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PRIORITY PRESS - 36th Annual Meeting of the European Group for Blood and Bone Marrow Transplantation (EBMT)

Vienna, Austria / March 21-24, 2010

Over the last 10 years, a major advance in the management of high-risk malignancies has been the concept of the so-called graft-vs.-leukemia effect in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. While such an approach can substantially decrease the risk of recurrence in many patients, it also poses new challenges. In addition, new techniques such as cord blood transplantation are likely to increase the number of severely immunosuppressed patients, and so increase the risk of opportunistic infections such as invasive fungal infections (IFIs).

New formulations of amphotericin B, new azoles such as voriconazole and posaconazole, and echinocandins such as caspofungin have all become available in the last decade. However, there is a lack of consensus concerning the most appropriate type of strategy to apply to different patients—whether antifungal prophylaxis is preferable in certain patients and when pre-emptive or empirical therapy should begin. Ideally, there should be clear guidelines based on firm evidence from clinical trials to help guide physicians in their decision-making. Yet in many cases, direct comparisons are often lacking, and often the comparator is inappropriate, as in the case of a seminal study of voriconazole (N Engl J Med 2002 Aug 8;347(6):408-15) in which the comparator was amphotericin B deoxycholate, a formulation of amphotericin B rarely used nowadays due to its poor toxicity profile. An added complication of applying current clinical trial data is that allogeneic HSCT recipients are underrepresented in many clinical trials. This is unfortunate because there is a considerable risk of IFI in such patients and mortality from invasive Aspergillus infection in historical cohorts is as high as 90%.

Directed, Pre-emptive and Empirical Therapy

Attempts to provide a definitive answer to the question of when to start directed therapy have been hindered by a lack of a clear definition of probable and proven infection (the setting in which therapy is considered as directed). “Until recently, clinical trials had a whole range of definitions for probable and proven IFI,” explained Dr. Andrew Ullmann, Johannes Gutenberg University, Mainz, Germany. “The ‘modified criteria’ included probable fungal infection without mycological evidence of disease but with specific lung infiltrates considered indicative of invasive aspergillosis.” However, using this definition of probable fungal infection, there is a clear divergence in outcome between patients with proven disease and those with probable disease. In cases of no mycological evidence of disease, “I think we should talk more of pre-emptive therapy,” stated Dr. Ullmann.

The success of treatment of HSCT recipients with evidence of IFI is reflected in the findings of two major studies, one already mentioned comparing voriconazole and amphotericin B deoxycholate (N Engl J Med 2002 Aug 8;347(6):408-15.) and the other comparing different doses of liposomal amphotericin B (Clin Infect Dis 2007 May 15;44(10):1289-97). Treatment success and survival in both cases are poor. Thus, for the 37 HSCT recipients in the voriconazole arm of the first study, a favourable response was reported in 32%. In 17 HSCT recipients in the second study, favourable response was attained in 47% and survival at 12 weeks was 40%. “As clinicians, I don’t think we should be satisfied with this,” Dr. Ullmann told delegates. In the empirical setting (therapy administered after persistent febrile neutropenia), the results are not much better: success rates with antifungals such as liposomal amphotericin, voriconazole and caspofungin range from 26% to 50%.

A Case for Prophylaxis

“Although the outcomes of treatment in the era of mold-active agents are definitely better, they are still far from optimal. So prophylaxis does make sense, particularly in high-risk populations where patients are likely to endure long periods of immunosuppression,” stated Dr. Daniel Couriel, Sarah Cannon Cancer Center, Nashville, Tennessee. When considering antifungal prophylaxis in HSCT recipients, it is necessary to remember that these patients will likely be neutropenic for as long as 100 days. As monocytes, neutrophils and natural-kill-cell counts recover, followed by recovery of B cells and CD8 cells, there is then the risk of graft-vs.-host disease (GvHD), giving rise to “probably the most immunosuppressive conditions in medicine,” according to Dr. Couriel. These patients are thus at high risk of infection. The risk of Candida infection occurs relatively early, but Aspergillus infection can occur later, in association with GvHD. Given the high mortality with directed and empirical therapy, prophylactic therapy may be justified.

The concept of antifungal prophylaxis in bone marrow-transplant recipients was initially validated with a placebo-controlled trial of fluconazole (N Engl J Med 1992 Mar 26;326(13):845-51). Since then, a number of trials have shown at least equivalence and sometimes superiority (usually against fluconazole). A recent study compared posaconazole with fluconazole as prophylaxis in patients with severe GvHD who were receiving immunosuppressive therapy. The primary end point was incidence of IFI from randomization to day 112 (end of treatment period) (N Engl J Med 2007 Jan 25;356(4):335-47). There were no significant differences between treatments for the primary end point although a numerical trend in favour of posaconazole was apparent (5.3% vs. 9%, P=0.074). However, the differences were significant while on treatment. In results not presented previously, Dr. Ullmann affirmed, “Fifty-two patients (17.4%) on fluconazole had possible fungal infection, that is, presence of lung infiltrates, vs. 26 patients (8.6%) on posaconazole, a difference that was significant (P=0.013).”

Partly as a result of this study, posaconazole is now recommended by a number of guidelines as prophylactic treatment in high-risk patients.

Prophylaxis in a Real-life Setting

Dr. Ullmann presented some preliminary data from an observational study in his hospital which has adopted posaconazole prophylaxis in allogeneic-HSCT recipients for most patients. In 2008, he and colleagues collected data from 52 patients with follow-up of 100 days. There were four cases of proven infection (the infectious agent turned out to be Zygomycetes in one case) and 15 had so-called probable disease (lung infiltrates). Compliance (defined as more than 70 days on posaconazole therapy, with bridging therapy allowed if oral therapy was inappropriate) was 60.6% in those without infiltrates compared to 36.8% in those with probable or proven disease. Of the patients without infiltrates, only 3% died compared to 58% for those with infiltrates. While these results from a clinical setting were encouraging, they did seem to highlight the need for good compliance. Thus, for patients where oral compliance was difficult, in the opinion of Dr. Ullmann, “An intravenous formulation of posaconazole would be useful.”

Summary

Advances in allogeneic stem cell transplantation, while increasing the chances of cure, have increased the number of patients at risk of IFIs. New agents with different mechanisms of action have helped improve outcomes and provide different options in the management of these patients. However, the optimal use of these agents has yet to be established. So far, directed, pre-emptive and empirical approaches have yielded relatively poor results. While early diagnosis using molecular or advanced imaging techniques may lead to improvement, there is currently a strong case for prophylaxis. Prophylactic agents must meet a number of requirements, such as a good safety profile and a broad spectrum of action. The novel posaconazole is indicated for prophylaxis in high-risk patients and may offer benefit in this setting.