Infections Post Transplant

Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients

Summary:

Although the efficacy and safety of voriconazole to treat invasive fungal infections have been demonstrated in prospective trials, its use for secondary prophylaxis to prevent reactivation of these infections remains unknown. Delaying the scheduled treatment of leukemia until complete resolution of fungal infection may have major implications for prognosis. We report 11 leukemic patients with previous aspergillus (n=10) and candida (n=1) infection who received voriconazole 400 mg/day intravenously or orally for between 44 and 245 days. Nine patients were scheduled for allogeneic stem cell transplant, and two for consolidation therapy for acute leukemia. None of the patients had a relapse of fungal infection, and scheduled treatment was delayed only once. Voriconazole was well tolerated, except in one patient who had abnormal liver tests secondary to hepatic graft-versus-host disease, and one who had visual disturbances. This small but homogeneous series indicates that voriconazole may be useful to prevent fungal relapse during at-risk periods in leukemic patients. Prospective trials are warranted to confirm these encouraging results.

Main

More than half of leukemic patients affected by aspergillosis die from their fungal infection.1 Although new, more effective antifungal drugs have increased survival in patients with a first episode of fungal infection; deep-seated foci of infection often remain after treatment. Reactivation during a new neutropenic episode and in patients undergoing stem cell transplant is estimated to be 30–50%, and is associated with a poor prognosis. The largest homogeneous series of stem cell transplant patients is a joint study from the European Organization for Research and Treatment of Cancer (EORTC)-Invasive Fungal Infection Cooperative Group (IFICG) and the European Group for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party in which data from 48 transplant patients with previous aspergillosis were retrospectively collected. The overall risk of aspergillus relapse was 33% (16/48), and the death rate among patients with aspergillus relapse was 88%.2

However, although fungal relapse is a major risk, delaying leukemia treatment or stem cell transplant may have a major impact on the risk of leukemic relapse. A survey conducted in the EBMT and EORTC groups in 1995 revealed that 20% of 75 European stem cell transplant centers were reluctant to propose stem cell transplant with myeloablative conditioning regimens to patients with previous invasive fungal infection.3 Other reports show that although the risk of fungal relapse cannot be neglected, this risk may be offset by the benefit of transplant.2,4,5,6,7 However, given the lack of prospective studies of secondary antifungal prophylaxis in this setting, the best approach to reduce the risk of fungal relapse during at-risk periods in the course of leukemic therapy remains unclear.

Voriconazole, a triazole antifungal agent, is fungicidal against aspergillus and candida species, including non-albicans candida, and other rare fungal infections such as Fusarium or Scedosporium species that occur in stem cell transplant patients.8 In the first-line treatment of aspergillosis, it has been shown to be more effective and better tolerated than amphotericin B.9 Despite a substantial number of side effects (ie, visual disturbances, confusion, skin reactions, and liver-function abnormalities), and potential drug interferences, especially with ciclosporine, voriconazole is widely used after stem cell transplant and allogeneic SCT recipients represented one-fourth of the study population in the aspergillus comparative study.9 The efficacy of voriconazole in primary therapy, the fact that it is well-tolerated, and is available in both oral and intravenous formulations indicates that it may be useful as secondary prophylaxis in leukemic patients with previous fungal infection who require a further course of chemotherapy.

We report our experience in 11 leukemic patients with previous aspergillosis or candidiasis, who received secondary prophylaxis with voriconazole during myeloablative allogeneic stem cell transplantation or consolidation therapy for acute leukemia.

Patients and methods

Between June 2000 and September 2002, 11 leukemic patients with previous proven (n=6) or probable (n=5) invasive fungal infections (aspergillus n=10, candida n=1) according to MSG-EORTC definitions10 were referred to the hematology units of our three departments for allogeneic stem cell transplant (n=9) or consolidation treatment for acute leukemia (n=2). Briefly, the proven cases were documented by biopsy, the probable cases were documented either by a positive culture from broncho-alveolar lavage fluid in case of lung infection, or by a positive sinus aspiration in case of sinusitis (Table 1). A total of 9 of the patients had received antifungal polyenes as first-line treatment. Among the eight patients who had received voriconazole as salvage treatment, none had been clinically resistant. In the five patients with residual fungal disease at the time of transplant or consolidation (Table 2), two were kept on continuous therapy with voriconazole, and three were given a course of voriconazole, after a disruption in antifungal therapy. In 10 patients, the scheduled treatment of leukemia (allogeneic stem cell transplantation or consolidation chemotherapy) was administered according to the planned protocol. In patient 11, the consolidation course had been delayed for 4 months because of previous candidiasis. All of the patients who underwent allogeneic stem cell transplant were scheduled to receive myeloablative regimens with total body irradiation and cyclophosphamide (n=6), or busulfan and cyclophosphamide (n=3). Considering the risk/benefit ratio expected in these patients with a high risk of fungal relapse and subsequent death, it was proposed that these patients receive an antifungal prophylaxis on an individual basis, in order to cover the new at-risk period of fungal infection. Among the different alternatives, considering that the drug interferences with voriconazole are manageable, and considering also the clinical efficacy of voriconazole on aspergillosis,9 and its double i.v. and oral availability, voriconazole was chosen. All patients with previous fungal history, and referred to the three centers for SCT or consolidation therapy between 2000 and 2002 were treated with the same strategy.

Table 1 Characteristics of the 11 patients with previous history of invasive fungal infections, who received voriconazole as secondary prophylaxis
Table 2 Main characteristics of the treatment period and outcome of the 11 patients who received voriconazole as secondary prophylaxis

Voriconazole was administered for secondary prophylaxis to cover either the initial stem cell transplant phase, or neutropenia following consolidation therapy. The median time after the previous episode of invasive fungal infection was 10 months (Table 2). At the start of secondary prophylaxis, the invasive fungal infection was in complete remission (no clinical or imaging evidence of fungal infection) in six patients, and in partial remission (persistence of clinical or imaging evidence or both) in five patients (Table 2).

Prophylaxis was started on day 8 before transplant (ie, before starting the administration of the conditioning chemotherapy), or 1 or 2 days before starting consolidation chemotherapy. All patients received an intravenous loading dose of 600 mg of voriconazole and then 200 mg twice daily either intravenously or orally until the end of the at-risk period. In transplant patients, this was defined as at least 3 months after allogeneic stem cell transplant or until cessation of immunosuppressive treatment in case of graft-versus-host disease; in patients who had undergone consolidation treatment, it was defined as the resolution of neutropenia (PMN>500/mm3). All patients underwent daily clinical examination for the recurrence of fungal infection, and all were prospectively monitored for galactomannan blood antigenemia (Platelia Aspergillus, Biorad) twice a week during the neutropenic phase, and then once a week thereafter. In addition, transplant patients were monitored once a week as outpatients until at least the end of the third month. All of the patients underwent close clinical follow-up for fungal infection until the end of the study period, or until death.

The success of secondary prophylaxis was defined as the absence of documented relapse of the fungal infection, and the absence of new proven or probable invasive fungal infection.

All patients were evaluated for side-effects of the drug by daily clinical examination and routine biological tests including blood count, biochemistry and liver tests at least twice a week during hospitalization, and then once a week during the rest of the treatment period. In the event of serious adverse effects, voriconazole was stopped and replaced by an i.v. polyene.

Results

None of the 11 patients experienced fungal relapse or new fungal disease, despite profound neutropenia (mean: 22 days, range 15–33) and intensive immunosuppression, and all but one (see Patient 11 below) were able to adhere to the planned treatment schedule. Of the nine stem-cell transplant recipients, seven developed acute graft-versus-host disease (GVHD), two of whom had grade III disease and received steroids (2 mg/kg/day of prednisone) for at least 14 days and then tapered doses until the end of the at-risk period. Three of these patients developed chronic extensive GVHD, which required prolonged steroid administration after day 100. Three patients died from refractory GVHD between 4 and 8 months, and three from leukemic relapse between 9 and 16 months after transplant. At the last date of follow-up on May 1, 2003, five patients were still alive. Of these, four were disease-free between 14 and 33 months after transplant, and one had leukemic relapse.

The patients received voriconazole for a median 137±57 days (range 44−245 days). The reasons for stopping prophylaxis were the end of immunosuppressive therapy because GVHD was either controlled or absent (patients 2,4,7,9), end of consolidation therapy (patients 10,11), death (patients 5,6), decision to provide supportive treatment in a patient with refractory GVHD who died 15 days later (patient 3), fever and colonization with Candida krusei (patient 1), or cholestatic syndrome (patient 8). In this patient, voriconazole was stopped prematurely due to liver test abnormalities, but these were later attributed to histologically proven GVHD. The patient received Amphotericin B lipid complex as secondary prophylaxis thereafter, until day 100. Patient 1 was switched from voriconazole to liposomal amphotericin B at the time of fever and C. krusei colonization.

In one patient (patient 11) with previous large liver abscesses due to candida, CT scan revealed a transient worsening of the hepatic lesions during the first consolidation course. Voriconazole was stopped and amphotericin B deoxycholate was given intravenously (1 mg/kg) during the febrile episode. Blood cultures remained negative and liver tests were unchanged. After recovery from neutropenia, CT findings were similar to those obtained prior to chemotherapy, and voriconazole was administered again. No fungal reactivation was observed during the second course. One patient (Patient 9) experienced transient visual disorders but was able to continue with the treatment.

Discussion

Our case series shows that voriconazole may be used as secondary prophylaxis in patients at high risk of fungal relapse because of prolonged neutropenia and severe immunosuppression due to allogeneic transplant with myeloablative regimens. All of our patients except one adhered to the planned chemotherapy or transplant schedule, none died during chemotherapy-induced neutropenia, there were no severe side effects, and we did not encounter any difficulties in managing cyclosporin levels during immunotherapy. Voriconazole was stopped in only one patient with liver test abnormalities, which were subsequently found to be related to liver GVHD on biopsy. Since autopsy was not performed in the six patients who died, we cannot eliminate the presence of fungal infection at the time of death in these patients. However, aspergillus was clearly not the primary cause of death and was not the main cause to compromise the benefit of transplant since three patients died from leukemia relapse, and three died from refractory GVHD. These findings have to be interpreted considering several points: (1) there are no prospective data on secondary antifungal prophylaxis in hematology patients with previous invasive fungal infection. (2) Despite recent data on a large series of patients receiving secondary prophylaxis,11only small retrospective series mentioning the exact doses and sequence of antifungals have been reported so far. (3) Although we cannot consider that the necessity of secondary prophylaxis has been clearly established in formal studies, there is a practical consensus for giving antifungals to patients who are going to experience a new prolonged neutropenic phase, or transplant.3 This is supported in the larger retrospective series by a better overall prognosis in patients who have received any secondary prophylaxis, than in patients who have not (2).

To our knowledge, the only other report to date of the use of voriconazole for secondary prophylaxis in two patients with acute leukemia and a history of invasive aspergillosis also showed no infectious complications after prolonged administration.12 With the addition of our series, voriconazole appears to be a promising candidate to prevent relapse of fungal infections in immunocompromised patients because of its broad-spectrum action, low toxicity, and clinical efficacy. Comparison of these initial findings with those of other antifungal agents used for secondary prophylaxis is difficult because the studies are retrospective, and in small series of heterogenous patients. Among 31 patients with previous candidiasis reported in seven different series,5,6,13,14,15,16,17 22 received amphotericin B or fluconazole as secondary prophylaxis; of the 10/22 (32%) with relapsed candidiasis, nine died. Of a total of 111 patients with previous aspergillosis, including 56 allogeneic stem-cell transplant recipients, reported in 10 different series,2,4,12,18,19,20,21,22,23,24 60 patients received either deoxycholate, liposomal amphotericin B, or itraconazole as secondary prophylaxis, and the overall rate of aspergillus relapse was 31/111 (28%). Of note, the EORTC-IFICG and EBMT joint retrospective study2 showed that patients receiving prophylaxis with absorbable or intravenous antifungals had less relapses of aspergillus than those who did not receive prophylaxis. However, it is likely that these are minimal rates of relapse because reports tend to focus on favorable outcomes, and this makes it difficult to determine the exact extent of relapse.

Other approaches either alone or in combination have also been proposed to reduce the risk of fungal relapse in the course of allogeneic transplant or leukemia therapy, but there are limitations to these methods. First, while surgery is effective in patients with a unique, easily accessible site of infection, no contraindication to lung surgery, and in whom the operation can be performed quickly,20 it is not realistic in patients with bilateral lung lesions, and it may also delay chemotherapy or transplant until the wound has healed, by which time the patient may no longer be in remission. Second, although the use of nonmyeloablative approaches to allogeneic transplant has been shown to reduce the duration of neutropenia,24 the evidence to date that these approaches may reduce the risk of fungal infection, when compared to more classical, myeloablative approaches, is limited.25,26,27 Third, the role of prophylactic granulocyte transfusions is still hypothetical.28 None of these approaches is likely to replace the need for a broad-spectrum, safe, antifungal drug during the at-risk period. We are aware of interferences recently reported between itraconazole and cyclophosphamide.29 However, in our series, although voriconazole and conditioning chemotherapy were concomitantly administered, we did not observe any unexpected toxicity of the conditioning regimen.

Despite the small size of our series, our findings show that the use of voriconazole for secondary prophylaxis during at-risk periods, and especially transplant periods in leukemic patients may allow required treatment to proceed as scheduled. It is well tolerated over a prolonged period of time, and is available in both intravenous and oral formulations, which allow outpatient treatment of allogeneic transplant patients during the second at-risk period, and patients with GVHD who no longer have neutropenia. Further investigation in prospective trials is warranted to confirm these findings.

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Acknowledgements

This study has been partially presented as a poster at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 27–30 September 2002 (Abstract M 894). We thank the mycology departments of each center for providing the mycology data, and Pamela Johnson for her help in the finalization of the manuscript.

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Cordonnier, C., Maury, S., Pautas, C. et al. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant 33, 943–948 (2004). https://doi.org/10.1038/sj.bmt.1704469

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Keywords

  • voriconazole
  • fungal prophylaxis
  • aspergillus
  • candida
  • invasive fungal infection
  • acute leukemia
  • stem cell transplantation

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