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.IMPORTANCEThis 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.

INTRODUCTION:High quality hospital care for serious ill persons requires exemplary team-based communication and decision-making. However, there is a need for evidence-based interventions in this area. This study's aim is to gain insight in the adoption and implementation of the COaching Doctors to improve Ethical decision-making (CODE) intervention, composed of one-on-one professional coaching in doctors and an alert to identify patients potentially receiving excessive treatment. METHODS:Mixed-method process evaluation study using focus group interviews, sub-analysis of the ethical decision-making climate questionnaire (EDMCQ) in nurses and doctors and a satisfaction survey in doctors. RESULTS:Of the 423 clinicians, 198 (60.2%) nurses and 63 (67.0%) doctors filled-out the EDMCQ and 20 nurses and 12 doctors participated to the focus-group interviews respectively. Thirty-five (70%) of the 50 coached doctors filled-out the satisfaction survey. Doctors estimated their leadership skills higher than the nurses prior to the study period (P = 0.006) but no longer after the study period (P = 0.366). Nurses estimated ethical awareness and reflection higher (respectively, P = 0.002 and P = 0.049) and non-avoiding end-of-life decisions and active involvement of nurses lower than the doctors (respectively P < 0.001 and P = 0.023) after the study period but not before the study period (all P-values >0.05). Doctors testified of increased awareness in ethical decision-making, more open interactions with patients and nurses, and more courage to intervene instead of doing nothing. Nurses spoke of an increased awareness to act as patient advocate, increased deliberation among peer nurses and frustration when they felt no effect of activating the CODE alert. Both doctors and nurses advised for more active involvement of nurses. The mean overall satisfaction score in doctors was 8.69 on 10. CONCLUSION:The CODE study intervention was effective in raising awareness and self-reflection, yet did not succeed to close the (communication) gap between doctors and nurses in team-based ethical decision-making. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05167019.

Acute myeloid leukemia (AML) comprises 32% of adult leukemia cases, with a 5-year survival rate of only 20-30%. Here, the immunophenotypic landscape of this heterogeneous malignancy is explored in a single-center cohort using a novel quantitative computational pipeline. For 122 patients who underwent induction treatment with intensive chemotherapy, leukemic cells were identified at diagnosis, computationally preprocessed, and quantitatively subtyped. Computational analysis provided a broad characterization of inter- and intra-patient heterogeneity, which would have been harder to achieve with manual bivariate gating. Statistical testing discovered associations between CD34, CD117, and HLA-DR expression patterns and genetic abnormalities. We found the presence of CD34+ cell populations at diagnosis to be associated with a shorter time to relapse. Moreover, CD34- CD117+ cell populations were associated with a longer time to AML-related mortality. Machine learning (ML) models were developed to predict 2-year survival, European LeukemiaNet (ELN) risk category, and inv(16) or NPM1mut, based on computationally quantified leukemic cell populations and limited clinical data, both readily available at diagnosis. We used explainable artificial intelligence (AI) to identify the key clinical characteristics and leukemic cell populations important for our ML models when making these predictions. Our findings highlight the importance of developing objective computational pipelines integrating immunophenotypic and genetic information in the risk stratification of AML.

Background 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.Materials 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.Results 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).Conclusions 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. Microbial cell-free DNA sequencing may facilitate a non-invasive diagnosis of invasive fungal disease (IFD) in particular non-Aspergillus IFD. However, similar to currently available diagnostics, it cannot be used as a "rule-out" test. Sequencing was also successfully performed on bronchoalveolar lavage fluid.

Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of

Guadecitabine is a novel hypomethylating agent (HMA) resistant to deamination by cytidine deaminase. Patients with relapsed/refractory acute myeloid leukemia (AML) were randomly assigned to guadecitabine or a preselected treatment choice (TC) of high-intensity chemotherapy, low-intensity treatment with HMAs or low-dose cytarabine, or best supportive care (BSC). The primary end point was overall survival (OS). A total of 302 patients were randomly assigned to guadecitabine (n = 148) or TC (n = 154). Preselected TCs were low-intensity treatment (n = 233 [77%; mainly HMAs]), high-intensity chemotherapy (n = 63 [21%]), and BSC (n = 6 [2%]). The median OS were 6.4 and 5.4 months for guadecitabine and TC, respectively (hazard ratio 0.88 [95% con fidence interval, 0.67-1.14]; log-rank P = .33). Survival bene fit for guadecitabine was suggested in several prospective subgroups, including age <65 years, Eastern Cooperative Oncology Group performance status 0 to 1, refractory AML, and lower peripheral blood blasts <= 30%. Complete response (CR) + CR with partial hematologic recovery rates were 17% for guadecitabine vs 8% for TC ( P < .01); CR+CR with incomplete count recovery rates were 27% for guadecitabine vs 14% for TC ( P < .01). Safety was comparable for the 2 arms, but guadecitabine had a higher rate of grade >= 3 neutropenia (32% vs 17%; P < .01). This study did not demonstrate an OS bene fit for guadecitabine. Clinical response rates were higher for guadecitabine, with comparable safety to TC. There was an OS bene fit for guadecitabine in several prespeci fied subgroups. This study was registered at www.clinicaltrials.gov as #NCT02920008.

The aim of this study was to assess whether coaching doctors to enhance ethical decision-making in teams improves (1) goal-oriented care operationalized via written do-not-intubate and do-not attempt cardiopulmonary resuscitation (DNI-DNACPR) orders in adult patients potentially receiving excessive treatment (PET) during their first hospital stay and (2) the quality of the ethical climate. We carried out a stepped-wedge cluster randomized controlled trial in the medical intensive care unit (ICU) climate questionnaire (ethical decision-making climate questionnaire, EDMCQ) before and after the study, and anonymously identified PET via an electronic alert during the entire study period. All departments were randomly assigned to a 4-month coaching. At least one month of coaching was compared to less than one month coaching and usual care. The first primary endpoint was the incidence of written DNI-DNACPR decisions. The second primary endpoint was the EDMCQ before and after the study period. Because clinicians identified less PET than required to detect a difference in written DNI-DNACPR decisions, a post-hoc analysis on the overall population was performed. To reduce type I errors, we further restricted the analysis to one of our predefined secondary endpoints (mortality up to 1 year). Of the 442 and 423 clinicians working before and after the study period, respectively 270 (61

The gut microbiota makes critical contributions to host homeostasis, and its role in the treatment of acute myeloid leukemia (AML) has attracted attention. We investigated whether the gut microbiome is affected by AML, and whether such changes are associated with hallmarks of cachexia. Biological samples and clinical data were collected from 30 antibiotic- free AML patients at diagnosis and matched volunteers (1:1) in a multicenter, cross-sectional, prospective study. The composition and functional potential of the fecal microbiota were analyzed using shotgun metagenomics. Fecal, blood, and urinary metabolomics analyses were performed. AML patients displayed muscle weakness, anorexia, signs of altered gut function, and glycemic disorders. The composition of the fecal microbiota differed between patients with AML and control subjects, with an increase in oral bacteria. Alterations in bacterial functions and fecal metabolome support an altered redox status in the gut microbiota, which may contribute to the altered redox status observed in patients with AML. Eubacterium eligens, reduced 3-fold in AML patients, was strongly correlated with muscle strength and citrulline, a marker of enterocyte mass and function. Blautia and Parabacteroides, increased in patients with AML, were correlated with anorexia. Several bacterial taxa and metabolites (e.g., Blautia, Prevotella, phenylacetate, and hippurate) previously associated with glycemic disorders were altered. Our work revealed important perturbations in the gut microbiome of AML patients at diagnosis, which are associated with muscle strength, altered redox status, and anorexia. These findings pave the way for future mechanistic work to explore the function and therapeutic potential of the bacteria identified in this study.

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.

Background: Patients with relapsed and refractory (R/R) acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM) require effective treatment options due to their high mortality rates. The inhibition of 2 anti-apoptotic proteins, B-cell lymphoma 2 (BCL2) and myeloid cell leukemia 1 (MCL1), has shown promise as a therapeutic approach for these cancers. Two novel BH3 mimetics, VOB560 and MIK665, selectively inhibit BCL2 and MCL1, respectively, induce apoptosis in hematological cancer cells and showed efficacy in preclinical models. In combination, VOB560 and MIK665 demonstrated strong synergy and promoted cell death in various hematological cancer models. VOB560 binds to BCL2, disrupting its interaction with pro-apoptotic proteins, causing cell death. MIK665 selectively inhibits MCL1, activating caspases and promoting cell death. Here we report the early clinical findings of the combination of VOB560 and MIK665 from the dose escalation phase in the treatment of hematological malignancies. Methods: This was a phase 1b, open-label, multi-center, dose-escalation/-expansion study (NCT04702425) in patients with R/R NHL, AML or MM. In the escalation phase, VOB560 was administered weekly (QW) intravenously (IV) at 25 and 50 mg in combination with MIK665 administered IV at 25 and 50 mg QW. Primary objectives of the dose-escalation phase were to characterize the safety and tolerability of VOB560 in combination with MIK665, and to identify the maximum tolerated dose and/or recommended doses and regimens for all indications. Secondary objectives were to assess preliminary antitumor activity and pharmacokinetics. Decision was made to halt recruitment in April 2023 for strategic reasons and not to progress further in the expansion phase of the study. This decision was not the consequence of any safety concerns. Results: Thirty-seven patients were enrolled in the dose escalation phase. Patients' diagnoses were AML (n=29, 78.4%), MM (n=4,10.8%), and NHL (n=4, 10.8%). NHL included diffuse large B cell lymphoma (n=3, 8.1%) and follicular lymphoma (n=1, 2.7%). Thirty-six patients permanently discontinued study, due to progressive disease (n=25), physician's decision (n=7), adverse events (AE; n=3) and patient's decision (n=1). Complete remission (CR) was observed in 2 AML patients receiving VOB560 50 mg in combination with MIK665 25 mg QW. One patient relapsed after 7 months, while, the other AML patient, solely on study treatment, was in CR after 18 months. One AML patient showed partial remission. No objective responses were observed in the MM and NHL cohorts. Five patients experienced dose limiting toxicities (DLTs). DLTs included perimyocarditis (n=1) receiving VOB560 25 mg and MIK665 25 mg, tumor lysis syndrome (TLS, n=1) receiving VOB560 50 mg and MIK665 25 mg, differentiation syndrome (n=1) receiving VOB560 25 mg and MIK665 50 mg, muscle cramp (n=1) receiving VOB560 50 mg and MIK665 50 mg, and decreased ejection fraction (n=1) receiving VOB560 50 mg and MIK665 50 mg. AEs were reported in 37 patients (100%), of which 25 patients (67%) had grade ≥ 3 AEs. Treatment-related AEs (TRAEs) were reported in 23 patients (62.2%). Most frequent TRAEs reported in ≥ 5% of patients were diarrhea and nausea (6 patients each, 16.2%), vomiting, pyrexia and TLS (3 patients each, 8.1%). Anemia, neutropenia, thrombocytopenia, aspartate aminotransferase increased, and infusion-related reaction were reported in 2 patients each (5.4%). Seven patients (18.9%) reported grade ≥ 3 TRAEs. Three patients (8.1%) experienced grade 3 (severe) TLS, while 1 patient (2.7%) each experienced grade 3 (severe) neutropenia, myopericarditis, muscle spasm and differentiation syndrome. No fatal grade 5 serious AE (SAE) was reported. Eighteen patients (48%) experienced SAEs; 6 SAEs were treatment related. These included TLS, hyperphosphatemia, myopericarditis, muscle spasms, leukocytosis, oxygen saturation decreased and differentiation syndrome. Patients who developed troponin increase underwent cardiac MRI, which showed no observable functional or structural changes to the heart. Conclusions: Early clinical data of VOB560 in combination with MIK665 reported an acceptable safety profile in patients with hematological malignancies. The observed activity in the AML patients supports the notion that targeting MCL1 and BCL2 is a promising approach in hematological malignancies.

Background Vancomycin is a commonly prescribed antibiotic to treat gram-positive infections. The efficacy of vancomycin is known to be directly related to the pharmacokinetic/pharmacodynamic (PK/PD) index of the area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) of the pathogen. However, in most countries, steady-state plasma concentrations are used as a surrogate parameter of target AUC/MIC, but this practice has some drawbacks. Hence, direct AUC-guided monitoring of vancomycin using model-informed precision dosing (MIPD) tools has been proposed for earlier attainment of target concentrations and reducing vancomycin-related nephrotoxicity. However, solid scientific evidence for these benefits in clinical practice is still lacking. This randomized controlled trial (RCT) aims to investigate the clinical utility of MIPD dosing of vancomycin administered via continuous infusion in hospitalized adults. Methods Participants from 11 wards at two Belgian hospitals are randomly allocated to the intervention group or the standard-of-care comparator group. In the intervention group, clinical pharmacists perform dose calculations using CE-labeled MIPD software and target an AUC24h of 400 to 600 mg × h/L, whereas patients in the comparator group receive standard-of-care dosing and monitoring according to the institutional guidelines. The primary endpoint is the proportion of patients reaching the target AUC24h/MIC of 400–600 between 48 and 72 h after start of vancomycin treatment. Secondary endpoints are the proportion of patients with (worsening) acute kidney injury (AKI) during and until 48 h after stop of vancomycin treatment, the proportion of patients reaching target AUC24h/MIC of 400–600 between 72 and 96 h after start of vancomycin treatment, and the proportion of time within the target AUC24h/MIC of 400–600. Discussion This trial will clarify the propagated benefits and provide new insights into how to optimally monitor vancomycin treatment. Trial registration EudraCT number: 2021-003670-31. Registered June 28, 2021. ClinicalTrials.gov identifier: NCT05535075. Registered September 10, 2022. Protocol version 3, protocol date: April 21, 2023.

BACKGROUND:Invasive pulmonary aspergillosis (IPA) is a relatively common infection in patients with acute myeloid leukaemia (AML), and is associated with high mortality rates. Optimising early detection is key to reduce the burden of IPA in this population. In this retrospective cohort study, we evaluated the added value of baseline chest CT before start of classical induction chemotherapy. METHODS:Adult patients receiving first-line intensive chemotherapy for AML were included if a baseline chest CT scan was available (±7 days). Data were collected from the electronic health record. IPA was classified using the EORTC/MSGERC 2020 consensus definitions. RESULTS:Between 2015 and 2019, 99 patients were included. During first-line treatment, 29/99 (30%) patients developed a probable IPA. Baseline chest CT was abnormal in 61/99 (62%) and 14/61 (23%) patients had typical radiological signs for IPA. An abnormal scan showed a trend towards higher risk for IPA (hazard ratio (HR): 2.12; 95% CI 0.95-4.84). Ground glass opacities were a strong predictor for developing IPA (HR 3.35: 95% CI 1.61-7.00). No probable/proven IPA was diagnosed at baseline; however, a bronchoalveolar lavage (BAL) at baseline was only performed in seven patients. Twelve-week mortality was higher in patients with IPA (7/26, 27% vs. 5/59, 8%; p = .024). CONCLUSION:Baseline chest CT scan could be an asset in the early diagnosis of IPA and contribute to risk estimation for IPA. In patients with an abnormal baseline CT, performing a BAL should be considered more frequently, and not only in patients with radiological findings typical for IPA.

Acute myeloid leukemia (AML) comprises 32% of adult leukemia cases with a five-year survival rate of only 20–30%. Here, the immunophenotypic landscape of this heterogeneous malignancy is explored in a single-center cohort using a novel quantitative computational pipeline. For 122 patients who underwent induction treatment with intensive chemotherapy, leukemic cells were identified at diagnosis, computationally preprocessed and quantitatively subtyped. Computational analysis provided a broad characterization of inter- and intra-patient heterogeneity, unachievable with manual bivariate gating. Statistical testing discovered associations between CD34, CD117 and HLA-DR expression patterns and genetic abnormalities. We found presence of CD34 + cell populations at diagnosis to be associated with a shorter time-to-relapse. Moreover, CD34- CD117 + cell populations were associated with a longer time to AML-related mortality. Machine learning (ML) models were developed to predict two-year survival, European LeukemiaNet (ELN) risk category and inv(16) or NPM1 mut , based on computationally quantified leukemic cell populations and limited clinical data, both readily available at diagnosis. We used explainable artificial intelligence (AI) to identify the key clinical characteristics and leukemic cell populations important for our ML models when making these predictions. Our findings highlight the importance of developing objective computational pipelines integrating immunophenotypic and genetic information in the risk stratification of AML.

Topic: 32. Platelet disorders Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder, caused by autoantibody-mediated deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13). Real-world data from Germany, France, and the United Kingdom confirm that caplacizumab allows rapid recovery of iTTP. Caplacizumab has been commercialized and reimbursed in Belgium since September 1, 2019. Real-world data on the treatment of iTTP patients with caplacizumab in Belgium are lacking. Aims: To provide real-world data on the use of caplacizumab in Belgium. Methods: This retrospective study analyzed hospital chart review data for patients with iTTP (≥18 years old) who were hospitalized and treated with caplacizumab in 13 Belgian hospitals (September 1, 2019, to January 15, 2022). Patients were included if they had caplacizumab treatment initiated and ended within the study period. Patient demographics, treatment characteristics, efficacy and safety outcomes, and healthcare resource utilization are presented. To identify differences in disease management, analyses were performed in 2 subgroups: first diagnosed episodes and relapse episodes. Results: A total of 39 iTTP episodes (25 first diagnoses, 14 relapse episodes) were identified in 33 patients (18–89 years old) who were treated with caplacizumab (Table). Females developed 21 episodes and males developed 18 episodes, with a higher proportion of females than males in the relapse episode subgroup (71.4% vs 28.6%). Mean (standard deviation [SD]) number of doses of caplacizumab per episode was 39.2 (14.7) for first diagnosed episodes and 31.9 (8.4) for relapse episodes. Caplacizumab was initiated quickly after hospital admission for first diagnosed episodes (2.7 days) and relapse episodes (0.4 days). Caplacizumab was generally initiated on the same day as iTTP diagnosis confirmation by ADAMTS13 activity-testing (level <10%); 2 centers started treatment before disease confirmation due to delayed results. Mean (SD) duration of hospital stay was 16.0 (10.3) days for first diagnosed episodes and 9.1 (2.9) days for relapse episodes. Exacerbation was observed in 2/39 (5.1%) episodes and relapse occurred in 6/39 (15.4%) episodes. Treatment was interrupted at the time both exacerbations occurred because there was a lack of symptoms of ongoing disease; 1 patient did not have ADAMTS13-testing at time of interruption and 1 had ADAMTS13 level <10%. Of 6 patients who developed a relapse, 3 patients in the first diagnosis subgroup had a short time (~7 days) between termination of caplacizumab in their first reported episode and relapse; treatment was stopped in these patients due to platelet count normalization and symptom resolution, however, ADAMTS13 was <10%. No patients were refractory to treatment or passed away. Bleeding events occurred in 3/25 (12.0%) and 2/14 (14.3%) of episodes in the first diagnosis and relapse episodes, respectively. Summary/Conclusion: Caplacizumab was initiated quickly after hospital admission in combination with therapeutic plasma exchange and immunosuppressive therapy. Although ADAMTS13 testing is well established at diagnosis, our results show that additional ADAMTS13 testing should be used to optimize treatment and guide treatment discontinuation. Exacerbations and relapses may have been avoided if treatment duration was tailored to normalization of ADAMTS13 activity. Our results are in line with other published real-world data. Disease management of iTTP in Belgium is in line with international ISTH guidelines and caplacizumab is used as front-line therapy.Keywords: ADAMTS13, Platelet, Bleeding disorder, Thrombotic thrombocytopenic purpura (TTP)

Background CYAD-01 is an autologous chimeric antigen receptor (CAR) T-cell product based on the natural killer (NK) group 2D (NKG2D) receptor, which binds eight ligands that are overexpressed in a wide range of haematological malignancies but are largely absent on non-neoplastic cells. Initial clinical evaluation of a single infusion of CYAD-01 at a low dose in patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, and multiple myeloma supported the feasibility of the approach and prompted further evaluation of CYAD-01. The aim of the present study was to determine the safety and recommended phase 2 dosing of CYAD-01 administered without preconditioning or bridging chemotherapy.Methods The multicentre THINK study was an open-label, dose-escalation, phase 1 study for patients with relapsed or refractory acute myeloid leukaemia, myelodysplastic syndromes, or multiple myeloma, after at least one previous line of therapy. Patients were recruited from five hospitals in the USA and Belgium. The dose-escalation segment evaluated three dose levels: 3 x 108 (dose level one), 1 x 109 (dose level two), and 3 x 109 (dose level three) cells per infusion with a 3 + 3 Fibonacci study design using a schedule of three infusions at 2-week intervals followed by potential consolidation treatment consisting of three additional infusions. The occurrence of dose-limiting toxicities post-CYAD-01 infusion was assessed as the primary endpoint in the total treated patient population. The trial was registered with ClinicalTrials.gov, NCT03018405, and EudraCT, 2016-003312-12, and has been completed.Findings Between Feb 6, 2017, and Oct 9, 2018, 25 patients were registered in the haematological dose-escalation segment. Seven patients had manufacturing failure for insufficient yield and two had screening failure. 16 patients were treated with CYAD-01 (three with multiple myeloma and three with acute myeloid leukaemia at dose level one; three with acute myeloid leukaemia at dose level two; and six with acute myeloid leukaemia and one with myelodysplastic syndromes at dose level three). Median follow-up was 118 days (IQR 46-180). Seven patients (44%) had grade 3 or 4 treatment-related adverse events. In total, five patients (31%) had grade 3 or 4 cytokine release syndrome across all dose levels. One dose-limiting toxicity of cytokine release syndrome was reported at dose level three. No treatment-related deaths occurred, and the maximum tolerated dose was not reached. Three (25%) of 12 evaluable patients with relapsed or refractory acute myeloid leukaemia or myelodysplastic syndromes had an objective response. Among responders, two patients with acute myeloid leukaemia proceeded to allogeneic haematopoietic stem-cell transplantation (HSCT) after CYAD-01 treatment, with durable ongoing remissions (5 and 61 months).Interpretation Treatment with a multiple CYAD-01 infusion schedule without preconditioning is well tolerated and shows anti-leukaemic activity, although without durability outside of patients bridged to allogeneic HSCT. These phase 1 data support the proof-of-concept of targeting NKG2D ligands by CAR T-cell therapy. Further clinical studies with NKG2D-based CAR T-cells are warranted, potentially via combinatorial antigen targeted approaches, to improve anti-tumour activity.Funding Celyad Oncology.Copyright (c) 2023 Elsevier Ltd. All rights reserved.

OBJECTIVE:A late conversation about palliative care needs can lead to suboptimal care in the final months/weeks of life. Insight into factors related to patients' communication about palliative care is needed. This study aims to identify the factors associated with starting/intending to start a conversation about palliative care with the physician.METHODS:We performed a cross-sectional interviewer-administered survey among people with incurable cancer. Purposive sampling was used, taking into account theoretically relevant heterogeneity. The questionnaire was developed based on the theory of planned behavior. Uni- and multivariable logistic regression analyses were performed.RESULTS:Out of 80 participants, ten (13%) started the palliative care conversation and 18 (23%) intended to do so. People holding a positive attitude towards starting/intending to start the conversation (odds ratio [OR] 4.74; 95% CI 2.35-9.54), perceiving more benefits of it (OR 2.60; 95% CI 1.37-4.96) and perceiving a positive attitude towards the behavior in family/friends (OR 2.07; 95% CI 1.26-3.41) and the physician (OR 2.19; 95% CI 1.39-3.45) were more likely to start/intend to start a palliative care conversation; people perceiving more disadvantages (OR 0.53; 95% CI 0.32-0.87) and barriers (OR 0.31; 95% CI 0.15-0.63) were less likely to do so. These factors explained 64% of the variance.CONCLUSIONS:Our findings show that psychological and perceived socio-environmental factors, particularly patients' attitudes, are associated with starting a conversation about palliative care. Theory-based interventions targeting these strong associations might have a high potential to empower people with cancer to take the initiative in communication about palliative care and to improve timely initiation of palliative care.

Background Systemic mastocytosis (SM) is a rare myeloproliferative disease that results from a clonal proliferation of abnormal mast cells in one or more extra-cutaneous organs. Systemic mastocytosis with an associated hematological neoplasm (SM-AHN) is the second most common subgroup and is diagnosed when WHO criteria for both SM and a hematological neoplasm of non-mast cell lineage are met. The SM-AHN category as currently proposed is highly heterogeneous in terms of pathogenesis, clinical presentation, and prognosis. Case presentation We present the first reported case of SM-AHN associated with two hematological malignancies of different lineages, a monocytic myeloid sarcoma and a B-cell chronic lymphatic leukemia. Cytogenetic and molecular analyses revealed a distinct clonal origin of the two associated malignancies. The SM-myeloid sarcoma clone demonstrated an abnormal karyotype, trisomy 8 and del(13)(q12.3q14.3), as well as mutations in KITD816V, DNMT3A and RUNX1. The DNMT3A mutation could be detected years before disease onset, supporting its potential role as early driver of leukemogenesis. No genetic aberrations could be identified in the CLL clone, which is assumed to present coincidentally. Conclusions This report highlights the importance of full diagnostic work-up in SM patients in whom an associated hematological malignancy is suspected. Moreover, the importance of genetic analysis is highlighted, as it provides additional insights in the underlying clonal pathogenesis of different phenotypes, can aid in risk stratification, and may help identify potential therapy targets.

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.