Strategy for Managing Patients with Prior Invasive Aspergillosis through Allogeneic Transplant.

Background: A history of invasive aspergillus infection (IA) often leads to exclusion of patients from future allogeneic hematopoietic stem cell transplant (AHSCT). With the advent of newer, more potent antifungal drugs, IA is better controlled and patients are more likely to be considered for AHSCT. We evaluated the clinical course and outcome of this patient population and propose a strategy to manage these complex cases.

Methods: A retrospective chart review was performed on adult patients that received AHSCT from November 2000 through October 2005 to identify cases with preceding IA. Demographic data, underlying disease, probability of IA as assessed by Mycoses Study Group (MSG) criteria, primary therapy of IA, secondary prophylaxis, adverse effects of antifungal agents, graft-versus-host disease (GVHD) status, steroid use, survival and relapse of IA were collected.

Results: IA prior to AHSCT was identified in 4.13% (9 of 218) patients (8 proven, 1 probable by MSG criteria) who underwent AHSCT in the 5 years reviewed. Pulmonary IA was documented in 6 and 1 each had sinusitis, otitis externa and localized skin infecion. Underlying diseases were AML (5), and 1 each of MDS, CLL, pre B-ALL, and mantle cell lymphoma. Three underwent surgical resection (lung nodule, ear and sinus disease) and all received primary therapy with a variety of antifungal agents, either sequentially or in combination (4 Amphotericin B lipid complex, 4 Itraconazole [I], 6 Voriconazole [V], 4 Caspofungin [C]). Median duration of primary IA therapy was 150 days (range: 42 – 393). Median duration from diagnosis of IA to AHSCT was 180 days (range: 42 – 870). In all cases IA had completely resolved before AHSCT. Secondary prophylaxis consisted of: V + C for the duration of neutropenia post AHSCT, followed by V in 5 cases. The remainder received single agent V in 2 cases, single agent I in 1 case or multiple agents in 1 case of A. terreus. Secondary prophylaxis was continued indefinitely or until death in all cases. GVHD requiring steroids developed in 7 patients with only 1 IA reactivation and death in a patient with A. terreus at 72 days. Two other non IA deaths occurred; 1 due to multiorgan failure 2 weeks post AHSCT, and 1 due to pulmonary embolism and enteric bleed at 547 days. Median survival was 547 days and median followup of survivors was 625 days (range: 280 – 960) post AHSCT. Probability of survival, post AHSCT, at 100 days was 78% (95%CI: 36% – 94%) and at 2 years was 58% (95%CI: 16% – 85%).

Conclusions: The availability of newer, more active antifungal agents has improved the outcome of patients with IA. In our study, a majority of patients with IA prior to AHSCT (8 of 9) did not relapse with a strategy of treating the infection to complete remission before transplant, and utilizing aggressive secondary prophylaxis with a voriconazole-based regimen in most cases (7 of 9). One relapse and subsequent death occurred in a patient with A. terreus, a species typically resistant to Amphotericin B. As also suggested by a recent large study, V appears to be a useful agent for secondary prophylaxis during and after AHSCT, as it covers all species of aspergillus. Combination therapy may be useful during neutropenia in this high risk group. Our data suggests that patients with a history of prior IA can safely undergo AHSCT with a low risk of recurrence of IA. Ideal duration of secondary prophylaxis is unknown. Larger studies are needed to assess the utility of this approach.