Statistical Correlations Between Quantifiable Disease Variables and Prognosis in Hematological Malignancy Patients Treated with Itraconazole as An Empirical Antifungal Therapy: A Prospective Multicenter Observational Study in Korea
Authors: Kim Jin Seok , Shin Ho Jin , Cheong June-Won , Lee Jong Wook , Lee Kyoo Hyung , Yang Deok-Hwan , Lee Won-Sik , Kim Hawk , Park Joon Seong , Kim Sung Hyun , Lee Sang Min , Song Eun-Kee , Chae Yee Soo , Park Jinny , Do Young Rok , Min Yoo Hong 
Published: April 2020

Abstract
We identified the clinical characteristics including disease status for expecting success outcome of empirical antifungal therapy for invasive fungal infection (IFI) using itraconazole in immunocompromised patients with hematological malignancies. The prospective multicenter observational study was performed at 26 medical centers for 9 months. Three hundred seventy six patients with hematological malignancies (median age 48) had been enrolled and analyzed. The patients with possible and probable categories for IFI according to the EORTC/MSG criteria were included. We excluded the patients with proven IFI. IV itraconazole was administered as routine schedule. Oral itraconazole solution was used after the IV itraconazole. Underlying disease consisted of 61% of AML and 15% of ALL. Overall success rate of empirical antifungal therapy with itraconazole was 196/376 (51%). Acute leukemia in non-CR status and advanced stage of MDS patients showed a lower trend of success rate. Combined co-morbidities, underlying lung disease, poor ECOG performance status (≥2), abnormal chest X-ray at the time of initiation of empirical antifungal therapy, no early initiation of empirical antifungal therapy (the duration of baseline neutropenic fever ≥3 days) and antifungal prophylaxis other than itraconazole were associated with decreased overall success rate. Multivariate analysis revealed that poor ECOG performance status (≥2) (P=0.01, HR = 1.90, 95% CI 1.17–3.06) and abnormal chest X-ray (P=0.02, HR = 2.00, 95% CI 1.12–3.58) were significantly associated with poor outcome of empirical antifungal therapy with itraconazole. Overall success rate of empirical antifungal therapy was not affected by antifungal prophylaxis. Defervescence in setting of neutropenia was 70% (264/276). Higher rate of defervescence was observed in the patients with early stage of MDS (92% vs. 40%, P = 0.02). Median time to defervescence after empirical itraconazole therapy was 3 days. Short mean time to defervescence was observed in the patients with acute leukemia in CR status (P = 0.002) or early stage of lymphoid malignancies (P = 0.03). Baseline fungal infections were diagnosed in 13 patients (3%). Of the patients with baseline fungal infections, 7 patients (54%) had a successful outcome. All 7 patients with successful outcome had baseline fungal infection with candidemia. The rate of breakthrough fungal infection was 4% (16/376). Breakthrough aspergillus infection was documented in the half of theses patients (8/16). The rate of breakthrough fungal infection also was not different according to the different disease status. Premature discontinuation of itraconazole therapy because of toxicity or lack of efficacy occurred in 35% (131/376). The proportion of patients who survived for at least 7 days after completion of itraconazole therapy was 90% (338/376). IV itraconazole followed by oral itraconazole solution is an effective regimen for empirical antifungal therapy in the haematological malignancy patients with persistent neutropenic fever. Poor performance status and abnormal chest X-ray were predictive factors for failure of empirical antifungal therapy with itraconazole in the patients with hematological malignancies.
Table 1. Outcomes (overall success rate) according to the clinical characteristics
Yes No P Co-morbidities 37/90 (41%) 156/286 (55%) 0.03 Diabetes mellitus 6/20 (30%) 187/356 (53%) 0.07 Lung disease 3/14 (21%) 190/362 (53%) 0.03 ECOG performance status -≥2 (vs. 0 or 1) 45/123 (37%) 148/253 (59%) &lt; 0.001 Galactomannan test – positive 3/9 (33%) 33/74 (45%) 0.73 Abnormal chest X-ray 23/70 (33%) 156/278 (56%) 0.001 Abnormal chest CT 14/51 (28%) 5/8 (63%) 0.10 Duration of baseline neutropenia ≥7 days (vs. &lt;7 days) 101/206 (49%) 92/170 (54%) 0.35 &gt;10 days (vs. ≤10 days) 60/122 (49%) 133/254 (52%) 0.58 Duration of baseline neutropenic fever ≥3 days (vs. &lt;3 days) 89/193 (46%) 104/183 (57%) 0.04 ≥5 days (vs. &lt;5 days) 55/124 (44%) 138/252 (55%) 0.06 Antifungal prophylaxis 95/183 (52%) 98/193 (51%) 0.84 Other drugs (vs. itraconazole) 51/114 (45%) 44/69 (64%) 0.02