Management of cytomegalovirus infection in haemopoietic stem cell transplantation

Abstract

These evidence-based guidelines expand and adapt previous guidance (Tomblyn et al, 2009; Andrews et al, 2011). While specifically focusing on allogeneic haemopoietic stem cell transplantation (HSCT), they are relevant to other areas of haematological oncology where there is an increased risk of cytomegalovirus (CMV) infection, such as haematological cancers where intense anti-T-cell therapy has been deployed (O'Brien et al, 2006). The production of these guidelines involved the following steps: CMV is a herpes virus. Primary infection is followed by lifelong latency. Clinical manifestations vary widely and should be diagnosed according to established, internationally accepted, standardized criteria (Ljungman et al, 2002a). CMV infection is diagnosed when CMV is detected, most commonly in the blood, using sensitive screening tools. It is termed primary CMV infection when infection occurs in a CMV IgG-negative patient and CMV reactivation when the patient, or donor, is known to be CMV antibody positive. In uncomplicated CMV infection, organ-specific signs and symptoms are absent, although non-specific symptoms, such as fever and malaise, may occur (Ljungman et al, 2002a, 2011). The diagnosis of CMV disease requires the presence of symptoms and signs compatible with end organ damage, together with the detection of CMV by a validated method in an appropriate clinical specimen (Ljungman et al, 2002a). If left untreated, asymptomatic CMV infection can progress to CMV disease, most commonly affecting the lung, gastrointestinal tract, eye, liver or central nervous system (CNS). CMV pneumonia is the most serious complication with a > 50% mortality (Ljungman, 1995). In addition to specific organ damage, CMV also has profound, poorly characterized, indirect immunosuppressive effects, leading to an increased incidence of fungal and bacterial infection (Nichols et al, 2002; Hakki et al, 2003; Blanquer et al, 2011) as well as higher rates of both acute and chronic graft-versus-host disease (GvHD) (Soderberg et al, 1996; Larsson et al, 2004; Wang et al, 2008). While some recent reports have suggested reduced relapse rates in selected patients who reactivate CMV (Behrendt et al, 2009; Elmaagacli et al, 2011), this finding remains controversial and should not hinder early aggressive treatment of CMV infection. Post HSCT, most patients will reactivate latent virus rather than acquire primary infection. Mechanisms of latency are not completely understood but prevention of reactivation appears to be primarily dependent upon a persistent, robust, T-cell-mediated, immune response (Sylwester et al, 2005; Ljungman et al, 2011). Not surprisingly, the intensity of immunosuppression and the degree of T-cell depletion in transplant protocols both critically affect the risk of reactivation (van Burik et al, 2007). Recipients of transplants from unrelated or human leucocyte antigen (HLA)-mismatched donors, where immunosuppression is increased and GvHD more likely, are particularly likely to reactivate CMV and these patients have a survival disadvantage. The deployment of T-cell depleting agents, such as alemtuzumab, or antithymocyte globulin (ATG) or increased/prolonged courses of immunosuppression to treat GvHD significantly increases the risk of CMV infection (Schmidt-Hieber et al, 2010). These risk factors can also increase the risk of persistent, recurrent or late onset disease (Buyck et al, 2010), usually associated with impaired immune reconstitution (Hakki et al, 2003; Zhou et al, 2009). Conversely, the reconstitution of specific anti-CMV cytotoxic T-lymphocytes (CTL) has been shown to be protective (Lamba et al, 2005). CMV disease is as much of a problem following non-myeloablative transplantation as it is in the myeloablative setting. Conflicting data have been reported regarding the relative risk of bone marrow (BM) compared to peripheral blood stem cells (PBSC) as a stem cell source (Nakamae et al, 2009; George et al, 2010; Pinana et al, 2010; Guerrero et al, 2012). Published incidence of CMV reactivation and CMV disease after umbilical cord blood transplantation (UCBT) varies significantly. UCBT recipients have been reported to be more susceptible to late complications of CMV, although this is not a universal finding and the relative role of T cell depletion in UCBT conditioning protocols requires further investigation (Boeckh et al, 2004; Takami et al, 2005; Walker et al, 2007; Beck et al, 2010; Brown et al, 2010; Sauter et al, 2011; Chiesa et al, 2012; Mikulska et al, 2012). CMV screening should be performed using commercially available CMV IgG assays. There is no gold standard assay and it is important that laboratories running these tests participate in external and internal quality assurance schemes. CMV-negative recipients of grafts from CMV-negative donors (R−/D−) very rarely develop major CMV-related complications and a CMV IgG-negative donor should be chosen in these circumstances when possible. There is debate about the relative importance of CMV serostatus and HLA compatibility in donor selection. Specifically, while HLA matching at HLA-A,B,C and DR remains the most important factor in donor selection, the value of choosing a CMV IgG-negative donor over mismatches at other loci, such as HLA DQ or DP, or in protocols with aggressive T cell depletion remains unresolved (Boeckh & Ljungman, 2009). It is also recognized that donor selection can be a complex process and optimum CMV matching may not always be possible (Kollman et al, 2001; Spellman et al, 2012). Provision of CMV-safe blood products is standard practice when both host and donor are negative, either derived from CMV IgG-negative recipients or achieved by leucodepletion. Both techniques are effective, although rare incidences of transfusion-transmitted infection have occurred using both approaches (Bowden et al, 1995; Ljungman et al, 2002b; Nichols et al, 2003). In the UK, universal leucodepletion has largely replaced blood products from CMV-negative donors as of May 2012. It is important to be aware of the need to check the baseline CMV IgG status of potential transplant candidates at the time of initial diagnosis, to avoid confusion caused by passive transmission of antibodies with transfusion of CMV IgG-positive blood products to negative recipients. Any transplant recipient who converts from CMV IgG-negative to CMV IgG-positive status pre-transplant will require careful assessment to separate passive antibody from true seroconversion, as this has major implications for donor selection. In this setting, a falling titre with time is suggestive of passively acquired antibody. Pre-allograft, it is recommended that samples for IgM antibody and CMV polymerase chain reaction (PCR) are sent as soon as a change in CMV status is suspected. If both are negative then this suggests the presence of passively acquired antibody. Blood products must be leucodepleted in the blood bank facility (Ratko et al, 2001) and evidence of quality control for leucoreduction should be available to all transplant centres for JACIE [Joint Accreditation Committee – International Society for Cellular Therapy (Europe) & European Group for Blood and Marrow Transplantation (EBMT)] accreditation purposes. R−/D− transplants still require to be monitored for CMV infection. Any cases of CMV infection occurring in this group of patients should be reported to the Serious Hazards of Transfusion (SHOT) scheme. CMV seropositivity in either host or donor pre-transplant continues to be associated with a poorer overall survival post-allogeneic transplantation as a result of increased non-relapse mortality (NRM) (Broers et al, 2000; Kroger et al, 2001; Albano et al, 2006; Tomonari et al, 2008). The degree of this risk is determined primarily by the CMV IgG status of the recipient. If a CMV IgG-negative recipient receives cells from a CMV IgG-positive donor (R−/D+) then CMV infection occurs in 20–30% of cases. CMV disease is unusual but NRM is increased, probably through the indirect effects of CMV on immune status post-transplant (Nichols et al, 2002; Ljungman et al, 2011; Pergam et al, 2012). There is a greater risk of CMV reactivation and progression to CMV disease in CMV seropositive recipients, where 80% are likely to reactivate CMV, irrespective of CMV status of donor (Ljungman et al, 2011). However, in most studies, major complications were further increased when the donor wass CMV IgG-negative (Ozdemir et al, 2007; Zhou et al, 2009; Ugarte-Torres et al, 2011). Prophylactic and pre-emptive strategies have both been used to reduce the incidence of CMV disease. Universal monitoring of CMV levels in the blood is essential irrespective of whether prophylaxis is administered. There is no evidence that intravenous immunoglobulin (IVIG), CMV-specific hyperimmune immunoglobulin or anti-CMV monoclonal antibodies are useful alone or in combination with antiviral agents in primary prophylaxis against CMV infection (Bowden et al, 1991; Ruutu et al, 1997; Boeckh et al, 2001). A recent Cochrane review in solid organ transplant did not recommend prophylactic immunoglobulin (Hodson et al, 2007). There have been several small studies published using CD4 or CD8 T cells (Walter et al, 1995; Einsele et al, 2002; Peggs et al, 2003, 2009; Hanley et al, 2011; Sili et al, 2012), or CMV peptide-loaded dendritic cell vaccination (Grigoleit et al, 2007) for treatment or prophylaxis of CMV infection, but too little evidence currently exists to make any recommendation at present although ongoing prospective studies are addressing this issue. Aciclovir prophylaxis has been extensively studied post-HSCT. A large randomized trial of 310 patients initially appeared to suggest a reduced incidence and delayed onset of CMV infection as well as a significant improvement in survival. More mature follow up has shown no significant difference in CMV reactivation between groups, although reactivation did occur later in the prophylactic group. A modest survival benefit was still seen in the most aggressively treated patients, though it is difficult to attribute this to anti-CMV activity alone (Prentice et al, 1994, 1997). Improved survival in allograft patients who received aciclovir prophylaxis post-engraftment was also shown in a meta-analysis in which the vast majority of donor/recipient pairs were CMV IgG-positive (Yahav et al, 2009). However, the impact of aciclovir on CMV reactivation/disease rates in the studies included was again minimal and survival advantage was potentially mediated through anti-herpes simplex effects. Subsequently, valaciclovir, 2 g four times a day, was compared with oral aciclovir at 800 mg four times a day, in 727 patients following high dose intravenous (iv) aciclovir in the immediate post-transplant period (Ljungman et al, 2002c). In this study, valaciclovir significantly reduced CMV infection and disease rates (P < 0·0001). There was a 50% reduction in the use of pre-emptive therapy although there was no difference in overall survival (Ljungman et al, 2002c). Similar results were shown in a smaller case controlled study using valaciclovir at a dose of 1 g three times a day (Vusirikala et al, 2001). The studies described above predominantly used myeloablative conditioning and T-cell-replete BM as the stem cell source. Studies in PBSC recipients, though smaller, suggested that the beneficial effects of high dose aciclovir prophylaxis appeared to be maintained (Verma et al, 2003; Hazar et al, 2004). However, aciclovir was shown to be significantly less effective in T-cell-depleted BM transplant recipients, where 83% of T-cell-depleted recipients still had a CMV reactivation compared to 41% of unmanipulated stem cell sources (P < 0·0001) (Nakamura et al, 2002). As most of these studies predated widespread use of pre-emptive therapy based on quantitative PCR, their significance is questionable in terms of current management of CMV, though a compelling argument can be made for its use for suppression of herpes simplex virus infection. Ganciclovir prophylaxis significantly reduced the incidence of CMV infection and disease during the period of prophylaxis (Goodrich et al, 1993; Boeckh et al, 1996). However neutropenia occurred in up to 30% of cases treated (Salzberger et al, 1997) and infective complications were increased (Boeckh et al, 1996). Ganciclovir was less effective in T-cell-depleted transplants and heavily immunosuppressed recipients (Maltezou et al, 1999). In a prospective randomized trial of ganciclovir versus aciclovir, cumulative rates of CMV disease were equivalent, although more patients in the aciclovir group required pre-emptive therapy (P = 0·2) (Burns et al, 2002). Post-prophylaxis, late onset CMV disease remained a problem (Boeckh et al, 2003) and prolonged exposure of CMV to ganciclovir, especially in the setting of T-cell depletion may encourage resistance, as occurs in solid organ transplantation (Eid et al, 2008). Valganciclovir prophylaxis has been reported to reduce risk of CMV disease in cord blood transplants (Montesinos et al, 2009). More intensive prophylactic regimens involving pre-transplant ganciclovir combined with high dose aciclovir prophylaxis or a combination of ganciclovir and foscarnet have been employed in high-risk paediatric and cord blood transplants where both have been reported to be successful in reducing CMV infection and disease (Shereck et al, 2007; Milano et al, 2011). Maribavir, when given from engraftment, initially showed favourable results in phase II studies; but, at the dose chosen, failed to show any effect on CMV disease or initiation of CMV pre-emptive therapy compared to placebo in a larger phase III study. There was a small impact on CMV DNA loads in plasma (Winston et al, 2008; Marty et al, 2011). Letermovir (AIC246), a maturation inhibitor of CMV, has been studied in phase 2 trials as anti-CMV prophylaxis in 133 HSCT patients with potentially encouraging results (Goldner et al, 2011). Neither of these drugs can be recommended for prophylaxis at present. In summary, post-HSCT, in contrast to solid organ transplantation, ganciclovir-induced myelosuppression limits its use for prophylaxis. Routine use of aciclovir or valaciclovir is relatively non-toxic but will result in some patients being overtreated and the effect in T-cell-depleted transplants is small. However, the potential benefits of prophylaxis using these drugs in selected patients include reducing the need for hospital admission, for iv pre-emptive therapy, reducing indirect effects of CMV reactivation on immune status post-transplant and delaying CMV reactivation until the patient has recovered from the toxicity associated with the transplant and is no longer on immunosuppression. In patients who have had previous CMV disease prior to transplant or with recurrent episodes of CMV infection, especially in the context of T-cell depletion or GvHD, secondary prophylaxis should be considered, in conjunction with prolonged CMV viral screening. If prophylaxis is given, then oral valaciclovir 2 g three times a day or valganciclovir 900 mg daily is an option (Boeckh & Ljungman, 2009). The current mainstay for managing CMV infection after HSCT is the rapid introduction of therapy, based on evidence of CMV replication in blood (Goodrich et al, 1991). Success of pre-emptive therapy is dependent on the availability of a rapid, sensitive assay to allow early treatment at low levels of viral infection. Historically, the CMV antigenaemia assay provided a rapid way to detect CMV infection and is still used as a cost-effective screening tool in many centres worldwide. However, it suffers from low sensitivity, is not accurately quantitative and, in HSCT patients, is limited by the leucopenia evident in the early stages post-transplant. Here, CMV antigenaemia testing may be negative despite active viral replication (Gondo et al, 1994; Koehler et al, 1995). The availability of real time quantitative PCR (RQ-PCR) approaches has revolutionized the area of CMV DNA monitoring. RQ-PCR techniques provide rapid, high throughput platforms that are significantly less affected by white cell counts (Einsele et al, 1995; Emery et al, 2000; Fishman et al, 2007; Gimeno et al, 2008). The choice of sample type for routine monitoring lies between plasma and whole blood and remains controversial. The choice is often based on practical issues surrounding local sample handling and There are published reports the of sample type over the In the plasma was as an sample to but this is less of an as there are a of platforms that can whole studies have shown that more CMV DNA can be from whole blood samples than from plasma et al, 2006; et al, 2008; et al, to therapy may also be more in whole blood compared to plasma given the higher CMV DNA loads in the & 2011). where white cells may be such as and can also be using However, to RQ-PCR has not been validated for diagnosis of CMV disease and no can be made for the use of this in this setting. A of and commercially available are used in many laboratories the The and assay used in these tests running will make up their as of the assay as well as a of of a also known as a is used in to a standard from which the of of CMV DNA of sample can be A of must be used when running a PCR assay are available commercially although some laboratories will their of running an control in assay as well as an control for a standard for of CMV from clinical samples was by the for and et al, 2010; et al, There are still significant in CMV DNA reported by These have been to the of However, it is likely that will still be seen using as A recent showed in the of a of and in the PCR included in the study. was most at the CMV DNA loads et al, It is likely that the standard will be used to on a will allow CMV DNA levels to be compared between centres and trials et al, with external quality assurance is There is no clinical trial evidence often CMV DNA in blood samples should be determined et al, 2010). However, assessment following allogeneic transplantation is for the et al, 1997). The of monitoring will on the of the degree of immune the presence of GvHD and response to antiviral In these clinical prolonged monitoring for may be There is no the CMV at which pre-emptive treatment should be (Boeckh & Ljungman, 2009; Ljungman et al, 2011). centres will antiviral therapy CMV DNA has been at any in while have much higher on the of local and clinical these will difficult to between centres until PCR testing is A randomized trial antigenaemia with RQ-PCR has that a CMV may be an for initiation of et al, 2008; Boeckh & Ljungman, 2009; et al, 2009). some patients to effective immune and avoid therapy while still susceptible patients the onset of CMV disease. of active CMV-specific T-cell may patients who not require treatment et al, 2001; et al, 2002; et al, 2002). In addition to the viral there is evidence that the initial viral and the of viral increase are important of of CMV disease et al, strategies are likely to be and early treatment is in patients, especially in with high initial viral loads rapid viral times in or who are heavily Ganciclovir requires by the viral It is It viral replication by with as a for viral DNA polymerase & is mediated by in either of these 2008). Ganciclovir has been extensively used to treat CMV infection and disease (Goodrich et al, 1991; et al, It is still as choice pre-emptive therapy in most HSCT centres et al, 2011). The standard dose is daily for with of daily for a further effects and are in symptoms dose daily symptoms daily dose daily review Valganciclovir is the of ganciclovir, it is to ganciclovir after oral A small randomized trial in HSCT patients showed that oral valganciclovir 900 mg daily to higher effective of active compared to iv ganciclovir and showed et al, 2009). was also shown in the context of GvHD (Einsele et al, 2006). prospective randomized trials valganciclovir and ganciclovir are in HSCT However, there are several randomized studies over patients, the use of oral valganciclovir 900 mg with iv these studies showed no difference in any of although the of study to was limited (Einsele et al, 2006; et al, 2006; et al, 2009; et al, 2011; et al, 2011). evidence of valganciclovir was derived from several case These studies reported response rates to using ganciclovir et al, 2006; et al, 2008; et al, 2010). CMV rates appeared low following pre-emptive therapy with valganciclovir for CMV in HSCT et al, 2009). In solid organ where valganciclovir was used extensively for prophylaxis it was shown to be to ganciclovir in both CMV infection and disease, with low rates of CMV et al, 2011). pre-emptive therapy in solid organ transplants the of in viral were the as for intravenous ganciclovir et al, 2005). not require and is through of viral DNA polymerase & randomized studies have compared the of foscarnet versus ganciclovir pre-emptive therapy of CMV infection et al, et al, 2002). was compared with ganciclovir both using CMV antigenaemia as a to of therapy et al, patients were to either There were no significant in rates of of treatment or progression to CMV disease in both Both drugs required dose of at in of all A larger study compared foscarnet = with ganciclovir = both using either RQ-PCR or antigenaemia as a to therapy et al, 2002). in CMV disease mortality or survival were was more with foscarnet and myelosuppression with evidence of foscarnet from case In patients were treated for CMV disease = or were given pre-emptive therapy of CMV reactivation in donor transplants = et al, 2010). patients had failed previous ganciclovir to of = or myelosuppression in = of patients with CMV disease and of treated cases More limited data were reported foscarnet use in cord blood transplantation et al, 2007; Takami et al, 2007). is a that not require by viral for The case using has been published by the disease of (Ljungman et al, 2001). patients were treated as primary = or secondary = pre-emptive therapy for CMV infection or for CMV disease = patients were treated with for a of rates were 50% for CMV disease, for primary and for secondary CMV infection. smaller that was effective but response rates from to with most significant rates et al, 2001; et al, 2001; et al, 2005). effects are shown in A more of 1 three times a has been used to treat patients with infection et al, but there is no using this for the treatment of or other of have been but their use has been studied in small of patients 2010; et al, et al, and no are possible. The of in combination therapy are reduced and increased both in et al, et al, the primary is of resistance, particularly in the The combination of foscarnet and ganciclovir at versus dose ganciclovir was in a small randomized study = in transplant patients, HSCT recipients et al, 2004). There was less myelosuppression but overall increased primarily in the combination – though to show a clinical effect – of the ganciclovir group the primary clinical of viral at compared to 50% in the combination group. not evidence exists to treatment using these drugs at et have also reported foscarnet and ganciclovir at for organ for foscarnet and ganciclovir and of these were together at dose for 2 followed by where drugs were given at dose but on was effective and the suggested a possible reduction in compared with et al, However, not evidence exists to make a recommendation regarding combination therapy in this The time of CMV DNA in patients is on but may be more rapid et al, et al, the of pre-emptive therapy, drugs can have a major increases in CMV DNA occur in of patients to immunosuppression and of replication (Buyck et al, 2010; et al, 2011). should be and no in therapy in the in the of CMV disease or in viral PCR It is difficult to be about for pre-emptive antiviral as to treatment can be very in increase in viral by after 2 of therapy is therapy is recommended and can often be delayed in high-risk patients, disease has or viral is is relatively in the stem cell transplant setting. to ganciclovir is at of treated patients and occurs after of prolonged therapy et al, 2007) but can occur after initial therapy (van et al, 2012; et al, 2012). between transplant and clinical is is less in patients than in patients episodes of late onset CMV infection. should be in patients on antiviral drugs where the CMV DNA has been or has increased for more than 2 although is still more likely in If is samples should be sent for CMV and A to the management of CMV disease is and treatment on which are affected and whether disease has or from asymptomatic CMV infection while on CMV disease can be treated with ganciclovir or foscarnet daily for 2 followed by although more prolonged treatment may be review is as therapy may be required et al, 2008). baseline CMV DNA of replication and a viral after therapy are associated with increased rates of treatment et al, and monitoring of these patients with for If CMV disease occurs during pre-emptive therapy or CMV pneumonia is at any then strategies should be to is more likely to be to the to control the virus as a result of impaired T cell than to resistance, courses of therapy have been given (van et al, 2012). However, in critically patients, where testing should be performed early to treatment approaches in this setting include ganciclovir to a day (Boeckh & Ljungman, or ganciclovir to foscarnet therapy is but may difficult to et al, 1996). and ganciclovir can be at dose et al, is an to ganciclovir, and is also with foscarnet in but should be used ganciclovir has failed or has been et al, as both drugs are the that ganciclovir this combination should be & although with foscarnet or is an include high dose which has been reported in patients et al, though no recommendation can be made in the of to its in the phase III study. some reports of of in combination with antiviral therapy remains the standard of for CMV disease in many centres et al, Ljungman et al, et al, There appears to be no advantage to using CMV-specific immunoglobulin (Ljungman et al, should be made to reduce or especially a inhibitor to is a possible as several studies have suggested a beneficial anti-CMV effect of this et al, 2007; et al, 2007; et al, 2008). The of is still to be et al, & 2012). with donor or T cells may be available clinical trials but be recommended as standard at present. The no of