Original Article
Early Treatment with Ganciclovir to Prevent Cytomegalovirus Disease after Allogeneic Bone Marrow Transplantation
N Engl J Med 1991; 325:1601-1607December 5, 1991
- Abstract
- Abstract
Background.
Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir for the early treatment of CMV infection in asymptomatic recipients of bone marrow transplants whose surveillance cultures for CMV became positive.
Methods.
Bone marrow—allograft recipients who were seropositive for CMV antibodies or who received seropositive marrow were screened for CMV excretion by culture of throat swabs, blood, urine, or bronchoalveolar-lavage fluid. In this double-blind trial, 72 patients who had marrow engraftment and were excreting virus were randomly assigned to receive either placebo or ganciclovir (5 mg per kilogram of body weight twice a day for one week, followed by 5 mg per kilogram per day) for the first 100 days after transplantation. Patients were followed for the development of biopsy-confirmed CMV disease, ganciclovir-related toxicity, and survival.
Results.
Between assignment to the study drug and day 100 after transplantation, CMV disease developed in only 1 of the 37 patients assigned to receive ganciclovir (3 percent), but in 15 of the 35 patients assigned to receive placebo (43 percent, P<0.00001). The ganciclovir recipients had rapid suppression of virus excretion; 85 percent had negative cultures after one week of treatment, as compared with 44 percent of the placebo group (P = 0.001). The principal toxic reaction was neutropenia; 11 ganciclovir recipients had an absolute neutrophil count below 0.75 x109 per liter, as compared with 3 placebo recipients (P = 0.052). Treatment was discontinued in 11 ganciclovir recipients and 1 placebo recipient because of neutropenia (P = 0.003). After treatment was stopped, the neutrophil count recovered in all patients. Overall survival was significantly greater in the ganciclovir group than in the placebo group both 100 days and 180 days after transplantation (P = 0.041 and 0.027, respectively).
Conclusions.
Media in This Article
Figure 1
Kaplan–Meier Product-Limit Estimates of the Probability of Survival during the First 180 Days after Transplantation among Ganciclovir and Placebo Recipients.Table 1
Characteristics of the Study Groups.Article Activity
- Article
CYTOMEGALOVIRUS (CMV) infection remains a formidable barrier to allogeneic bone marrow transplantation and continues to cause morbidity and mortality among recipients who are immunocompromised for other reasons.1 2 3 Patients who excrete CMV after allogeneic marrow transplantation are at increased risk for subsequent CMV pneumonia or gastrointestinal disease.1 , 4 In one study, recovery of CMV from the throat, urine, or blood after transplantation preceded CMV pneumonia or gastrointestinal disease in 78 percent of seropositive patients.4 The recovery of CMV had a positive predictive value of 52 percent for the occurrence of CMV pneumonia or enteritis, and CMV viremia alone had a positive predictive value of 68 percent.
Attempts at prophylaxis for CMV disease in bone marrow recipients have yielded mixed results. Vidarabine and interferon alfa were not found to be effective.5 , 6 Trials of intravenous immunoglobulins, predominantly in seronegative patients, have produced conflicting results.7 8 9 Recently, acyclovir was found to decrease the risk of CMV disease when given prophylactically to both marrow10 and kidney11 recipients. In marrow-transplant recipients, prophylaxis with acyclovir resulted in a 50 percent reduction in the probability of CMV disease. The use of screened seronegative blood products in CMV-seronegative patients with seronegative marrow donors is highly successful in preventing CMV disease.8 , 12 However, only a minority of patients undergoing marrow transplantation are seronegative for CMV and have seronegative donors.
Treatment of CMV pneumonia after bone marrow transplantation with vidarabine, interferon alfa, acyclovir, and CMV immune globulin alone or in combination was not successful in reducing the high mortality associated with the infection.13 14 15 16 17 Ganciclovir, an acyclic nucleoside that is structurally related to acyclovir and has potent activity against CMV in vitro, has been used successfully to treat CMV infection in immunocompromised recipients.18 19 20 Ganciclovir alone or in combination with corticosteroids was not effective as a treatment for CMV pneumonia in marrow recipients.21 , 22 However, the combination of ganciclovir with immune globulin increased the initial rate of response to treatment from 15 percent to 50 percent or more.23 24 25 The transient suppression of bone marrow function associated with ganciclovir treatment in some patients has been of particular concern.18 , 19 , 21 , 22
In this study we evaluated the efficacy and safety of ganciclovir in patients with bone marrow transplants who excreted CMV after engraftment and who were therefore at high risk for the subsequent development of CMV disease. In 1989, when our study began, very little was known about the safety of long-term administration of ganciclovir after marrow transplantation. Our study ended seven months before Schmidt et al. reported on the safety and effectiveness of long-term ganciclovir therapy as assessed with a different strategy of surveillance after allogeneic marrow transplantation.25
Methods
Study Design
We screened for possible enrollment all patients at least two years of age who received an allogeneic bone marrow transplant for hematologic cancer at the Fred Hutchinson Cancer Research Center and who were either seropositive for CMV before transplantation or had a seropositive donor. The study was conducted from February 1989 to August 1990. Cultures of throat swabs, blood, and urine were performed weekly until one or more cultures became positive or until day 80 after transplantation. A subgroup of these patients was also included in a prospective study of the value of bronchoalveolar lavage (performed on day 35 after transplantation) in predicting the subsequent development of CMV pneumonia. Additional criteria for study entry included successful engraftment (reflected by an absolute neutrophil count of 0.5 x 109 per liter for two or more days) and a serum creatinine concentration less than or equal to 220 μmol per liter. Patients were excluded from the study if their cultures became positive after day 80; if they had symptomatic CMV disease; if they had received therapy for CMV or an investigational antiviral drug, other than ganciclovir in double-blind fashion, within seven days of enrollment (e.g., open-label ganciclovir, phosphonoformate, or intravenous immune globulin more than once weekly); or if they had sensitivity to acyclovir or ganciclovir. All patients received high doses of acyclovir for a maximum of 30 days after transplantation.10
Patients were randomly assigned to receive ganciclovir or placebo within 72 hours of being judged eligible, with stratification according to the presence or absence of graft-versus-host disease (GVHD). The decision to proceed with a placebo-controlled study was based on concerns about the safety and efficacy of long-term ganciclovir when given to bone marrow—transplant recipients before the onset of CMV disease. It was believed that a double-blind trial was warranted because of the multiple possible causes of suppressed marrow function and the clinical complexity of allogeneic marrow transplantation. The protocol was approved by our institutional review board and by the Food and Drug Administration, and all patients or their legal guardians gave informed consent. Ganciclovir was given in a dose of 5 mg per kilogram of body weight twice daily for the first 7 days and then once daily for the first 100 days after transplantation or until the patient left Seattle, if earlier. The dosage was adjusted according to the level of renal function.
Additional cultures for the detection of virus were prepared from blood, urine, and throat swabs on a weekly basis until the end of the study. The study was terminated if CMV disease developed and was confirmed by biopsy or culture or if toxic reactions to the study drug occurred.4 , 10 Although our primary analyses addressed the period from study entry to day 100 after transplantation or departure from Seattle, whichever was earlier, patients were also followed for 180 days after transplantation to detect any late occurrences of CMV disease and to assess the effect on survival.
The study was designed to enroll 116 patients (58 in each treatment group), with an interim analysis when 58 patients could be evaluated. It was estimated that 50 percent of patients who excreted virus would subsequently have CMV disease, and that the enrollment of 116 patients would allow the detection of a 30 percent difference between the treatment groups in the proportion of patients with CMV disease (20 percent in the ganciclovir group and 50 percent in the placebo group) with a power of 0.90, with the use of a two-sided test and a significance level of 0.05. The study was terminated after the interim analysis showed a statistically significant difference between the ganciclovir and placebo groups in the occurrence of CMV disease.
Laboratory Procedures
Specimens were examined for virus by both centrifugation culture26 and conventional culture in which the specimens were inoculated onto monolayers of human fibroblasts and maintained for five weeks. Antibody to CMV was determined by enzyme immunoassay (Whittaker Bioproducts, Walkersville, Md.).
Statistical Analysis
Comparisons of the incidence of CMV infection and other events were analyzed with the Cochran—MantelHaenszel chi-square test, Fisher's exact test, or Student's t-test, as appropriate. Univariate comparison of the time to specific events was performed according to the method of Kaplan and Meier,27 with analysis by the log-rank test.28 Proportional-hazards regression techniques were used to analyze the predictive value of CMV excretion.29 The covariates in this analysis included the source of material for culture, underlying disease, age, sex, serologic status, HLA matching for transplantation, conditioning regimen, and acute GVHD. The analysis of mortality was performed on an intention-to-treat basis and included all the patients enrolled.
Results
Two hundred eighty-one patients were screened for virus excretion. Eighty-seven patients (31 percent) had no positive cultures for CMV when screened for a minimum of 72 days after transplantation, and 67 patients (24 percent) died, relapsed, or were discharged early without a positive CMV culture. Eighteen patients (6 percent) had CMV disease coincident with a positive surveillance culture and before randomization; 17 patients (6 percent) had no positive surveillance cultures before the diagnosis of CMV disease. Twenty eligible patients declined to participate.
Of the 72 patients enrolled in the study (26 percent of those screened), 37 received ganciclovir and 35 received placebo (Table 1Table 1
Characteristics of the Study Groups.). The two groups were balanced, except that more patients in the ganciclovir group received HLA-mismatched marrow (P = 0.03). The mean time from transplantation to the first positive culture was 47 days in the ganciclovir group and 40 days in the placebo group (P = 0.19 by Student's t-test), with study entry a mean of 54 and 48 days after transplantation, respectively (P = 0.13 by Student's t-test).Effect of Ganciclovir on CMV Disease
CMV disease developed in 15 of the placebo recipients (43 percent) and 1 of the ganciclovir recipients (3 percent) within the first 100 days after marrow transplantation, while they were receiving the study drug (P<0.00001) (Table 2Table 2
Occurrence of CMV Disease.). CMV pneumonia developed in four placebo recipients during the first week after entry into the study; later in six placebo recipients, and in one ganciclovir recipient after 14 days of treatment, on day 58 after transplantation. A biopsy-proved CMV infection of the tongue was diagnosed in another ganciclovir recipient on day 83 after transplantation, 12 days after ganciclovir was stopped because of neutropenia (see below). Six of the 11 patients with pneumonia died. All were placebo recipients.Four other ganciclovir recipients had CMV disease during the post-treatment observation period between day 100 and day 180 after transplantation; one patient had CMV pneumonia, and three had gastrointestinal disease. One of the patients with gastrointestinal disease also had CMV retinitis. There were no new cases of CMV disease in the placebo group after day 100, although one patient who had both CMV pneumonia and gastrointestinal disease before day 100 had a recurrence of gastrointestinal disease on day 125 after transplantation. Despite the occurrence of late CMV disease in the ganciclovir group, the beneficial effect of ganciclovir on CMV disease remained significant when we analyzed events through day 180 after transplantation (P = 0.013) (Table 2).
Effect of Ganciclovir on CMV and Herpes Simplex Virus Excretion
By day 7 after the initiation of therapy, the patients given ganciclovir had a marked reduction in virus excretion, as compared with the patients given placebo (P = 0.001 by Cochran—MantelHaenszel test) (Table 3Table 3
Detection of Excretion of CMV.). By day 21 of the study and thereafter, patients receiving ganciclovir had no detectable excretion of CMV.Twenty-eight of the 37 ganciclovir-treated patients (76 percent) and 23 of the 35 placebo-treated patients (66 percent) were seropositive for antibody to herpes simplex virus before transplantation. Only one of these patients in the ganciclovir group (4 percent) and seven in the placebo group (30 percent) excreted herpes simplex virus during the study (P = 0.016 by Fisher's exact test). This ganciclovir recipient had a positive culture two days after drug administration started, but a negative culture after eight days of therapy, and did not excrete virus thereafter. Another ganciclovir recipient had varicella–zoster virus infection after four days of ganciclovir therapy and was treated with acyclovir (see below).
Culture Results and Predictive Value of Virus Excretion
Fifty-eight patients were enrolled in the study on the basis of the results of centrifugation culture and 14 on the basis of conventional culture. CMV was detected most often in urine cultures (42 patients) and less often in blood cultures (17 patients [15 by centrifugation culture and 2 by conventional culture]). Twelve patients had positive cultures of two specimens simultaneously, and in one all three specimens were positive. Four patients were entered into the study because of a positive culture of bronchoalveolar-lavage fluid. Two of these patients had no other detectable excretion of CMV, whereas the other two excreted CMV later in their course. Of the four patients, three were assigned to placebo treatment but none had pneumonia; one had CMV enteritis.
We analyzed the predictive value in the placebo group of virus excretion in the throat, blood, and urine for the subsequent development of CMV disease. Viremia was the only significant predictor of CMV disease or CMV pneumonia in both univariate analysis (P = 0.0009 for all disease and P = 0.01 for pneumonia by proportional-hazards regression analysis) and multivariate analysis (relative risk = 5.8, P = 0.007 for all disease; relative risk = 5.6, P = 0.03 for pneumonia). There were no predictors of CMV gastrointestinal disease. Recovery of virus from the throat or urine was not predictive of subsequent disease, although recovery of virus from the urine approached significance as a predictor of all CMV disease, according to the univariate analysis (P = 0.07).
Toxicity of Ganciclovir
Patients in the ganciclovir group received the study drug for a median of 32 days (range, 4 to 72), and patients in the placebo group for 27 days (range, 0 to 78). During the study, 24 ganciclovir recipients (65 percent) and 25 placebo recipients (71 percent) had possible side effects. When adverse events were grouped according to organ system, most such events were more common in the placebo group, except for effects on the central nervous system ( 11 ganciclovir recipients and 5 placebo recipients), cardiovascular system (7 ganciclovir recipients and 4 placebo recipients), and hematopoietic system (see below). Headaches were reported as a predominant symptom by five ganciclovir recipients and two placebo recipients. Tremor occurred in two patients, both ganciclovir recipients; they also received cyclosporine. A seizure-like event occurred in one patient after eight doses of ganciclovir, during a recurrence of herpes zoster in a cranial nerve. Electroencephalography showed no seizure activity, but magnetic resonance imaging suggested encephalitis. The patient was treated with acyclovir for herpes zoster with possible encephalitis, with complete clinical resolution.
Twenty-six ganciclovir recipients (70 percent) required one or more changes in dosage, as compared with 30 placebo recipients (86 percent). Dosage changes in the placebo group were prompted by the development of CMV disease in 14 patients, institution of acyclovir therapy for herpes simplex or varicella–zoster virus infection in 7 patients, withdrawal or early discharge in 7 patients, renal dysfunction (serum creatinine level, ≥130 μmol per liter) in 4 patients, leukemic relapse in 3 patients, dosage error in 3 patients, and neutropenia and noncompliance in 1 patient each. The most common reason for a change in the dose of ganciclovir was neutropenia, for which the drug was stopped in 11 patients. Less common reasons were withdrawal or early discharge in seven patients, dosage error in four patients, renal dysfunction in three patients, leukemic relapse in three patients, and thrombocytopenia, mental confusion, a need for acyclovir, and CMV disease in one patient each.
Neutropenia was more common among the ganciclovir recipients than among those given placebo (Table 4Table 4
Effect of Ganciclovir Treatment on the Absolute Neutrophil Count.*). Fifteen had an absolute neutrophil count below 1.0X109 per liter for two consecutive days, as compared with seven placebo recipients (P = 0.12); this low count was reached after a median of 35 days of treatment in the ganciclovir group and 54 days in the placebo group. Eleven ganciclovir recipients had counts below 0.75 X109 per liter, as compared with three placebo recipients (P = 0.052), and six ganciclovir recipients had counts below 0.5 X109 per liter, as compared with one placebo recipient (P = 0.11). Among the patients with a nadir below 0.75X 109, the median time to recovery of the absolute neutrophil count was four days in the ganciclovir group and nine days in the placebo group (P = 0.76 by Student's t-test).The drug was stopped because of a decreasing neutrophil count in 11 patients in the ganciclovir group and 1 patient in the placebo group (P = 0.003). The count was 0.97 X 109 per liter in 1 ganciclovir recipient and below 0.75X109 per liter in 10 ganciclovir recipients and the placebo recipient. It recovered spontaneously to more than 0.75X109 per liter in 9 of the 10 ganciclovir-treated patients after a median of 3 days (range, 2 to 16), and in the 10th patient after 20 days of treatment with granulocytemacrophage colony-stimulating factor (GM-CSF). CMV disease subsequently developed in only 1 of the 11 ganciclovir recipients whose treatment was discontinued. This patient had CMV infection of the tongue, as described above.
Mortality
Survival was better in the ganciclovir group on both day 100 and day 180 after transplantation (Fig. 1Figure 1
Kaplan–Meier Product-Limit Estimates of the Probability of Survival during the First 180 Days after Transplantation among Ganciclovir and Placebo Recipients.). There was one death (due to leukemic relapse) in the ganciclovir group during the first 100 days after transplantation, as compared with six deaths in the placebo group, all due to CMV disease (P = 0.041). Mortality in the ganciclovir group was also lower 180 days after transplantation (P = 0.027) because of the reduction in CMV disease. The three deaths that occurred after day 100 in the ganciclovir group were attributed to Pneumocystis carinii, acute respiratory distress syndrome secondary to fungemia, and noninfectious interstitial pneumonia. Five patients died after day 100 in the placebo group (which had a total of 11 deaths); 1 of these deaths was attributed to persistent CMV disease, 3 to leukemic relapse, and 1 to noninfectious pneumonia.Discussion
We evaluated the efficacy of ganciclovir treatment in bone marrow—allograft recipients in a double-blind, placebo-controlled study in which treatment was started when virus was first recovered from the throat, urine, or blood or from bronchoalveolar-lavage fluid. Early treatment with ganciclovir was associated with a significant decrease in subsequent CMV disease and significantly better survival. Among the ganciclovir recipients, disease attributable to CMV was reduced by 93 percent (15 cases among the placebo recipients and 1 among the ganciclovir recipients) in the first 100 days of treatment, with a reduction in both pneumonia and gastrointestinal disease due to CMV. The only ganciclovir recipient who had CMV disease during the study had CMV pneumonia but survived. There were four new cases of CMV disease among the ganciclovir recipients after day 100, when treatment was stopped, and none among the placebo recipients, but the beneficial effect of ganciclovir remained significant 180 days after transplantation (P = 0.013). There was a significant decrease in mortality in the ganciclovir group both 100 days and 180 days after transplantation, as a result of this decrease in CMV disease.
These data support and extend the study by Schmidt et al., in which ganciclovir treatment was initiated if bronchoalveolar-lavage fluid obtained on day 35 was positive for CMV and the patient was asymptomatic.30 In that unblinded study, ganciclovir decreased the incidence of CMV pneumonia by 77 percent, from 65 percent (13 of 20 patients) to 15 percent (3 of 20), with minimal toxicity. Mortality after transplantation was not analyzed.
The mechanism of protection appears to be the rapid and complete suppression of replication of CMV by ganciclovir. The effect on virus excretion became evident within the first week of treatment. All ganciclovir recipients were culture-negative after the second week and thereafter. This rapid effect on virus replication is consistent with published reports of ganciclovir treatment of established CMV disease. Shepp et al.21 reported that the median time to negative cultures of urine, blood, and respiratory secretions was two, six, and eight days, respectively, in bone marrow recipients treated with ganciclovir for CMV pneumonia. In patients with the acquired immunodeficiency syndrome (AIDS) who were treated for CMV retinitis, excretion of virus in the urine stopped after a median of seven days, and excretion in the blood and throat secretions after eight days.18 Both the importance of CMV replication in the pathogenesis of CMV disease in marrow-allograft recipients and the rapidity with which replication can be interrupted are suggested by our observation that CMV disease developed in four patients in the placebo group during the first week of the study, but in none in the ganciclovir group.
A previous study from our institution suggested that virus excretion may serve as a marker to identify patients at high risk for CMV disease.4 In that retrospective study, viremia was found to be predictive of both pneumonia and gastrointestinal disease due to CMV, whereas recovery of virus from the throat was predictive only of gastrointestinal disease. In the current analysis, viremia was found to be predictive of all forms of CMV disease, whereas neither recovery from the throat nor recovery from the urine was predictive. The difference may be explained by the sample size, patient population, or design of the previous study and may have implications for screening patients. Twelve of the 15 patients in the placebo group who had CMV disease (80 percent) had viremia before the onset of disease, as compared with only 7 of 20 patients in the placebo group without CMV disease (35 percent). Viremia thus had a predictive value of 63 percent for subsequent CMV disease, a figure similar to that found in our previous study.4 The three patients who did not have viremia excreted virus in the urine. These data suggest that screening blood by centrifugation culture may be sufficient to identify the majority of patients at risk for CMV disease.
Hematologic toxicity, especially neutropenia, has been the most consistent side effect of ganciclovir 18 , 21 22 23 , 30 , 31 in this study; 15 of 37 ganciclovir recipients (40 percent) had an absolute neutrophil count of less than 1.0 X 109 per liter. This proportion is similar to those observed in studies of patients with AIDS who were treated for CMV disease, in which clinically serious neutropenia developed in 14 to 40 percent of patients,18 , 31 and in the study by Schmidt et al., in which the treatment of 7 of 20 ganciclovir recipients (35 percent) was modified because of neutropenia.30 Not all investigators have observed bone marrow toxicity associated with ganciclovir.32 , 33 A double-blind, placebo-controlled trial of ganciclovir for the treatment of CMV gastrointestinal disease after marrow transplantation found no difference between ganciclovir and placebo groups in apparent drug toxicity to bone marrow.33 Ganciclovir was given for only 14 days in that study, as compared with a median of 32 days in this study. In our study the difference between the numbers of ganciclovir and placebo recipients whose absolute neutrophil counts were 0.75X 109 per liter or less approached significance (P = 0.052 by log-rank test), and treatment was stopped in significantly more ganciclovir recipients (11 vs. 1, P = 0.003). There appears to be a trend toward neutropenia among patients treated with ganciclovir.
Nevertheless, hematologic toxicity was a manageable problem. When treatment was stopped, the neutrophil count recovered in all ganciclovir recipients, although one received GM-CSF. These findings suggest that when the neutrophil count reaches the arbitrarily defined level of 0.75X109 per liter, discontinuation of the drug will generally result in prompt recovery without long-term suppression. The response to GM-CSF in the single patient given it suggests that this agent may have a role if administered either concomitantly with ganciclovir or in response to neutropenia. Except for neutropenia, there was no difference between the study groups in side effects, including renal and central nervous system toxicity.
This study also shows that ganciclovir treatment initiated at the time of virus excretion is not wholly adequate to prevent CMV disease after bone marrow allografting. Such treatment was 93 percent effective in eliminating CMV disease, but the strategy of early treatment was only 50 percent effective in preventing disease in all patients, since CMV disease had occurred in 35 of 281 patients (12 percent) before or at the time of the detection of virus excretion. These results are similar to those of the study of Schmidt et al., in which 13 of 104 patients (13 percent) had CMV pneumonia without having had a positive culture of bronchoalveolar-lavage fluid.30
An alternative approach to early treatment with ganciclovir is prophylaxis for all patients at risk for CMV disease — i.e., all who are seropositive. This would require the administration of ganciclovir to a substantial number of patients who might not benefit from it and who might have toxic reactions. Of the 281 patients screened for this study, 87 (31 percent) did not excrete CMV during at least the first 72 days of the post-transplantation period. A decision to treat all seropositive patients would depend on the toxicity and cost of ganciclovir when given prophylactically. The development of better virologic or immunologic methods for identifying patients at risk for disease would help to target therapy and avoid the possible risks and expense associated with general prophylaxis.
Finally, the occurrence of late disease after treatment was stopped is of potential concern. In patients given acyclovir for prophylaxis against herpes simplex virus infection, the immune response to the virus is not reconstituted, and disease develops after suppression is stopped.34 It has been suggested that patients whose CD8+ CMV-specific cell-mediated response is reconstituted may be protected from CMV disease after transplantation.35 , 36 Patients given early ganciclovir treatment may not have reconstitution of these responses and thus may be at risk for late CMV disease. One alternative is to extend the period of ganciclovir prophylaxis in patients at risk. Risk factors for late CMV disease are not well characterized, although patients with acute or chronic GVHD who excrete virus and who do not have reconstituted CMV-specific cell-mediated immune responses may be candidates for extended prophylaxis. The addition of immune globulin to prevent late disease seems unlikely to be of benefit since its mechanism of action is postulated to be immunologic, not antiviral.23 24 25 , 37
We have shown that ganciclovir has dramatic efficacy in the early treatment of CMV excretion, with significant decreases in the incidence of CMV disease in the first 100 days after transplantation and in overall postoperative mortality. This approach was more effective in reducing CMV disease than was the use of screening with bronchoalveolar lavage (efficacy, 93 percent vs. 77 percent) and obviated the expense and morbidity associated with bronchoscopy. Ganciclovir treatment was effective in patients who excreted virus, but it did not benefit patients who had CMV disease before virus excretion was detected. Hematologic toxicity occurred but could be managed by discontinuation of the drug. Further studies will be required to define the role of ganciclovir for prophylaxis rather than early treatment after allogeneic marrow transplantation and to determine the CMV-specific immune status of patients who have undergone suppression of CMV infection with ganciclovir.
Supported by a grant from Syntex Research and by grants (CA-18029, CA15704, and HL-36444) from the National Institutes of Health. Dr. Goodrich was supported in part by an award from the Poncin Scholarship Fund, Seattle.
*Deceased.
Source Information
From the Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle (J.M.G., M.M., C.A.G., M.C., J.D.M.), and the Institute of Clinical Medicine, Syntex Research, Palo Alto, Calif. (C.D.,D.F.E., W.C.B., B.D.). Address reprint requests to Dr. Goodrich at the Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, 1124 Columbia St., Seattle, WA 98104.
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