCT, particularly avoidance of treatment-limiting toxicities with conventional CMV therapy and the emergence of both refractory and drug-resistant treatment failures. Experts considered CMV viral load, resistance profile, and route of administration as critical to treatment selection. For newer CMV therapeutic options, experts listed a lack of long-term use data, concerns over potential resistance, high cost, and limited availability as challenges restricting adoption and successful patient management. CONCLUSIONS: Experts achieved consensus around patient risk stratifications and factors influencing therapeutic options. Recommendations emerging from this Delphi study may support practicing physicians when confronted with challenging CMV scenarios in patients with HSCT.
Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Humanos , Citomegalovirus , Prognóstico , Consenso , Transplante Homólogo/efeitos adversos , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/tratamento farmacológico , Fatores de Risco , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
ABSTRACT: Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only cure for many hematologic malignancies. However, alloSCT recipients are susceptible to opportunistic pathogens, such as human cytomegalovirus (HCMV). Letermovir prophylaxis has revolutionized HCMV management, but the challenge of late HCMV reactivations has emerged. Immunological surrogates of clinically significant HCMV infection (csCMVi) after discontinuation of letermovir remain to be defined. Therefore, we studied natural killer (NK)-cell reconstitution along with the global and HCMV pp65-specific T-cell repertoire of 24 alloSCT recipients at 7 time points before (day +90) and after (days +120-270) cessation of letermovir prophylaxis. Patients who experienced csCMVi had lower counts of IFN-γ+ HCMV-specific CD4+ and CD8+ T cells than HCMV controllers. Furthermore, patients with csCMVi displayed late impairment of NK-cell reconstitution, especially suppression of "memory-like" CD159c+CD56dim NK-cell counts that preceded csCMVi events in most patients. Moreover, several surrogates of immune reconstitution were associated with the severity of HCMV manifestation, with patients suffering from HCMV end-organ disease and/or refractory HCMV infection harboring least HCMV-specific T cells and "memory-like" NK cells. Altogether, our findings establish an association of delayed or insufficient proliferation of both HCMV-specific T cells and "memory-like" NK cells with csCMVi and the severity of HCMV manifestations after discontinuation of letermovir prophylaxis.
Assuntos
Acetatos , Infecções por Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais , Quinazolinas , Humanos , Células Matadoras Naturais/imunologia , Citomegalovirus/imunologia , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/imunologia , Quinazolinas/uso terapêutico , Quinazolinas/farmacologia , Masculino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Acetatos/uso terapêutico , Acetatos/farmacologia , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Feminino , Adulto , Ativação Viral , Linfócitos T/imunologia , Memória Imunológica , IdosoAssuntos
Infecções por Citomegalovirus , Vacinas contra Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/etiologia , Vacinas contra Citomegalovirus/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Homólogo , Ativação Viral/imunologiaRESUMO
Hemorrhagic cystitis (HC) is a highly impacting complication in allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 12%-37% of patients. The impact of transplant- and patient-specific variables has been described, with a possible role for JCV and BKV, which may be cooperating with cytomegalovirus (CMV). Here, we analyze 134 letermovir-exposed, CMV-free patients, treated with the same cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, describing risk factors for HC. The overall incidence of HC was 23%. Patients with HLA mismatched transplant, higher comorbidity score, and receiving three alkylating agents with TBF (thiotepa, busulfan, and fludarabine) conditioning regimen had a higher risk of HC in multivariate analysis (OR: 4.48, 6.32, and 1.32, respectively). A HC-score including male gender, TBF conditioning, and HLA-mismatch stratifies the risk of HC in the first 100 days after HSCT. The role of BKV and JCV was not highly impacting in those patients, suggesting a possible synergistic effect between CMV and JCV in causing HC. HC can be interpreted as the combination of patient-related factors, chemotherapy-related toxicities-especially due to alkylating agents-and immunological elements.
Assuntos
Acetatos , Cistite Hemorrágica , Cistite , Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Quinazolinas , Humanos , Masculino , Citomegalovirus , Cistite/diagnóstico , Cistite/epidemiologia , Cistite/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fatores de Risco , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/etiologia , Alquilantes , Doença Enxerto-Hospedeiro/etiologia , Estudos RetrospectivosRESUMO
Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.