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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

During the course of treatment, the immune system of allogeneic hematopoietic stem cell transplantation (HSCT) recipients undergoes extreme changes. Initially, the patients will be extremely neutropenic, although neutrophil counts recover quickly. Other cell types take weeks or longer to recover. These changing cell populations condition the risk of different types of infection in the pre- and post-engraftment period (Biol Blood Marrow Transplant 2009;15(10):1143-238). In the case of fungi, Candida infections usually occur during the pre-engraftment and early post-engraftment phase while Aspergillus infections show two peaks, the first during initial neutropenia and the second at later times, in particular in association with chronic graft-vs.-host disease (GvHD). The overall mortality associated with Aspergillus infection is high with the highest death rate being reported in allogenic HSCT recipients, noted Prof. Raoul Herbrecht, University Hospital of Strasbourg, France. The mortality is even higher in real life than in clinical trials, which tend to include selected patients, he added. Given the increasing number of allogeneic HSCT procedures in the last 10 years, more patients are at risk of developing invasive fungal infections (IFIs). With respect to aspergillosis, developments of particular importance mentioned in the most recent IDSA guidelines include extended-spectrum triazoles (voriconazole as primary therapy and posaconazole for prophylaxis in high-risk patients), newer and less toxic formulations of amphotericin B as an alternative agent in some patients, and the echinocandins such as caspofungin as salvage therapy (Clin Infect Dis 2008;46(3):327-60).

Empirical vs. Pre-emptive Therapy

Empirical antifungal therapy is widely used in patients with neutropenic fever of unknown origin. This approach has doubtlessly saved many lives but it also has drawbacks. “There are many causes of non-fungal fever, and it is estimated that 60% are treated for 5% to 15% IFI,” pointed out Dr. Oscar Marchetti, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. “Thus, many patients are exposed to drug toxicities.” He added that an empirical strategy with new drugs is also very expensive. Pre-emptive therapy, which aims to aggressively treat only “suspected” invasive aspergillosis, has been added as a key recommendation in the 2008 IDSA guidelines.

In one study that compared empirical and pre-emptive therapy, high-risk febrile neutropenic patients were randomized to receive empirical therapy (fever-driven) or pre-emptive antifungal therapy only in cases of pneumonia, shock, skin lesions, sinusitis, orbititis, hepatosplenic abscesses, grade 4 mucositis or Aspergillus colonization, or galactomannan antigen titres greater than 1.5 (Clin Infect Dis 2009;48(8):1042-51). In both groups, amphotericin B deoxycholate or liposomal amphotericin B was used. Using the pre-emptive approach, antifungal therapy was started after a median of 13 days of fever compared to 7 days with the empirical approach. “Although less antifungal agents were used in the pre-emptive arm, there were significantly more IFIs,” stated Dr. Marchetti. However, for the primary end point of overall survival, there was no difference between the two arms.

Another approach described by Dr. Charles Craddock. Queen Elizabeth Hospital, London, UK, was based exclusively on high-resolution computed tomography (HRCT) findings. As Dr. Craddock pointed out, “For administrative reasons, galactomannan testing is generally not available in the UK.” According to the study design, allogeneic HSCT recipients (receiving itraconazole prophylaxis) who had positive HRCT findings were given caspofungin while antifungal therapy was withheld from those with negative findings. In total, 17 out of 99 patients (17%) received antifungals with the pre-emptive therapy algorithm when 53 out of 99 (54%) would have done so if an empirical approach had been used (a reduction of 68%). The outcomes in the 17 patients who received pre-emptive therapy were good: 11 responded to first-line caspofungin and four to second-line therapy. Two of the non-responders died, but only one of those was due to fungal infection. “This was the first study to use HRCT as the sole trigger of pre-emptive therapy, and the approach seems safe in a high-risk population … though the results would need to be confirmed in larger studies,” concluded Dr. Craddock.

IMPROVIT: Prophylaxis in Allograft Patients

Given the improved outcomes with early initiation of antifungal therapy, coupled with the difficulties of providing early diagnosis, prophylaxis is a potentially attractive option. Indeed, prophylaxis with agents such as fluconazole has been validated by a number of studies but few data have been available for allogeneic HSCT recipients.

The open-label IMPROVIT study randomized 489 patients aged =12 years undergoing allogeneic HSCT to oral voriconazole or itraconazole prophylaxis after intravenous loading doses. “We wanted to test oral agents because they have clear potential advantages,” stated Dr. David Marks, Bristol Bone Marrow Transplant Unit, Bristol, UK. Unlike previous trials, patients received myeloablative and reduced intensity regimens, better reflecting modern transplant practice. Patients could switch back to intravenous dosing in situations where oral therapy might be ill-advised (e.g. diarrhea or mucositis). The primary endpoint was success of antifungal prophylaxis defined as a composite of survival 180 days post-transplant, no proven/probable breakthrough IFI, no study-drug discontinuation (>14 days off therapy) during the 100-day prophylactic period. “The primary end point therefore had a tolerability component built in,” Dr. Marks reported to delegates. “Tolerability is extremely important. In this setting more than any other, patients have enormous trouble taking their drugs,” he added.

A two-step analysis of the primary end point showed first that voriconazole was both non-inferior and superior to itraconazole. Success was reported in 115 out of 234 patients (49.1%) in the voriconazole arm vs. 88 out of 255 (34.5%) in the itraconazole arm (P=0.0004). This difference was largely driven by the tolerability component of the primary end point (voriconazole was administered for a median of 97 days vs. 68 days for itraconazole). Although some might criticize an efficacy end point with a strong tolerability component, Dr. Marks pointed out that investigators would probably put the patients on another drug, “which would get the credit for efficacy” adding that when a different drug is administered, it might be considered a failure. Both agents appeared effective at preventing breakthrough infections. Only three proven cases of IFI were reported in the voriconazole arm compared to six in the itraconazole arm. “Long-term primary prophylaxis with voriconazole is an effective, safe option for preventing IFIs in these patients,” concluded Dr. Marks.

Summary

Infections are a significant problem in the allogeneic HSCT setting. Changes in management of the underlying malignancies are resulting in more immunocompromised patients who are particularly susceptible to opportunistic infections. In the case of fungal infections, new agents and new formulations of existing strategies are helping to combat these infections but their use has yet to be optimized. With advances in molecular diagnostic techniques, it may be increasingly possible to initiate therapy early enough to be effective. New algorithms using HRCT imaging have also shown promise in the pre-emptive setting. Finally, more data are emerging to confirm that prophylaxis can be effective in these high-risk patients.