Reduced Incidence of Early Invasive Fungal Infection in Allogeneic Transplant Patients Following Micafungin Prophylaxis

Invasive fungal infection (IFI) is both highly prevalent and highly morbid in the allogeneic transplant (HSCT)patient population. We have previously documented an incidence of IFI in our HSCT patient cohort of 20%(2006–2007). At the time of the initial analysis, low dose amphotercin B (LDAB) (10mg/m2) was the routine prophylaxis given for the neutropenic phase post HSCT. This study was carried out to analyse whether an alteration in prophylaxis strategy for patients during the neutropenic phase post HSCT was effective in reducing the incidence of IFI in this heavily immunocompromised patient group. We also aimed to identify risk factors for IFI which would help to guide prophylactic strategies beyond the neutropenic phase.

A retrospective analysis of all patients undergoing allogeneic stem cell transplant between January 2010 and June 2011 was carried out. 67 patients thus identified were reviewed and the incidence and risk factors for IFI in this group was compared to our historical control group from 2006–2007 (n=69). Patients with a prior history of IFI were excluded. EORTC criteria were used to define possible, probable or proven IFI. Diagnostic criteria guiding treatment of IFI did not change between the two study periods. Micafungin 100mg iv was the prophylaxis given to inpatients undergoing myeloablative or unrelated donor non myeloablative transplantation. For outpatient based non- myeloablative transplants, fluconazole 200 mg orally daily was the prophylaxis of choice. Prophyaxis was started on day +1 and was continued until absolute neutrophil count (ANC) was >0.5× 109/L.

The overall incidence of IFI was 10/67 (15%), with 5% proven/probable and 10% possible IFI's. The median time to diagnosis of IFI was 78 days from date of transplant. This represents a decrease in incidence of IFI compared to the earlier cohort (20%). The reduction in IFI seen in our current cohort of patients who received micafungin or fluconazole prophylaxis appears to be largely attributable to a reduction in the rate of early (before day +30) IFI in the group of patients treated with iv micafungin (Table 1). Only one of the 43 patients given micafungin prophylaxis developed an IFI in the first 30 days following transplantion.

Timing of IFI; median time to diagnosis of IFI was 78 days. Only two patients developed an IFI during the neutropenic phase post chemotherapy (20%), 4 patients developed IFI between days 30 and 100 and 4 patients developed an IFI after day 100. (38%, 17% and 45% in earlier cohort.

Risk factors for IFI were assessed(Table 2). Of striking significance is the finding that those patients who developed steroid refractory graft versus host disease (GVHD) had an incidence of IFI of 56% (5 of 9 patients developed an IFI) compared to those patients with GVHD who did not require second line therapy of whom only 7% developed an IFI.

50% (5/10) of patients who developed an IFI have died compared to 9% of the patients in the no IFI group (5/57). Mortality attributable to IFI was 30% in the IFI group.

We demonstrate a reduction in early IFI in patients prophylaxed with micafungin in this small series of uniformly treated patients. Late IFI remains a problem and we have identified a subgroup of patients for whom further prophylaxis is warranted. Prophylaxis with a mold active azole should be given to all patients who develop steroid refractory GVHD given the unacceptably high incidence of IFI in this patient subset.

Sutherland:Centocor Ortho Biotech research & Development: Research Funding.