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MEDICAL FRONTIERS - 35th Annual Meeting of the European Group for Blood and Marrow Transplantation

Göteborg, Sweden / March 29-April 1, 2009

Currently, invasive aspergillosis is the most common invasive fungal infection (IFI) to occur in hematology patients, responsible for over half of the infections reported in the hematopoietic stem-cell transplantation (HSCT) population. According to Dr. Maiken Cavling Arendrup, Head, Mycology Unit, Statens Serum Institute, Copenhagen, Denmark, patients receiving allogeneic SCT are at particularly high risk to develop IFIs due to both the severity and the duration of neutropenia sustained.

Survey of 18 hematological wards involving 11,802 patients between 1999 and 2003 showed that 538 patients developed a proven or probable IFI for an overall incidence rate of 4.6% of which approximately two-thirds were caused by moulds (90% Aspergillus) and over one-third by yeasts (90% Candida species, mostly non-albicans).

In a study cited by Dr. Arendrup, the mortality rate among acute myeloid leukemia (AML) patients with an Aspergillus infection was 38%, while mortality from a Zygomycetes-attributable infection in the same cohort was 67%. Mortality from Fusarium-related IFI was also high at 47%. The majority of AML patients who developed an Aspergillus infection in this series were in relapse.

Mortality from IFIs in hematological patients is still high but may be declining, noted Dr. Arendrup. She cited a recent multicentre study carried out in the US which reported a mortality rate of only 36% at 12 weeks compared to historical rates of 50% to 80%. Among factors influencing the mortality rate are the introduction of galactomannan testing permitting earlier detection of an IFI, and greater numbers of diagnostic bronchoalveolar lavage (BAL) and CT scans, which allow for early introduction of voriconazole.

Therapeutic Drug Monitoring

Many factors affect azole absorption, including genetic polymorphisms of cytochrome CYP2C19, gastrointestinal function, liver or renal dysfunction and drug-drug interactions. Blood levels therefore can be highly variable, especially after oral administration. For example, posaconazole needs to be taken with fatty food to be well absorbed and as such, patients who are not ingesting adequate amounts of fatty food may be suspected of having poor drug concentrations, therefore therapeutic drug monitoring (TDM) is recommended. Genetic polymorphisms of CYP2C19 can also affect voriconazole metabolism, depending on whether patients are poor or extensive metabolizers.

According to Dr. Peter Donnelly, Radboud University Nijmegen Medical Centre, The Netherlands, due to the “enormous variability” in drug levels following administration of the azoles both in and between patients, the utility of TDM is thus questionable. However, the experience of Pascual et al. (Clin Infect Dis 2008;46:201-11) showed the value of TDM. Among 52 patients who underwent TDM, voriconazole trough levels varied from <u><</u>1 mg/L (most of whom received oral voriconazole) to >5.5 mg/L (most of whom received the i.v. formulation). In six patients with persistence or progression of the infection and low trough levels, all six responded to treatment after the dose was increased. The authors concluded that TDM improved the efficacy and safety of therapy.

Here at the EBMT, Winterová et al. (Poster P 844) reported results of a retrospective analysis of 51 patients who had undergone allogeneic SCT at their centre between 2005 and 2008. Multiple plasma samples were tested using a high-performance liquid chromatography assay. Almost all patients received oral voriconazole at a total daily dose ranging from 200 mg to 800 mg.

Results demonstrated that a high percentage of patients did not achieve sufficient therapeutic drug concentrations after receiving the standard daily dose of voriconazole. In 8% of the plasma samples tested from 20 patients, drug concentrations were undetectable (<0.2 µg/mL) while in some 42% of samples from 31 patients given 400 mg/day, plasma concentrations were still below levels associated with a better response to therapy. . After increasing the daily dose to 600 mg in 11 patients, drug trough plasma levels increased to >1.0 µg/mL in four patients and >0.5 µg/mL in three patients. In the remaining four patients, drug concentrations remained the same or lower following an increase in the dose.

Although results may appear equivocal, the authors concluded that measuring plasma levels does facilitate dosage adjustment and can enhance response to antifungal treatment in high-risk patients.

Pre-emptive Therapy of Invasive Aspergillosis

Recently, the EORTC-MSG study group updated definitions for IFIs (specifically, invasive aspergillosis [IA]) and these updated criteria were used to recategorize data from the Global Comparative Aspergillosis Study (GCAS) published in 2002. As discussed by Dr. Raoul Herbrecht, Head of Haematology, University Hospital of Strasbourg, France, the main differences between the 2002 and the 2008 criteria are that the halo or air crescent signs indicative of probable disease in 2002 were downgraded to only possible disease based on the new criteria. Patients with a nodule without a halo sign or focal infiltrate and no mycology were excluded from the original analysis.

Now, “we can accept this type of patient as a possible infection, provided we have host factors including persistence of fever and signs despite broad-spectrum antibiotics,” Dr. Herbrecht stated. In the original analysis, positive mycology in BAL was considered a definite case; now, positive mycology in BAL is only considered a probable case, and galactomannan levels are now taken into account.

Following recategorization of all IA, investigators identified 108 possible IA cases—54 of them having received voriconazole and 54 amphotericin B. At 12 weeks, results—presented here for the first time—showed that 64.8% of those who received voriconazole had a favourable response, approximately 10% higher than in the original publication, compared with 38.9% of those who received amphotericin, some 7% higher than in the original analysis. The difference of 25.9% between the two groups in the recategorization analysis remained significant (P=0.012) (Figure 1).

Figure 1.

Survival in patients with possible IA at 80% in the voriconazole group was also approximately 10% higher than survival rates in the original 2002 analysis, as it was for the amphotericin B group at 68.6% (N Engl J Med 2002;347(6):408-15)(Figure 2). The difference between the two groups on the recategorization analysis did not reach statistical significance because of the small numbers of patients involved in eac
oted.

Figure 2.

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For the 239 patients who were recategorized as having probable/proven cases of IA, there were lower response rates down to 50% from 52.8% in the voriconazole arm and down to 25.2% from 31.6% in the amphotericin B arm. This difference between t
icant 24.8%; IC 95%:12.5-37.1;(P=0.0001) (Table 1).

Table 1.

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“I think we can confirm that early treatment of IA is associated with improved outcomes,” Dr. Herbrecht concluded, “and I think we can also conclude that voriconazole is appropriate for the pre-emptive treatment of IA, as it is associated with very high response rates and a very high survival rate at week 12.”

Secondary Prophylaxis for IFI

Literature reviews indicate the risk of recurrence or new occurrence of an IFI following allogeneic SCT can be as high as 20% to 50% in patients with a prior history of an IFI. Reducing the intensity of the conditioning regimen and making sure the final infection is resolved or reduced prior to proceeding to transplant likely help reduce the risk of recurrence, noted Dr. Catherine Cordonnier, Professor of Haematology, Hôpital Henri Mondor, Créteil, France.

In the VOSIFI study, Dr. Cordonnier and colleagues assigned 45 patients with a previous history of a proven or probable IFI within 12 months prior to SCT to either i.v. voriconazole (4 mg/kg/12 h) or oral voriconazole (200 mg/12h). “Prophylaxis was done within 48 hours’ post-chemotherapy to avoid any interference between voriconazole and chemotherapy,” she reported, “and it was given for 100 days after transplantation and could be extended for 50 days more under certain conditions.” The mean duration of voriconazole prophylaxis was 94 days, while the median follow-up was approximately one year.

Results from the modified ITT analysis (42 patients) indicated that only three out of the 42 patients developed a proven or probable infection during the study—“giving a 7% crude incidence rate,” Dr. Cordonnier observed. These three cases included one episode of recurrent Candida albicans, one recurrence of Scedosporium prolificans and one zygomycosis at days 3, 16 and 66, respectively, after transplant. Two of these three IFIs were relapses of a previous IFI.

Eleven patients or 24% of the cohort had died at study end point, only one due to their IFI (scedosporiosis). The adverse event rate was predictably high in this patient cohort but abnormal liver function tests was the cause of discontinuation in only two patients.

“Secondary prophylaxis with voriconazole is safe and effective at protecting patients from recurrent fungal infections following allogeneic SCT,” Dr. Cordonnier concluded, “and considering the expected rate of recurrence or new occurrence of IFIs of 20% to 50% in this population, the [crude incidence] rate of 7% we saw in this study is lower than what we expected.”

Questions and Answers

The following section is based on discussions with Dr. Raoul Herbrecht, Head of Haematology, University Hospital of Strasbourg, France; Dr. Peter Donnelly, Radboud University Nijmegen Medical Centre, The Netherlands; and Dr. Catherine Cordonnier, Professor of Haematology, Hôpital Henri Mondor, Créteil, France, during these scientific sessions.

Q: Do you think results of the GCAS would have been different if you had compared voriconazole to the liposomal form of amphotericin B?

Dr. Herbrecht: One of the criticisms of this study is that we chose the standard form of amphotericin B as the comparator drug but when the study was designed, liposomal amphotericin B was not approved for first-line treatment of IA so we could not use it. All we can say is that... so far, there are no better results than what we achieved with voriconazole in this study in any of the monotherapy trials or even with combination therapies, so I think the evidence supporting voriconazole in IA should be rated as A1 evidence. Of course, there is room for improvement and one way is to start treatment earlier, as soon as the disease is suspected in what I call pre-emptive therapy.

Q: Would you ever use the oral formulation for the primary treatment of IA?

Dr. Donnelly: It does surprise me that people try to manage primary treatment of IA with oral azole therapy but I am not sure that is a clever thing to do. What we do is give i.v. voriconazole for 10 to 14 days, then consider them for oral therapy as maintenance. You have to give the optimal dose for optimal exposure, and when you switch patients to the oral dose, you are automatically exposing them to only two-thirds of the i.v. dose. This is something that I think will be corrected shortly with recommendations to maintain the same exposure when patients are switched to oral voriconazole.

Q: If a patient fails primary prophylaxis on posaconazole, does that preclude the use of other azoles?

Dr. Cordonnier: If your patient is under prophylaxis with posaconazole and develops an aspergillosis infection—and you find you have no circulating levels of posaconazole—it’s probably not resistance to the azole class and you can use another azole. But if you have good circulating levels, then the recommendation is probably to change the class of the drug to treat the infection.