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33rd Annual Meeting of the European Group for Blood and Marrow Transplantation

Lyon, France / March 25-28, 2007

Invasive aspergillosis is a major problem in the management of patients who have undergone stem cell transplantation (SCT). According to figures presented by Prof. Noel Milpied, University Hospital, Bordeaux, France, the incidence of these infections has increased in recent years, “But the good news is that mortality due to aspergillosis or Candida, while still high, is far lower than it used to be.” He also stressed the importance of starting therapy early.

Any discussion about antifungal therapy should be based on a clear distinction of the different settings in which such therapy can be given. Patients undergoing SCT will generally be given prophylactic therapy, while empirical therapy is usually initiated if neutropenic fever does not remit despite systemic antibiotic therapy. Once invasive fungal infection is proven, first-line treatment can begin. If diagnosis is made early before clinical signs and symptoms, therapy is described as pre-emptive. Salvage therapy refers to treatment given to patients who have failed first-line antifungal therapy.

Empirical vs. Pre-emptive Therapy

Dr. Ben E. de Pauw, University Medical Center St. Radboud, Nijmegen, The Netherlands, expressed his views on indiscriminate use of empirical therapy. “Six or 7% of patients are at risk of invasive fungal disease yet the perceived need for empirical therapy is over 70%; on average, that means more than 90% of the patients are treated despite having no disease.” He attributed this to “the fear factor,” and that physicians do not know what species might be present. In outpatients, a shift has been observed from Candida albicans to other Candida species that are less susceptible to fluconazole, therefore in such patients, empirical treatment with one of the other agents might be preferable.

Dr. de Pauw reviewed some of the trials published on first-line treatment of aspergillosis. According to these trials, the response rate for amphotericin B is lower (32%) than voriconazole and the liposomal formulation of amphotericin B (50%). A relatively small trial in 32 caspofungin-treated patients also showed a relatively good response rate of 56%. Although the numbers in this study were too small to draw firm conclusions, Dr. de Pauw remarked, “At least we have something that works, and it might offer an alternative in certain conditions.”

Early Diagnosis: Avoiding Unnecessary Exposure to Antifungal Agents

Empirical therapy is popular because many studies have shown the early initiation of antifungal treatment markedly improves response and ultimately survival. If early diagnosis of invasive infection were possible, then antifungal treatment could be targeted to those who need it, and the remaining patients would not be exposed to the side effects of such drugs. As explained by Dr. Johan Maertens, University Hospital Leuven, Belgium, “New tools such as CT scans and laboratory assays to detect specific antigens or D-beta-glucan are making earlier diagnosis possible.” The CT scan of a patient with invasive aspergillosis typically shows a halo or “air crescent” sign. Diagnostic protocols have been drawn up using a combination of these new tools to provide high sensitivity and specificity. Unfortunately, these protocols also require skilled radiologists and access to molecular biology laboratories, thereby placing them beyond the capability of many centres. Although the pre-emptive approach is generally favoured by experts, if appropriate diagnostic support is available, some pharmacoeconomic analyses suggest that it is not cost-effective, even excluding the cost of the expensive diagnostic procedures.

Antifungal Therapy Options

In the study which compared voriconazole to amphotericin B, all end points favoured voriconazole, “But in some subgroups such as recipients of allogenic hematopoietic SCT, the response rate to voriconazole was very low,” indicated Prof. Claudio Viscoli, University of Genova, Italy. In one of the major studies with liposomal amphotericin B which compared different doses of the same compound, it was possible to achieve a 50% response rate, although no benefit was shown for higher doses.

“For the echinocandins, the data we have available so far are much more scattered,” Prof. Viscoli told delegates. In the pivotal study for the registration of caspofungin in the setting of salvage aspergillosis, the overall response rate was 45% (Maertens et al. Clin Infect Dis 2004;39(11):1563-71). In the subgroup of patients who received at least seven days of treatment, the response rate was 56%. In another compassionate open-label study, 88 patients, 48 of whom had invasive aspergillosis and who were refractory to an intravenous amphotericin preparation, received caspofungin. The response rate once again was between 40 and 50% (Kartsonis et al. J Infect 2005; 50(3):196-205). Another study investigated caspofungin in first-line therapy in patients with invasive aspergillosis (Candoni et al. Eur J Haematol 2005; 75(3):227-33). According to Prof. Viscoli, “This was a small study but again, the response rate of around 56% was reasonable.”

The advent of echinocandins has led to interest in combination therapy because they have a different mechanism of action and so an additive or even synergistic effect might be expected; however, clinical data are limited. A retrospective study included patients who received either voriconazole or a voriconazole/caspofungin combination. While retrospective studies are subject to many caveats, there was a difference in survival in favour of the combination group after three months but not after one year. In another published study, the main aim was to demonstrate safety rather than efficacy (Maertens et al. Cancer 2006;107(12):2888-97). The safety profile in the two groups was similar. Interestingly, in this study, the response rate in allogeneic and autologous hematopoietic SCT patients was better, at 54% and 80%, respectively, although the numbers were extremely small.

Pediatric Patients

According to Prof. Thomas Lehrnbecher, Johann Wolfgang Goethe University, Frankfurt, Germany, “Often the pediatric population is neglected, maybe because many people think that children are small adults.” There are differences however, particularly in newborns, and children with cancer are often quite different from adults with cancer in that they can receive more intense therapies. Moreover, some antifungal agents are eliminated by the liver or kidney and therefore dosing is limited by the lack of maturity of those organs.

Although caspofungin is not indicated for pediatric use, it was well tolerated in pediatric patients according to a retrospective multicentre study in immunocompromised children. It was given both empirically and to treat possible, probable and proven invasive infection, as monotherapy or in combination (Walsh et al. Antimicrob Agents Chemother 2005; 49(11):4536-45). Clinical adverse events were reported in just over half the patients, but none discontinued due to adverse events. Some laboratory parameters did show manageable treatment effects, but there was no difference between patients who had received cyclosporine A and those who had not. Response to treatment was favourable, despite the limitations of this survey. “Caspofungin seems to be safe and well tolerated, even when given over a prolonged period of time,” Prof. Lehrnbecher commented.

Summary

Mortality due to invasive fungal infections in patients with hematological malignancies undergoing SCT has decreased in recent years as novel therapies have become available. Early detection of invasive disease is now possible but not all centres will benefit and empirical therapy will still be important for some years to come. The echinocandin caspofungin is one of the promising therapies that can be used in a number of stages in the management of invasive aspergillosis.