An early diagnosis and treatment of invasive fungal disease (IFD) is associated with improved outcome, but the moderate sensitivity of noninvasive diagnostic tests makes this challenging. Invasive diagnostic procedures such as bronchoalveolar lavage (BAL) have a higher yield but are not without risk. The detection and sequencing of microbial cell-free DNA (mcfDNA) may facilitate a noninvasive diagnosis. In a prospective observational study, we collected plasma in the 120 hours preceding or following a BAL in patients with hematological malignancies suspected for a pulmonary IFD. The EORTC/MSGERC2020 criteria were used for IFD classification. Sequencing was performed by Karius (Redwood City, CA) using their Karius Test (KT) on plasma and a “research use only test” on BAL fluid if available. Cases with a probable/proven IFD were identified based on standard diagnostic tests on serum and BAL (microscopy, polymerase chain reaction, galactomannan, culture) and used to calculate the sensitivity, specificity, and additional diagnostic value of the KT. Of 106 patients enrolled, 39 (37%) had a proven/probable invasive aspergillosis, 7 (7%) a non-Aspergillus IFD, and 4 (4%) a mixed IFD. The KT detected fungal mcfDNA in 29 (28%) patients. Compared with usual diagnostic tests, the sensitivity and specificity were 44.0% (95% confidence interval [CI], 31.2–57.7) and 96.6% (95% CI, 88.5%–99.1%). Sensitivity of the KT was higher in non-Aspergillus IFD (Mucorales:2/3, Pneumocystis jirovecii: 3/5). On BAL, the sensitivity was 72.2% (95% CI, 62.1–96.3), and specificity 83.3% (95% CI, 49.1–87.5). Sequencing of mcfDNA may facilitate a noninvasive diagnosis of IFD in particular non-Aspergillus IFD. However, on plasma and similar to currently available diagnostics, it cannot be used as a “rule-out” test.

Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66–81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1–21. In the second cycle, patients received cytarabine 1000 mg/m² twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60–77%) vs 64% (55–73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients.

The IA-DUET study aimed to compare azole-echinocandin combination therapy with azole monotherapy for invasive aspergillosis. Recruitment was hindered by patient ineligibility, competing studies, and guidelines favoring combination therapy when azole resistance was unknown. The low IA-attributable mortality suggests future trials may benefit from cluster randomization or composite endpoints to enhance efficiency.

An accurate diagnosis of invasive aspergillosis (IA) in patients with underlying hematological malignancies relies heavily on galactomannan detection. In this study, we compared the VirCLIA chemiluminescence immunoassay (CLIA) with the frequently used Platelia enzyme-linked immunosorbent assay (ELISA) on serum from hematology patients with suspected IA. Patients were categorized according to EORTC/MSGERC 2020 definitions into proven/probable IA and possible/no IA. The first cohort included 161 patients at four centers, and the VirCLIA manufacturer’s cutoff of 0.200 was evaluated. Next, the optimal cutoff was determined using the Youden’s index. In a second independent cohort of 189 patients from four centers, this optimal cutoff was evaluated again. In the first cohort, sensitivities and specificities for probable/proven IA were 21.1% and 100.0% for ELISA (1.0 cutoff) and 36.6% and 95.6% (0.5 cutoff), compared to 11.3% and 97.8% for CLIA (0.200 cutoff). In the second cohort, the sensitivities of ELISA and CLIA were comparable (ELISA ≥ 1.0: 33.3%, CLIA ≥ 0.200: 38.1%). The area under the ROC curve was lower for CLIA than for ELISA in the first cohort (65.0% vs 78.7%, P = 0.005) but comparable in the second cohort (79.5% vs 81.3%, P = 0.649). Youden’s index identified 0.100 as the optimal CLIA cutoff with sensitivities of 35.2% and 61.9% in cohorts 1 and 2, respectively, at slightly reduced specificities of 85.6% and 90.5%. While the sensitivity of both assays was low to moderate at best, in patients with a high pre-test probability, we suggest 0.100 as the cutoff for the VirCLIA assay. IMPORTANCE: This study demonstrates a comparable performance of the novel chemiluminescence immunoassay (CLIA) and the conventionally used enzyme-linked immunosorbent assay for galactomannan serum testing in hematological patients at high risk for invasive aspergillosis. In patients with a high pre-test probability, a lower CLIA cutoff of 0.100 is preferred.

The spectacular improvement in long-term prognosis of patients with hematological malignancies since the 1980s, coupled with the subsequent improvement over the past decade in short- and mid-term survival in cases of critical illness, resulted in an increasing referral of such patients to the ICU. A remaining question, however, is how these patients perform in the long term with regard to survival and quality of life. Here we discuss the present multicenter study on survival beyond 1 year in critically ill patients with hematological malignancies. We conclude with suggestions on how we can further improve the long-term outcome of these patients.