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Viral Infections

A survey of allogeneic bone marrow transplant programs in the United States regarding cytomegalovirus prophylaxis and pre-emptive therapy

Abstract

Despite an extensive literature, no consensus has emerged regarding the optimal preventive strategy for CMV in allogeneic bone marrow transplantation (BMT). No survey of CMV prevention in BMT centers in the United States has yet been published. A questionnaire was sent to all allogeneic BMT programs in the United States, as listed in the November 1998 National Marrow Donor Program (NMDP) address roster. Questions included whether universal prophylaxis, pre-emptive therapy, or some other strategy was used for CMV prevention, and which CMV diagnostic tests were utilized. Eighty-one of 96 programs (86%) responded to the survey. Of these, 46 (56%) utilize a pre-emptive ganciclovir strategy, whereas 17 (21%) utilize universal prophylaxis, and 15 (19%) utilize a hybrid strategy based on risk stratification. The most commonly utilized CMV diagnostic tests are CMV-DNA by PCR (55 centers), shell vial centrifugation culture (52), tissue culture (42), pp65 antigenemia assay (38), and CMV-DNA by Digene hybrid capture (14). Of these, the CMV-DNA by PCR, pp65 antigenemia assay, and shell vial culture are the most frequently utilized as triggers for pre-emptive therapy. Quantitative assays are common (PCR 42%, Digene 64%). We conclude that centers currently performing allogeneic BMT in the United States employ a variety of strategies for CMV prevention, and differ in their diagnostic tests of choice for CMV monitoring. These results emphasize the need for large-scale studies to identify optimal diagnostic and management protocols. Bone Marrow Transplantation (2000) 26, 763–767.

Main

Cytomegalovirus (CMV) has long been recognized as a significant source of morbidity and mortality in the allogeneic bone marrow transplant recipient.123456789 In particular, CMV pneumonitis1011 but also other syndromes such as gastrointestinal CMV and CMV-related cytopenias12 have posed challenges to treatment, occurring often in the most fragile patients with significant graft-versus-host disease.13 CMV pneumonitis carries a significant mortality even despite optimal therapy with the combination of ganciclovir and immunoglobulin.14151617 CMV may also predispose to other complications, including fungal and other opportunistic infections.18

With the advent of effective antiviral therapy, the possibility of CMV prophylaxis has become a reality. Although early studies suggested a beneficial effect of acyclovir,1920 it has weak in vitro activity against CMV as compared with ganciclovir. Two randomized controlled trials assessed the impact of ganciclovir prophylaxis when administered to all allogeneic bone marrow transplant recipients to day 100 post transplant.2122 In these trials, CMV disease was strikingly reduced, but no survival benefit could be demonstrated. Neutropenia was a significant side-effect in the ganciclovir-treated group, with a concomitant higher risk of fungal infection.23 It has also been suggested that ganciclovir prophylaxis may delay the development of effective CMV-specific immune responses, and thus may lead to more late CMV disease.24

More recently, interest has focused on the possibility of pre-emptive therapy with ganciclovir based on screening for early CMV with a sensitive diagnostic test.252627282930313233343536 Tests used as triggers for pre-emptive therapy have included CMV-DNA by PCR,29333436 the pp65 antigenemia assay,273031343536 CMV-DNA by hybrid capture assay (Digene), CMV shell vial or tissue culture,25343536 and bronchoalveolar lavage.2628

Advocates of universal ganciclovir prophylaxis cite the benefits of a low rate of CMV pneumonitis.21223738 Advocates of pre-emptive strategies cite less neutropenia, less cost, and possibly less fungal infection as reasons to utilize pre-emptive therapy. Some clinicians have advocated intermittent (eg three times weekly) ganciclovir prophylaxis rather than daily prophylaxis as a way to avoid the problem of neutropenia, but concerns have been raised as to whether this strategy is adequate in high-risk recipients.39 Several centers have devised hybrid strategies40 in which patients judged to be at higher risk for CMV41 receive universal ganciclovir prophylaxis while those judged to be at lower risk are followed with monitoring and pre-emptive therapy.28

Few studies have directly compared prophylaxis and pre-emptive therapy. Boeckh et al31 performed a randomized comparison, and found that pre-emptive therapy based on antigenemia resulted in more CMV disease by day 100, but universal prophylaxis was associated with more early invasive fungal infections and more late CMV disease, and there was no difference in survival.31 This group has subsequently published a modification of the pp65 antigenemia-based strategy, in which ganciclovir is initiated for antigenemia at any level, instead of high-grade antigenemia, and is continued to day 100 after transplant.42 This strategy resulted in a lower incidence of CMV disease, comparable to that with ganciclovir prophylaxis, and also a low incidence of fungal infections. Compared with the previous antigenemia-based strategy, a somewhat higher incidence of late CMV disease was noted, consistent with a possible delay in reconstitution of immune responses to CMV in patients treated with ganciclovir early after transplant.24 Thus, this modified pp65 antigenemia-based strategy appears to combine the advantages of both prophylactic and pre-emptive strategies seen in the previous randomized trial, with a low incidence of both CMV disease and invasive fungal infections.42

Recent recognition of the importance of reconstitution of the anti-CMV cellular immune response4344 has led to the proposal of innovative strategies based on adoptive immunotherapy.44 Such strategies, although exciting, have yet to see widespread use.

No previous survey in the United States has examined the frequency of utilization of the different protocols in the medical literature for prevention of CMV after allogeneic BMT. A 1993 survey of 70 European programs45 in 20 countries found that 42 centers used high-dose acyclovir prophylaxis and seven used universal ganciclovir prophylaxis; 53 centers (76%) utilized pre-emptive strategies based on viremia.45 The current study initially arose from a survey designed for a book chapter on CMV in BMT9 for which the authors wished to give an accurate reflection of current practice.

Materials and methods

From December 1998 to January 1999, a survey was sent to all medical directors and coordinators of programs performing allogeneic BMT in the United States, as listed in the November 1998 National Marrow Donor Program (NMDP) address roster.

Questions included: which diagnostic tests for CMV were utilized by the center; which diagnostic tests were used as triggers for pre-emptive CMV therapy (if any); and whether programs practiced universal prophylaxis, pre-emptive therapy, or other strategy. For programs including a universal prophylaxis component, the frequency and duration of therapy were recorded. The survey did not specifically ask about IVIG or CMVIG in prophylaxis.

Definitions

‘Universal prophylaxis’ refers to programs which administer ganciclovir to all patients regardless of screening tests for CMV viremia (including programs which exempt CMV D−/R− from prophylaxis). ‘Pre-emptive ganciclovir therapy’ refers to programs which base their initiation of ganciclovir therapy on the results of screening tests, usually for CMV viremia. ‘Hybrid strategies’ are those that employ both prophylactic and pre-emptive components for different subgroups of patients.

Results

Of the 96 programs listed in the NMDP address roster, 81 responded to the survey.

Design of preventive programs

Numbers of centers utilizing different types of CMV preventive programs are shown in Table 1, and included 17 programs utilizing universal prophylaxis (21%), 46 using pre-emptive ganciclovir therapy (56%), and 15 utilizing hybrid strategies (19%). Of those employing universal prophylaxis, 15 centers use i.v. ganciclovir, one uses oral ganciclovir, and one program uses valacyclovir. Of those utilizing hybrid strategies, 10/15 programs use prophylaxis in unrelated transplants and pre-emptive therapy in matched related transplants. Some programs divide patients into different prevention groups based on donor and recipient serostatus.

Table 1  Overall design of CMV preventive programs

Diagnostic tests employed

The survey asked for all diagnostic methods for CMV used in each medical center (Table 2). Of the 46 programs reporting pre-emptive therapy as the primary strategy, and the 15 programs utilizing a hybrid strategy, the test(s) which is (are) utilized as the pre-emptive trigger(s) were recorded; the most commonly utilized were CMV-DNA by PCR (30), pp65 antigenemia (20), and shell vial and/or tissue culture (19). Many programs reported more than one trigger. In addition to measures of CMV viremia, three centers utilize bronchoalveolar lavage with CMV detection as a pre-emptive trigger. Occurrence of GVHD was listed as a trigger by three centers, and lung injury by one center.

Table 2  Utilization of CMV diagnostic testsa

Frequency of screening tests

Most programs (73/81), regardless of whether they employed prophylactic or pre-emptive strategies, reported routine use of screening for CMV viremia. Eight out of 81 programs reported obtaining tests for CMV viremia only in symptomatic patients. The majority (57 centers) reported screening weekly; nine centers reported screening once in 2 weeks. Several programs had differential frequencies of screening depending on the time post transplant.

Frequency and duration of universal prophylaxis

Of programs utilizing universal prophylaxis, either as a primary strategy or as a component of a hybrid strategy (n = 32), the frequency of prophylaxis was five times a week or more in 23/32, and duration was to day +100 in 19/32, with seven programs continuing to day +120, two programs to day +90 and one to day +80. One program continues until the CD4 count is >200 and CMV proliferative responses are evident. Several programs have decreasing frequency of prophylactic ganciclovir schedules over time. Six programs administer early i.v. ganciclovir during ablative chemotherapy, prior to receiving marrow or stem cells.

Neutropenia during ganciclovir prophylaxis and pre-emptive therapy

A question was also included regarding frequency of neutropenia with these various strategies for prevention of CMV. However, since this question was phrased subjectively, the responses were difficult to interpret and have therefore been excluded from further analysis.

Discussion

This survey illustrates the fact that, despite excellent randomized trials in the BMT literature, a diversity of practice patterns exists among programs in the United States regarding methods of CMV prevention. The most common strategy in use at the present time, utilized by over half of the programs responding to the survey, is one of pre-emptive ganciclovir therapy based on one or more screening tests. The next most common strategies are universal ganciclovir prophylaxis, and hybrid strategies utilizing both prophylaxis and pre-emptive therapy in different patient groups.

This questionnaire was not designed to compare CMV outcomes between these different strategies, nor to measure the incidence of late-occurring CMV after the period of prophylaxis or pre-emptive monitoring, which would have made the survey much more difficult to complete. It is important to note that this survey is purely descriptive, and does not imply the superiority of one preventive strategy or CMV diagnostic testing modality over another. Furthermore, the results of this questionnaire cannot be used to assess cost-effectiveness of these various strategies.

Interesting possible frontiers for the future include the further development of risk stratification as utilized in hybrid protocols; strategies based on the quantitative measurement of viral load; and the development of sophisticated measures of the transplant recipient’s immune responses to CMV. The use of newer antivirals, such as valacyclovir and valganciclovir, and the potential rise in ganciclovir resistance,464748 may also alter prophylaxis strategies in the future.

In summary, there are a variety of strategies for CMV prevention in current use in allogeneic bone marrow transplant programs, utilizing a variety of diagnostic tests for CMV. Further information on CMV incidence and severity and other infectious outcomes in these different protocols would be of interest. This diversity of practice suggest that further large trials comparing different strategies with regard to efficacy, neutropenia, and resource utilization would be useful.

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Avery, R., Adal, K., Longworth, D. et al. A survey of allogeneic bone marrow transplant programs in the United States regarding cytomegalovirus prophylaxis and pre-emptive therapy. Bone Marrow Transplant 26, 763–767 (2000). https://doi.org/10.1038/sj.bmt.1702608

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Keywords

  • CMV
  • prophylaxis
  • pre-emptive
  • allogeneic BMT

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