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Is Cytomegalovirus Surveillance Necessary for Patients With Low Reactivation Risk in an Autologous Hematopoietic Cell Transplantation Setting?
Abstract
Background
In an autologous hematopoietic cell transplantation (AHCT) setting, routine cytomegalovirus (CMV) surveillance is not indicated except in high-risk situations. On the other hand, some studies reported increased CMV reactivation in AHCT setting as a result of incorporation of novel agents into treatment algorithms, such as bortezomib and rituximab. We retrospectively analyzed CMV reactivation and infection rates in patients with no high-risk features, who were treated with AHCT.
Methods
During January 2010 to November 2015, all consecutive, CMV-seropositive patients were included. The viral copy numbers were measured twice a week from the start of the conditioning regimen until engraftment, once a week for the remaining time period until day 30 after AHCT and once weekly only for patients who had been diagnosed with CMV reactivation before and who developed primary/secondary engraftment failure during 31 to 60 days after AHCT.
Results
One hundred one (61.6%) men and 63 (38.4%) women were included in the study. The median age of study cohort was 51 years (range, 16–71 years). The indications for AHCT were Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma in 44 (26.8%), 41 (25%), and 79 (48.2%) patients, respectively. CMV reactivation occurred in 60 (37%) patients, and 13 patients (8%) received pre-emptive ganciclovir treatment.
Conclusions
On the basis of our results, it might be stated that CMV surveillance may be recommended during 40 days after AHCT in countries with a high CMV prevalence, even in patients without high-risk features regarding reactivation. Additionally, the risky conditions necessitating CMV screening after AHCT must be re-defined in the era of novel agents.
... Our findings reveal a higher risk of early death associated with post-ASCT CMV infection. Despite guidelines recommending selective CMV monitoring, reactivation is not uncommon after ASCT [59][60][61][62][63]. In our institution, CMV monitoring focuses on critical cases. ...
Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post–ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08–3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53–4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31–0.87) and total CD34⁺ cells collected ≥ 4 × 10⁶ cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32–0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05–4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03–7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45–34.59), post–ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09–28.84), and a lower conditioning melphalan dose (< 140 mg/m²; HR 2.75, 95% CI 1.23–6.17) experienced shorter OS. In contrast, post–ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17–0.79) and post–ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24–0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post–ASCT outcome prediction beyond clinical trials.
... In addition, the monitoring of blood CMV PCR and the pre-emptive treatment of asymptomatic CMV reactivations, which are standard after allogeneic transplantation, are not consensual after ASCT. 6 In conclusion, CMV lymphadenitis is a rare complication that should be considered following ASCT. As clinical presentation can mimic a lymphoma relapse, histopathological confirmation is needed. ...
Cytomegalovirus (CMV) reactivation is frequent after autologous stem cell transplantation (ASCT), but generalized CMV lymphadenitis is rare. We report a CMV lymphadenitis after an ASCT mimicking a relapse of a diffuse large B‐cell lymphoma. After histopathological documentation, CMV lymphadenitis should be treated to avoid systemic progression. CMV lymphadenitis is a rare complication following ASCT, which may mimic a relapse of lymphoma. Blood CMV viremia can be negative. Following histopathological documentation, CMV lymphadenitis should be treated to avoid systemic progression.
... 2015 yılına ait bir diğer çalışmadaysa (17) (19). Otolog KHN sürecinde CMV takibinin öneminin vurgulandığı 2017 yılına ait bir çalışmadaysa otolog KHN alıcılarında CMV reaktivasyonu değerlendirilmiş, çalışmaya dahil edilen 164 arasında CMV reaktivasyonu oranı %37 (n= 60) iken, 13 hastanın gansiklovir tedavi ihtiyacı olmuştur (20). Ülkemizde yapılan bir diğer çalışmadaysa (21), 2007-2016 yılları arasında otolog kök hücre nakli yapılan 352 hasta geriye dönük olarak incelenmiş, CMV PCR pozitifliği 51 hastada (%23) saptanırken 47 (%21.1) ...
... A Bortezomib-containing regiment could be either as a single drug or in combination. However, increasing numbers of studies have showed that multiple myeloma patients treated with Bortezomib-based regimens are at higher risk of developing a symptomatic CMV reactivation after autologous stem cell transplantation [48][49][50]. Li et al. [51] provided evidence that Bortezomib reduce the number of T lymphocytes resulting in susceptibility to HCMV infection. Together with our findings, this suggests that treatment with Bortezomib in HCMV positive patients could lead to a failure of therapy. ...
Human cytomegalovirus (HCMV) has been implicated in the development of human malignancies, for instance in colon cancer. Proteasome inhibitors were developed for cancer therapy and have also been shown to influence HCMV infection. The aim of this study was to investigate if proteasome inhibitors have therapeutic potential for colon carcinoma and how this is influenced by HCMV infection. We show by immunofluorescence and flow cytometry that the colon carcinoma cell line Caco-2 is susceptible to HCMV infection. Growth curve analysis as well as protein expression kinetics and quantitative genome analysis further confirm these results. HCMV has an anti-apoptotic effect on Caco-2 cells by inhibiting very early events of the apoptosis cascade. Further investigations showed that HCMV stabilizes the membrane potential of the mitochondria, which is typically lost very early during apoptosis. This stabilization is resistant to proteasome inhibitor Bortezomib treatment, allowing HCMV-infected cells to survive apoptotic signals. Our findings indicate a possible role of proteasome inhibitors in colon carcinoma therapy.
... Retrospektív analízisünkben a CMV-reaktiváció 37,5% volt, mely az esetek jelentős részében a transzplantációt követő 10-40. nap között jelent meg, más nemzetközi tanulmányok adataihoz hasonlóan [6,7,9,17,19]. Rossini és mtsai nagyobb arányban észlelték lymphomás betegekben CMV-reaktiváció kialakulását saját adatainkhoz viszonyítva, míg Marchesi munkacsoportja nem talált lényeges különbséget MM-és NHLbetegek között [20,5]. ...
Background:
Cytomegalovirus (CMV) disease impacts morbidity and mortality in hematopoietic cell transplant (HCT) recipients. This systematic review summarized data on the epidemiology, management, and burden of CMV post-HCT outside of Europe and North America.
Methods:
The MEDLINE, Embase, and Cochrane databases were searched for observational studies and treatment guidelines in HCT recipients across 15 selected countries from Asia-Pacific, Latin America, and Middle East (search period: 1 January 2011-17 September 2021). Outcomes included incidence of CMV infection/disease, recurrence, risk factors, CMV-related mortality, treatments, refractory, resistant CMV, and burden.
Results:
Of 2708 references identified, 68 were eligible (67 studies and one guideline; 45/67 studies specific to adult allogeneic HCT recipients). The rates of CMV infection and disease within 1 year of allogeneic HCT were 24.9%-61.2% (23 studies) and 2.9%-15.7% (10 studies), respectively. Recurrence occurred in 19.8%-37.9% of cases (11 studies). Up to 10% of HCT recipients died of CMV-related causes. In all countries, first-line treatment for CMV infection/disease involved intravenous ganciclovir or valganciclovir. Conventional treatments were associated with serious adverse events such as myelosuppression (10.0%) or neutropenia only (30.0%, 39.8%) and nephrotoxicity (11.0%) (three studies), frequently leading to treatment discontinuation (up to 13.6%). Refractory CMV was reported in 2.9%, 13.0%, and 28.9% of treated patients (three studies) with resistant CMV diagnosed in 0%-10% of recipients (five studies). Patient-reported outcomes and economic data were scarce.
Conclusion:
The incidence of CMV infection and disease post-HCT is high outside of North America and Europe. CMV resistance and toxicity highlight a major unmet need with current conventional treatments.
To ensure the safety of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT), evidence-based recommendations on infectious complications after HDC/ASCT are given. This guideline not only focuses on patients with haematological malignancies but also addresses the specifics of HDC/ASCT patients with solid tumours or autoimmune disorders. In addition to HBV and HCV, HEV screening is nowadays mandatory prior to ASCT. For patients with HBs antigen and/or anti-HBc antibody positivity, HBV nucleic acid testing is strongly recommended for 6 months after HDC/ASCT or for the duration of a respective maintenance therapy. Prevention of VZV reactivation by vaccination is strongly recommended. Cotrimoxazole for the prevention of Pneumocystis jirovecii is supported. Invasive fungal diseases are less frequent after HDC/ASCT, therefore, primary systemic antifungal prophylaxis is not recommended. Data do not support a benefit of protective room ventilation e.g. HEPA filtration. Thus, AGIHO only supports this technique with marginal strength. Fluoroquinolone prophylaxis is recommended to prevent bacterial infections, although a survival advantage has not been demonstrated.
No standardized guidelines exist for infectious prophylaxis following pediatric auto‐HSCT. We hypothesized significant variation in clinical practice. Thirty‐three Pediatric Transplant and Cell Therapy Consortium centers completed a survey to assess institutional management. The majority utilize viral (91%) and fungal prophylaxis (94%), but duration varies. Bacterial prophylaxis during neutropenia is instituted by 42%. Our study demonstrates marked practice variability in infectious prophylaxis across centers. Additional research is needed to address patterns of infectious complications and to develop meaningful clinical practice guidelines for pediatric auto‐HSCT.
Aim:
To determine the incidence of and the risk factors for cytomegalovirus (CMV) symptomatic infection and end-organ disease after autologous stem cell transplantation (ASCT).
Methods:
A total of 327 consecutive non CD34(+) selected autografts performed from the Hematology and Stem Cell Transplantation Unit of Regina Elena National Cancer Institute of Rome (Italy) in the period comprised between January 2003 to January 2015, were reviewed. Over the 327 autografts, 201 were performed in patients with multiple myeloma, whereas the remaining 126 in patients affected by non-Hodgkin's lymphoma and Hodgkin's lymphoma. The patients who underwent an ASCT for an acute leukemia (n = 20) in the same period were excluded from this analysis. CMV DNA load in the blood has been determined by polymerase-chain reaction in the case of a clinical suspicion of reactivation, therefore, no routine monitoring strategy was adopted. In the presence of signs and symptoms of CMV reactivation an antiviral treatment was performed.
Results:
Overall, 36 patients (11%) required a specific antiviral treatment for a symptomatic CMV reactivation (n = 32) or an end-organ disease (n = 4). We observed 20 and 16 cases of CMV reactivation among lymphoma (16%) and myeloma patients (8%), respectively. Among cases of end-organ disease, 3 were diagnosed as interstitial pneumonia and one remaining case as hemorrhagic enteritis. All cases of CMV reactivation were observed in IgG seropositive patients, with no documented cases of primary CMV infection. All patients were treated with a specific antiviral therapy, with a global rate of hospitalization of 55%; four patients received intravenous immunoglobulins. Transplant-related mortality was significantly higher in patients who experienced a CMV reactivation (8.4% ± 4.7% vs 1.7% ± 0.8%; P = 0.047). In univariate analysis, a pre-transplant HBcIgG seropositivity, a diagnosis of T-cell non-Hodgkin's lymphoma and higher median age at transplant were significantly associated with the risk of developing a clinically relevant CMV infection requiring specific antiviral therapy (P < 0.001, P = 0.042 and P = 0.004, respectively). In multivariate analysis, only a pre-transplant HBcIgG seropositivity (OR = 8.928, 95%CI: 1.991-33.321; P = 0.023) and a diagnosis of T-cell non-Hodgkin's lymphoma (OR = 4.739, 95%CI: 1.511-11.112; P = 0.042) proved to be independent predictors of a post-transplant clinically relevant CMV reactivation.
Conclusion:
A symptomatic CMV infection can occur in about 11% of adult patients with lymphoma or myeloma undergoing ASCT. A pre-transplant HBcIgG seropositivity and a diagnosis of T-cell non-Hodgkin's lymphoma should be considered as independent predictor factors of CMV reactivation.
Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2002. Since then there have been major developments in its diagnosis and management. Therefore, the CMV Drug Development Forum consisting of scientists, clinicians, regulators, and industry representatives has produced an updated version incorporating recent knowledge with the aim to support clinical research and drug development. The main changes compared to previous definitions are the introduction of a “probable disease” category and to incorporate quantitative nucleic acid testing (NAT) in some end-organ disease categories. As the field evolves, the need for updates of these definitions is clear and collaborative efforts between scientists, regulators, and industry can provide a platform for this work.