Primary Prophylaxis against Invasive Fungal Infections (IFI) with Posaconazole (POS) or Voriconazole (VRC) Shows Better Efficacy Compared to No Systemic Prophylaxis during Induction and Consolidation Chemotherapy Cycles of Adult Acute Leukemia Patients

IFI are a well-known cause of severe morbidity and mortality in leukemic patients with chemotherapy induced neutropenia. From 2007 to date, during the induction and consolidation cycles of either de novo or relapsed adult leukemic patients we have administered a primary prophylaxis against IFI with the azole agents POS or VRC. This was compared to a two-year historical control without systemic primary prophylaxis. The whole population (mean age 51.3 yrs; n male =94; n female =43) included ALL patients (n cycles=33); AML (n cycles=88); transformed AREB-2 (n cycles=9); transformed CML (n cycles=7). Most of the chemotherapy regimens administered were those used by clinical trials of the GOELAMS and GRAALL French cooperative groups. Three periods were compared:

• 2005–2006 where no systemic primary prophylaxis was administered (n=63; mean age 47.2 yrs), the principal agent used was amphotericine B deoxycholate in oral suspension, 1000 mg (10 ml) thrice a day);

• January to September 2007 where VRC was administered either orally or intravenously 200 mg bid (n=23; mean age 51.1 yrs) and

• October 2007 to date where POS was administered orally at the standard dose of 200 mg (5ml) thrice a day (n=50; mean age 56 yrs).

POS patients were significantly older (p<0.02) because of the present trend to treat most of the elderly patients as they are considered fit to receive chemotherapy. Prophylaxis was administered since the start of the chemotherapy until neutrophil recovery (PNN count ≥1×10⁹/L for at least 3 days). Most patients received daily G-CSF (lenogastrim, 263 mg/day) from the end of chemotherapy and most of them were placed in laminar airflow rooms. The incidence of IFI until 60 days post-chemotherapy (EORTC criteria) was significantly higher in group A compared to either group B or C (p=0.007) or compared to both groups together (p=0.002). IFI-A: 15/63 (10 proven: 1 aspergillus fumigatus, 1 candida krusei, 4 candida albicans, 3 candida glabrata, 1 candida tropicalis; 5 probable: 5 aspergillus sp); IFI-B: 1/23 (1 proven: 1 candida lusitaniae) IFI-C: 3/50 (2 proven: 1 candida krusei, 1 candida albicans) (1 probable: 1 aspergillus sp). No significant difference was found on the IFI incidence between groups B and C. Diagnosis or type of chemotherapy did not show any significant difference on the incidence of IFI. However, patients in first relapse, refractory or CR2 had a significant higher incidence of IFI (p = 0.03) compared to first time induction or consolidation cycles for RC1 patients. All the IFI in the POS group were observed in relapsed (n=2) or refractory patients (n=1), as it was the case of IFI in a refractory patient of the VRC group. Moreover, empirical antifungal therapy was most frequently administered in relapsed or refractory patients (p=0.03) compared to de novo or CR1 patients. Although most of the IFI were observed during the induction cycles (n=16), no significant difference was found with the consolidation cycles (n=3). Group C received more empirical antifungal therapy (18%) compared to 9.5% in the group B, without a significant difference. In conclusion, primary phrophylaxis with azole agents, either POS or VRC has had a significant impact to decrease the incidence of IFI in our population of leukemic patients. This prophylaxis appears to be even more critical in relapsed or refractory patients, who exhibit a higher risk of IFI. Moreover, preliminary cost-effectiveness analysis appears to be in favour of this therapeutic option.