Introduction

Despite significant advances in prevention and treatment, cytomegalovirus (CMV) infection continues to be an important cause of morbidity and mortality in the allogeneic hematopoietic stem cell transplantation (HSCT) recipient.^{1, 2, 3} Improvements in management have reduced the incidence of CMV disease from 20 to 30% in early transplantation series to 5–10% today.^{3, 4}

The use of alternative donors, T-cell depletion, non-myeloablative conditioning regimens, and cord blood transplantation has generated new populations of patients at high risk for CMV reactivation and CMV disease.^{3, 5, 6, 7, 8, 9} Similarly, the increasing number of patients treated with corticosteroid-containing regimens for graft-versus-host disease (GVHD) are at a higher risk for CMV-related morbidity and mortality.¹⁰

Hematopoietic stem cell transplantation recipients at risk for CMV disease (i.e., all CMV-seropositive HSCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) are usually placed on a CMV disease prevention program from the time of engraftment until at least 100 days after HSCT or longer in patients with active GVHD.² Two major disease prevention strategies have emerged, 'universal prophylaxis' and 'pre-emptive therapy'. In the latter, the use of an anti-CMV drug is limited to patients at high risk for CMV disease, identified by very sensitive and specific tests for the detection of active viral duplication in blood or serum.^{2, 3, 4, 11, 12}

Pre-emptive therapy is based on the premise that early detection of CMV reactivation will allow treatment of the patient before the development of CMV disease. In this way, only patients who have a higher probability of experiencing CMV disease are exposed to the toxicity of anti-CMV drugs. In one prospective trial, this strategy decreased CMV-related mortality.¹³

IV ganciclovir (GCV) has been the drug of choice for prophylactic and pre-emptive strategies in hematopoietic stem cell transplantation and extensive experience has been accumulated with this drug.^{2, 4, 10, 11, 12, 13, 14, 15, 16, 17, 18}

Valganciclovir (VGC) is the L-Valyl ester of GCV. After oral administration it is rapidly converted to GCV by intestinal and hepatic esterases with an absolute oral bioavailability of approximately 60%. After conversion to GCV, it follows the same metabolism and elimination and shares the same side effects and toxicities.¹⁹ Valganciclovir was approved by the FDA in March 2001 for the treatment of CMV retinitis in AIDS patients. A randomized open-label controlled study showed that oral VGC was as effective as IV GCV for induction treatment and was convenient and effective for the long-term management of CMV retinitis in patients with AIDS.²⁰

Valganciclovir has ideal properties for implementation in pre-emptive strategies for prevention of CMV disease in HSCT recipients; namely oral administration, good bioavailability, well-known toxicity and safety profile, and avoidance of infusional therapy at home. For these reasons, VGC was adopted in our center in March 2002 as our drug of choice for outpatient pre-emptive treatment of CMV infection. In this report, we review our accumulated experience with the use of this drug as the primary pre-emptive.

Patients and methods

Patients

Valgancyclovir was adopted for the outpatient management of CMV reactivation in our institution in March of 2002. Fifty-two patients underwent allogeneic HSCT between March 2002 and May 2003 and completed at least 100 days of follow-up. An IRB-approved retrospective review of charts, pharmacy records, electronic medical records (Powerchart^®), and virology laboratory records was performed in 49 of 52 patients undergoing allotransplantation during this interval. Three patients were excluded from the analysis as they died in the early post transplant period (<day +40) and therefore were not at risk for the development of CMV reactivation.

Hematopoietic stem cell transplantation

The conditioning regimen varied by disease, recipient status, and donor source: myeloablative total body irradiation (TBI) based, n=16 (with Cytoxan in 14 patients or VP16 in two patients), myeloablative chemotherapy only, n=25 (BuCy2 n=20, CBV n=4, BuCyVp16 n=1), or non-myeloablative (Flu/TBI n=5, Cy/ATG n=3). T-cell depletion via positive CD34 selection was used in four patients at high risk for GVHD. Thirty-six patients received grafts from related donors and 13 from unrelated donors through the National Marrow Donor Program. Patient characteristics and pre-transplant CMV serologies are shown in Tables 1 and 2.

Table 1 - Patient characteristics.

Full table

Table 2 - CMV serologies at transplantation.

Full table

Supportive care guidelines established by the Blood and Marrow Transplant Program at the H Lee Moffitt Cancer Center & Research Institute were followed. Briefly, GVHD prophylaxis varied according to the type of donor. Recipients of matched related transplants after myeloablative conditioning received cyclosporine/methotrexate. Recipients of matched unrelated transplants after myeloablative conditioning received tacrolimus/methotrexate. Recipients of non-myeloablative conditioning received cyclosporine/mycophenolate mofetil (MMF). Recipients of CD34+ selected grafts were given single agent cyclosporine. Acute GVHD was treated with Methylprednisolone (MP) intravenously 1 mg/kg q12 h (2 mg/kg/day) for 14 days before tapering. Prophylaxis for bacterial, fungal, and Pneumocystis Carinii infection included an oral quinolone, fluconazole, and Trimetoprim-Sulfametoxazole, respectively. Prophylaxis for Herpes Simplex infections included Acyclovir until immunosuppressive therapy was discontinued.

CMV detection assay

Routine surveillance CMV assays were performed on peripheral blood once a week from the day of admission until day +100. The Digene^® Hybrid capture assay was used to guide pre-emptive antiviral therapy.²¹ Briefly, single-strand DNA is generated from 3.5 ml EDTA anticoagulated blood by alkalinization using the manufacturer solutions and tubes. Then, a CMV-specific RNA probe is added and the tube is incubated at 70° for 2 h. Thereafter, the DNA–RNA hybrids are transferred to specific antibody-coated capture tubes. After incubation with an alkaline-phosphatase-conjugated antibody specific for DNA–RNA hybrids, a colorimetric substrate is added and the sample is read with a luminometer. A semiquantitative result is obtained by comparison with a standard. The result is informed as positive, negative, or equivocal. The turn around time for the test is approximately 8 h, which allows the clinician to start therapy within 24 h of obtaining the sample. Prior studies have reported the sensitivity, specificity, positive, and negative predictive values of 87.7, 98.3, 98.6, and 85.2% for the hybrid capture assay and 76.6, 100, 100, and 75.5% for the CMV pp-65 antigenemia when compared for the detection of CMV infection in immunocompromised patients.²² The specificity of hybrid capture assay compares favorably with other DNA methods like PCR as noted in previous reports in which the specificity of hybrid capture was 98.9% and the specificity of PCR was 100% for the detection of CMV infection in a cohort of allogeneic stem cell transplant recipients. The negative predictive value for hybrid capture assay was 100%.^{23, 24}

Cultures from urine, bronchoalveolar lavage, or organ tissues were prepared by shell vial culture when indicated by the clinical setting.

Pre-emptive therapy for CMV reactivation and treatment of CMV disease

When a CMV assay by hybrid capture was found to be positive, outpatients with an absolute granulocyte count above 500/mm³ and who did not have severe gastrointestinal GVHD started oral VGC (Valcyte^®) at a dose of 900 mg twice a day with food for 14 days, followed by 900 mg once a day until at least 7 days after a negative CMV test in the absence of clinical signs or symptoms of infection. If the hybrid capture assay was still positive after at least 7 days of oral therapy, or the patient was intolerant to oral VGC, treatment could be changed to IV GCV or foscarnet at the discretion of the clinician. Owing to the cost/charge differential of delivering VGC and IV GCV as an inpatient vs outpatient, only outpatients received VGC.

In the event of CMV disease, IV GCV 5 mg/kg every 12 h for 21 days and IVIG 500 mg/kg QOD 10 doses were administered (for pneumonitis), followed by IV GCV 5 mg/kg IVP QD, 5 days/week and IVIG 500 mg/kg weekly for 4 weeks in the absence of clinical signs or symptoms of ongoing infection.

Definitions

Cytomegalovirus infection and disease were defined according to published recommendations.²⁵ Cytomegalovirus infection was defined as the presence of CMV DNA in the peripheral blood detected via Digene^® Hybrid Capture assay. A diagnosis of CMV pneumonia required the presence of signs or symptoms of lower respiratory disease (hypoxemia, infiltrates) together with viral isolation from bronchoalveolar lavage or lung tissue. A diagnosis of CMV enteritis required symptoms together with lesions found in endoscopy and the virus detected from biopsy material by culture, histopathology, immunohistochemistry, or DNA hybridization. Cytomegalovirus Hepatitis required abnormal liver function together with virus isolated from biopsy material. Disease of CNS required symptoms and virus detection by culture or PCR from the cerebrospinal fluid.

Other definitions used in this analysis are:

1. Response: The conversion from a positive test (Digene^® Hybrid capture) to a negative one during the next 14 days after initiation of oral VGC.
2. Failure: Persistence of a positive test after 14 days of therapy, or progression from CMV infection to CMV disease while on therapy or development of CMV disease before infection could be detected by a positive test.
3. Toxicity: Need to change to alternative therapy due to progressive anemia, leukopenia, thrombocytopenia, renal insufficiency, or other unexpected side effect.
4. Episode: For the purposes of this analysis, episode refers to a single positive assay, regardless of whether it prompted intervention or not.

Statistical analysis

Differences in white cell count, platelets, hemoglobin, and serum creatinine before and after VGC therapy were compared using the Wilcoxon Matched pair Test for paired non-parametric data.

Results

Among the 49 consecutive patients undergoing allotransplantation included in this analysis, 24 patients developed at least one positive assay for CMV by Digene^® Hybrid Capture for a rate of reactivation of 48% (95% CI: 34, 63%). 46 episodes of CMV reactivation were detected in 24 patients (12 patients with one discrete episode, eight patients with two, two patients with three, one patient with five episodes, and one patient with seven episodes) (Table 3). Of these 46, 30 episodes of CMV reactivation in 18 patients were treated with oral VGC as described above (Table 4). The rate of conversion from positive to negative by hybrid capture assay after 7 days of oral VGC was 83% (25/30) (95% CI: 65, 94%). This may be an underestimate because information from day 7 hybrid capture status was unavailable in three patients. The rate of conversion after 14 days of therapy was 93% (28/30) (95% CI: 78, 99%). The median duration of therapy was 21 days (range 10–21). All patients received 3 weeks of therapy as described in the methods. Only two patients failed oral VGC. The first one with mucositis grade 3 became negative on IV GCV. The second one subsequently failed IV GCV and became negative on IV Foscarnet. During the period of the study, one case of CMV enteritis was diagnosed in a patient with acute GVHD and persistently positive hybrid capture assay while on IV GCV. This patient recovered with IV Foscarnet. There were no cases of CMV pneumonitis. The incidence of CMV disease was 1.9%.

Table 3 - Episodes of CMV detection per patient.

Full table

Table 4 - Treatment given for positive CMV assays detected by Digene^® hybrid capture.

Full table

In two patients, treatment was changed to IV GCV after 1 week because of nausea and vomiting in the setting of acute GVHD. They are not considered treatment failures based on the definition used in this analysis.

Sixteen episodes of CMV reactivation in eight patients were not treated with VGC. Three episodes were not treated at all for the following reasons: Two of them happened before day 0 and both patients were observed with subsequent negative assays without intervention, the third one was in a patient dying of recurrent acute myeloid leukemia. The remaining 13 episodes were treated with IV GCV or Foscarnet because of various reasons, predominantly because of clinician choice, n=7, nausea and vomiting, n=4, or other, n=2. Sixty-six percent of the episodes of CMV infection occurred in the setting of acute or chronic GVHD but the response to VGC was excellent independently of this as noted by the high conversion to a negative assay.

Three episodes in three patients treated with VGC were followed by relapses with positive Hybrid capture assay within 4 weeks of finishing therapy (median of 3 weeks after), all of them were retreated, became negative after another course of VGC. Two patients relapsed again 3 months later, one was retreated successfully and the second one died of recurrent acute myeloid leukemia. Seven more patients had recurrent episodes of viremia but all of them more than 1 month after VGC therapy was finished and all of them responded to a repeat course of VGC.

Toxicity

Parameters for toxicity usually associated with IV GCV were followed during VGC therapy. The median WBC the day VGC started was 6.5 10⁹/l (range 1.9–14.5), and decreased to 3.1 10⁹/l (range 0.5–13.9) at the end of the therapy (P=0.007). The median platelet counts before and after therapy were 10⁵ 10⁹/l (range 8–377) and 74 10⁹/l (range 6–304) (P=0.03). The median hemoglobin before and after therapy was 9.9 gm/l (range 8–13.9) and 9.7 gm/l (range 7.3–12.2) (P=0.49). The median creatinine before and after therapy was 0.9 mg/dl (range 0.6–1.9) and 0.9 (range 0.5–1.6) (P=0.76).

None of the patients required discontinuation of the oral formulation secondary to specific gastrointestinal intolerance in the absence of gut GVHD.

Discussion

Despite its widespread use in the management of HIV-related CMV infection, there have been surprisingly few reports of the use of VGC in the post-allotransplant setting. Clinical studies to date have primarily focused on the toxicity profile and have demonstrated a similar pattern of mild leukopenia, thrombocytopenia with minimal GI side effects. Leather et al.²⁶ reported their experience with VGC in terms of toxicity using the same dose and schedule used in HIV patients and found that only two of 22 episodes required discontinuation in therapy secondary to nausea and/or vomiting. The proportion of patients converting to a negative assay was not reported.

The results of this analysis demonstrate that oral VGC at a dose of 900 mg twice daily for 2 weeks and then once daily for 1 additional week is a safe and effective alternative to intravenous GCV as pre-emptive therapy for CMV reactivation in allogeneic HSCT recipients. More than 80% of the patients converted to a negative hybrid capture assay after 1 week of therapy and more than 90% converted after 2 weeks of therapy. These results compared favorably with the conversion rates reported in the literature for IV GCV and Foscarnet. In a prospective multicenter phase III trial that compared pre-emptive therapy with these two agents, the rate of conversion to a negative PCR test was 90% for Foscarnet and 87% for GCV after 3 weeks of therapy. The incidence of CMV disease in that trial was 5%.²⁸ Only one case of CMV enteritis was diagnosed in our study in a patient with presumably GCV-resistant CMV that recovered with foscarnet therapy.

Valganciclovir was well tolerated and the main observed toxicity as expected was mild neutropenia, which is a well-known side effect of GCV. There was a mild decrease in platelet counts but hemoglobin and creatinine remained stable. We preferred not to use oral GCV in patients with documented GVHD affecting the gut. Our approach may indeed have been conservative in this regard based on data recently presented by Einsele. These data came from a prospective comparison of the pharmacokinetics of VGC and GCV in HSCT recipients. In this study, the bioavailability of VGC was 35% higher than in GCV, the peak level was lower and the trough level higher. Patients with GVHD showed a decrease in bioavailability of about 15% after VGC compared to patients without GVHD. There was no significant difference in toxicity and no difference in the incidence of CMV disease. The author concluded that the bioavailability of GCV after oral administration of VGC was excellent, even in patients suffering from intestinal GVHD.²⁷

A potential limitation of this retrospective analysis is the inability to definitively compare the outcomes reported here vs the clinical experience with IV GCV. The rates of CMV infection and disease seen in our retrospective analysis were comparable to other reports in the literature.^{13, 28} Even among the few patients with subsequent positive assays after completion of a 3 week treatment course with oral VGC, recurrent viremia did not appear to occur at a higher frequency or have a worse outcome than in those patients with recurrent positive assays after IV GCV based on our single-institution historical data. It should be noted that we took a rather aggressive approach to pre-emptive therapy by using a very sensitive assay and intervening on the first positive result, rather than requiring two consecutive positive assays, which may be the practice at some centers. Although this is the same clinical threshold that was employed for initiating IV GCV at our center, we cannot exclude the possibility of overtreating for a false positive result. However, we believe that the likelihood of unnecessary intervention is low in light of the high-risk nature of the population treated.

In addition to its comparable efficacy and acceptable toxicity profile when compared to IV GCV, the use of oral VGC include other possible advantages such as the avoidance of IV therapy, catheter manipulation, and line care, and the reduced outpatient expenses associated with oral therapy. Furthermore, oral therapy allowed the initiation of treatment within 24 h of a positive CMV assay in most patients obviating the common delays associated with the initiation of outpatient IV therapy, or even admission to the hospital to initiate IV therapy.

Limitations of this study include its small numbers, retrospective nature, and the lack of a comparator arm. The retrospective nature of this analysis does not provide the rationale as to why certain patients were treated with IV GCV beyond the clinical bias of the treating physician. In addition, approximately one-third of the patients received grafts from matched unrelated donors who may be at higher risk of developing opportunistic infections, such as CMV. Regardless, we saw no difference in the conversion rate between recipients of sibling vs unrelated grafts, although the limited number of patients provided inadequate power to detect such a difference.

In summary, from this analysis we conclude that a pre-emptive strategy of oral VGC appears to be safe and effective for the prevention of CMV disease in allogeneic hematopoietic stem cell recipients. We believe this is the first published report demonstrating both the safety and efficacy of oral VGC as the primary pre-emptive strategy for the development of CMV infection after allotransplantation.

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Acknowledgements

We thank all the clinicians, nurses, and pharmacists from our transplantation team who helped to take care of this group of patients.