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

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1 (2000) 26, Macmillan Publishers Ltd All rights reserved /00 $ A survey of allogeneic bone marrow transplant programs in the United States regarding cytomegalovirus prophylaxis and pre-emptive therapy RK Avery 1,3, KA Adal 1, DL Longworth 1, BJ Bolwell 2,3 Departments of 1 Infectious Disease, 2 Hematology-Oncology, and the 3 Transplant Center, Cleveland Clinic Foundation, Cleveland, OH, USA Summary: Despite an extensive literature, no consensus has emerged regarding the optimal preventive strategy for CMV in allogeneic bone marrow transplantation (BMT). No survey of 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, preemptive 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 preemptive 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. (2000) 26, Keywords: CMV; prophylaxis; pre-emptive; allogeneic BMT Cytomegalovirus (CMV) has long been recognized as a significant source of morbidity and mortality in the allogeneic bone marrow transplant recipient. 1 9 In particular, CMV pneumonitis 10,11 but also other syndromes such as gastrointestinal CMV and CMV-related cytopenias 12 have posed Correspondence: Dr RK Avery, Department of Infectious Disease, Desk S-32, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA Received 9 March 2000; accepted 26 June 2000 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 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, 19,20 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. 21,22 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 Tests used as triggers for pre-emptive therapy have included CMV-DNA by PCR, 29,33,34,36 the pp65 antigenemia assay, 27,30,31,34 36 CMV-DNA by hybrid capture assay (Digene), CMV shell vial or tissue culture, 25,34 36 and bronchoalveolar lavage. 26,28 Advocates of universal ganciclovir prophylaxis cite the benefits of a low rate of CMV pneumonitis. 21,22,37,38 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 strategies 40 in which patients judged to be at higher risk for CMV 41 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 preemptive therapy. Boeckh et al 31 performed a randomized comparison, and found that pre-emptive therapy based on

2 764 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 response 43,44 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 programs 45 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 BMT 9 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, preemptive 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 gan- Table 1 Overall design of CMV preventive programs Universal prophylaxis 17 (21%) a Pre-emptive ganciclovir therapy 46 (56%) Hybrid strategies 15 (19%) Other (treat symptomatic CMV only) 3 (4%) a i.v. ganciclovir 15, oral ganciclovir 1, valacyclovir 1. ciclovir 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. 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 cen- Table 2 Utilization of CMV diagnostic tests a Any use of test Pre-emptive trigger c Tissue culture and/or shell vial Antigenemia CMV-DNA by PCR 55 (23) b 30 CMV-DNA by Digene hybrid capture 14 (9) 7 a Many centers reported more than one diagnostic test utilized. b Numbers in parentheses refer to numbers using quantitative versions of the assay. c Other pre-emptive triggers included: bronchoalveolar lavage at day +30 or 35 (3), occurrence of GVHD (3), occurrence of lung injury (1).

3 ters 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. 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 preemptive 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, 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. References 1 Meyers JD, Flournoy N, Thomas ED. Risk factors for cytomegalovirus infection after human marrow transplantation. J Infect Dis 1986; 153: Schmidt GM. Prophylaxis of cytomegalovirus infection after bone marrow transplantation. Semin Oncol 1992; 19 (3 Suppl. 7): Holland HK, Saral R. Cytomegaloviral virus infection in bone marrow transplantation recipients: strategies for prevention and treatment. Support Care Cancer 1993; 1: Forman SJ, Zaia JA. Treatment and prevention of cytomegalovirus pneumonia after bone marrow transplantation: where do we stand? Blood 1994; 83: Goodrich JM, Boeckh M, Bowden R. Strategies for the prevention of cytomegalovirus disease after marrow transplantation. Clin Infect Dis 1994; 19: Reusser P. The challenge of cytomegalovirus infection after bone marrow transplantation: epidemiology, prophylaxis, and therapy. Bone Marrow Transplant 1996; 18 (Suppl 2): Tsinontides AC, Bechtel TP. Cytomegalovirus prophylaxis and treatment following bone marrow transplantation. Ann Pharmacother 1996; 30: Prentice HG, Kho P. Clinical strategies for the management of cytomegalovirus infection and disease in allogeneic bone marrow transplantation. Bone Marrow Transplant 1997; 19: Adal KA, Avery RK. Prevention of cytomegalovirus infection after allogeneic bone marrow transplantation. In: Bolwell BJ (ed). Current Controversies in Bone Marrow/Stem Cell Transplantation. Humana Press: New Jersey, 1999, pp Ljungman P. Cytomegalovirus pneumonia: presentation, diagnosis, and treatment. Semin Respir Infect 1995; 10: Riddell SR. Pathogenesis of cytomegalovirus pneumonia in immunocompromised hosts. Semin Respir Infect 1995; 10: Torok-Storb B, Simmons P, Khaira D et al. Cytomegalovirus and marrow function. Ann Hematol 1992; 64 (Suppl.): A Miller W, Flynn P, McCullough J et al. Cytomegalovirus infection after bone marrow transplantation: an association with acute graft-v-host disease. Blood 1986; 67: Emanuel D, Cunninghan I, Jules-Elysee K et al. Cytomegalovirus pneumonia after bone marrow transplantation success- 765

4 766 fully treated with the combination of ganciclovir and highdose intravenous immune globulin. Ann Intern Med 1988; 109: Reed EC, Bowden RA, Dandliker PS et al. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med 1988; 109: Schmidt GM, Kovacs A, Zaia JA et al. Ganciclovir/immunoglobulin combination therapy for the treatment of human cytomegalovirus-associated interstitial pneumonia in bone marrow allograft recipients. Transplantation 1988; 46: Ljungman P, Engelhard D, Link H et al. Treatment of interstitial pneumonitis due to cytomegalovirus with ganciclovir and intravenous immune globulin: experience of European Bone Marrow Transplant Group. Clin Infect Dis 1992; 14: Husni RN, Gordon SM, Longworth DL et al. Cytomegalovirus infection is a risk factor for invasive aspergillosis in lung transplant recipients. Clin Infect Dis 1998; 26: Meyers JD, Reed EC, Shepp DH et al. Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic bone marrow transplantation. New Engl J Med 1988; 318: Prentice HG, Gluckman E, Powles RP et al. The impact of long-term acyclovir on cytomegalovirus infection and survival in allogeneic bone marrow transplantation. Lancet 1994; 343: Goodrich JM, Bowden RA, Fisher L et al. Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med 1993; 118: Winston DJ, Ho WG, Bartoni RN et al. Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Ann Intern Med 1993; 118: Salzberger B, Bowden RA, Fackman RC et al. Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome. Blood 1997; 90: Li CR, Greenberg PD, Gilbert MJ et al. Recovery of HLArestricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994; 83: Goodrich JM, Mori M, Gleaves CA et al. Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation. New Engl J Med 1991; 325: Schmidt GM, Horak DA, Niland JC et al. A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants. New Engl J Med 1991; 324: Boeckh M, Bowden RA, Goodrich JM et al. Cytomegalovirus antigen detection in peripheral blood leukocytes after allogeneic marrow transplantation. Blood 1992; 80: Zaia JA, Schmidt GM Chao NJ et al. Use of preemptive ganciclovir based solely on asymptomatic pulmonary cytomegalovirus infection in marrow transplant recipients long-term follow-up. Blood 1994; 84 (10 Suppl. 1): 249a. 29 Einsele H, Enhinger G, Hebart H et al. Polymerase chain reaction monitoring reduces the incidence of cytomegalovirus disease and the duration and side effects of antiviral therapy after bone marrow transplantation. Blood 1995; 86: Bacigalupo A, Tedone E, Isaza A et al. CMV-antigenemia after allogeneic bone marrow transplantation: correlation of CMV-antigen positive cell numbers with transplant-related mortality. Bone Marrow Transplant 1995; 16: Boeckh M, Gooley TA, Myerson D et al. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation a randomized double-blind study. Blood 1996; 88: Mandanas RA, Saez RA, Selby GB, Confer DL. Cytomegalovirus surveillance and prevention in allogeneic bone marrow transplantation: examination of a preemptive plan of ganciclovir therapy. Am J Hematol 1996; 51: Ljungman P, Lore K, Aschan J et al. Use of a semi-quantitative PCR for cytomegalovirus DNA as a basis for pre-emptive antiviral therapy in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1996; 17: Hebart H, Muller C, Loffler J et al. Monitoring of CMV infection: a comparison of PCR from whole blood, plasma-pcr, pp65-antigenemia and virus culture in patients after bone marrow transplantation. Bone Marrow Transplant 1996; 17: Nicholson VA, Whimbey E, Champlin R et al. Comparison of cytomegalovirus antigenemia and shell vial culture in allogeneic marrow transplantation recipients receiving ganciclovir prophylaxis. Bone Marrow Transplant 1997; 19: Boeckh M, Gallez-Hawkins GM, Myerson D et al. Plasma polymerase chain reaction for cytomegalovirus DNA after allogeneic marrow transplantation: comparison with polymerase chain reaction using peripheral blood leukocytes, pp65 antigenemia, and viral culture. Transplantation 1997; 64: Atkinson K, Downs K, Golenia M et al. Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection. Br J Haematol 1991; 79: Von Bueltzingsloewen A, Bordigoni P, Witz F et al. Prophylactic use of ganciclovir for allogeneic bone marrow transplant recipients. Bone Marrow Transplant 1993; 12: Przepiorka D, Ippoliti C, Panini A et al. Ganciclovir three times per week is not adequate to prevent cytomegalovirus reactivation after T-cell depleted marrow transplant. Bone Marrow Transplant 1994; 13: Verdonck LF, Dekker AW, Rozenberg-Arska M, van den Hoek MR. A risk-adapted approach with a short course of ganciclovir to prevent cytomegalovirus (CMV) pneumonia in CMV-seropositive recipients of allogeneic bone marrow transplants. Clin Infect Dis 1997; 24: Takenaka K, Gondo H, Tanimoto K et al. Increased incidence of cytomegalovirus (CMV) infection and CMV-associated disease after allogeneic bone marrow transplantation from unrelated donors. Bone Marrow Transplant 1997; 19: Boeckh M, Bowden RA, Gooley T et al. Successful modification of a pp65 antigenemia-based early treatment strategy for prevention of cytomegalovirus disease in allogeneic marrow transplant recipients (letter). Blood 1999; 93: Ljungman P, Aschan J, Azinge JN et al. Cytomegalovirus viraemia and specific T-helper cell responses as predictors of disease after allogeneic marrow transplantation. Br J Haematol 1993; 83: Walter EA, Greenberg PD, Gilbert MJ et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. New Engl J Med 1995; 333: Ljungman P, DeBock R, Cordonnier C et al. Practices for cytomegalovirus diagnosis, prophylaxis, and treatment in allogeneic bone marrow transplant recipients; a report from the Working Party for Infectious Diseases of the EBMT. Bone Marrow Transplant 1993; 12: Erice A, Chow SW, Biron K et al. Progressive disease due to

5 ganciclovir-resistant cytomegalovirus in immunocompromised patients. New Engl J Med 1989; 320: Reusser P, Cordonnier C, Einsele H et al. European survey of herpesvirus resistance to antiviral drugs in bone marrow transplant recipients. Bone Marrow Transplant 1996; 17: Erice A, Borrell N, Li W et al. Ganciclovir susceptibilities and analysis of UL97 region in cytomegalovirus (CMV) isolates from bone marrow recipients with CMV disease after antiviral prophylaxis. J Infect Dis 1998; 178: