Abstract There is a strong argument for the use of antifungal prophylaxis in high‐risk patients given the significant mortality associated with invasive fungal disease, the late identification of these infections, and the availability of safe and well‐tolerated prophylactic medications. Clinical decisions about which patients should receive prophylaxis and choice of antifungal agent should be guided by risk stratification, knowledge of local fungal epidemiology, the efficacy and tolerability profile of available agents, and estimates such as number needed to treat and number needed to harm. There have been substantial changes in practice since the 2008 guidelines were published. These include the availability of new medications and/or formulations, and a focus on refining and simplifying patient risk stratification. Used in context, these guidelines aim to assist clinicians in providing optimal preventive care to this vulnerable patient demographic.
Abstract In acute myeloid leukemia (AML), risk stratification based on cytogenetics and mutation profiling is essential but remains insufficient to select the optimal therapy. Accurate biomarkers are needed to improve prognostic assessment. We analyzed RNA sequencing and survival data of 430 AML patients and identified HMGA2 as a novel prognostic marker. We validated a quantitative PCR test to study the association of HMGA2 expression with clinical outcomes in 358 AML samples. In this training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. High expression levels of HMGA2 ( H + ) were associated with a lower frequency of complete remission (58.8% vs 83.4%, P < 0.001), worse 3-year overall survival (OS, 13.2% vs 43.5%, P < 0.001) and relapse-free survival (RFS, 10.8% vs 44.2%, P < 0.001). A positive HMGA2 test also identified a subgroup of patients unresponsive to standard treatments. Multivariable analyses showed that H + was independently associated with significantly worse OS and RFS, including in the intermediate cytogenetic risk category. These associations were confirmed in a validation cohort of 260 patient samples from the UK NCRI AML17 trial. The HMGA2 test could be implemented in clinical trials developing novel therapeutic strategies for high-risk AML.
Antifungal prophylaxis can reduce morbidity and mortality from invasive fungal disease (IFD). However, its use needs to be optimised and appropriately targeted to patients at highest risk to derive the most benefit. In addition to established risks for IFD, considerable recent progress in the treatment of malignancies has resulted in the development of new 'at-risk' groups. The changing epidemiology of IFD and emergence of drug resistance continue to impact choice of prophylaxis, highlighting the importance of active surveillance and knowledge of local epidemiology. These guidelines aim to highlight emerging risk groups and review the evidence and limitations around new formulations of established agents and new antifungal drugs. It provides recommendations around use and choice of antifungal prophylaxis, discusses the potential impact of the changing epidemiology of IFD and emergence of drug resistance, and future directions for risk stratification to assist optimal management of highly vulnerable patients.
Summary In this Phase 1b study, the safety and tolerability of maintenance therapy, comprising lenalidomide (0–25 mg, days 5–25) in combination with azacitidine (50–75 mg/m 2 , days 1–5) every 28 d, was explored in 40 patients with acute myeloid leukaemia ( AML ) in complete remission after chemotherapy. Eligibility included AML in first complete remission ( CR 1) with adverse risk karyotype ( n = 8), fms‐related tyrosine kinase 3‐internal tandem duplication ( FLT 3 ‐ ITD ) ( n = 5), age ≥60 years ( n = 31) or AML in second remission ( CR 2) ( n = 14). Dose‐limiting toxicity was not reached. Common toxicities were haematological, infection, injection pain, constipation, fatigue and diarrhoea. In CR 1, median relapse‐free ( RFS ) and overall survival ( OS ) was 12 and 20 months, respectively. In CR 2, median RFS was 11 months, with median OS not yet reached. Among 29 patients with intermediate cytogenetic risk, RFS was 50% at 24 months. There were five patients with concomitant FLT 3 ‐ ITD and nucleophosmin ( NPM 1 ) mutation; none have relapsed and all are still alive after 17–39 months. Maintenance lenalidomide/azacitidine augmented the function of cytotoxic T lymphocytes, particularly in patients with NPM 1 mutation. The lenalidomide/azacitidine maintenance combination was effective in suppressing residual DNA (cytosine‐5‐)‐methyltransferase 3 alpha ( DNMT 3A)‐positive disease, resulting in sustained remission in patients with concurrent NPM 1 mutation. Azacitidine/lenalidomide as maintenance therapy for high‐risk AML warrants further exploration.
This study reports the following: (1) frequency of TP53 comutation within each component of the European LeukemiaNet 2022 acute myeloid leukemia risk classification, (2) relevance of TP53 mutated variant allelic fraction <10%, (3) prognostic impact of -7, -5/del(5q), -17/abn(17p), complex karyotype/monosomal karyotype, or myelodysplasia-related gene mutations with/without mutated TP53.
Since the publication of the original article the authors noticed the the affiliation details for Paresh Vyas are incorrect. The correct affiliation details for this author are given below:
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