Emerging roles for tRNAs in hematopoiesis and hematological malignancies.

tRNAs are central players in decoding the genetic code linking codons in mRNAs with cognate amino acids during protein synthesis. Recent discoveries have placed tRNAs as key regulators of gene expression during hematopoiesis, especially in hematopoietic stem cell (HSC) maintenance and immune development. These functions have been shown to be influenced by dynamic changes in tRNA expression, post-transcriptional base modifications, tRNA-interacting proteins, and tRNA fragmentation; these events underlie the complexity of tRNA-mediated regulatory events in hematopoiesis. In this review, we discuss these recent findings and highlight how deregulation of tRNA biogenesis can contribute to hematological malignancies.

T cell-redirecting therapies in hematological malignancies: Current developments and novel strategies for improved targeting.

T cell-redirecting therapies (TCRTs), such as chimeric antigen receptor (CAR) or T cell receptor (TCR) T cells and T cell engagers, have emerged as a highly effective treatment modality, particularly in the B and plasma cell-malignancy setting. However, many patients fail to achieve deep and durable responses; while the lack of truly unique tumor antigens, and concurrent on-target/off-tumor toxicities, have hindered the development of TCRTs for many other cancers. In this review, we discuss the recent developments in TCRT targets for hematological malignancies, as well as novel targeting strategies that aim to address these, and other, challenges.

Exploring the nexus of nuclear receptors in hematological malignancies.

Hematological malignancies (HM) represent a subset of neoplasms affecting the blood, bone marrow, and lymphatic systems, categorized primarily into leukemia, lymphoma, and multiple myeloma. Their prognosis varies considerably, with a frequent risk of relapse despite ongoing treatments. While contemporary therapeutic strategies have extended overall patient survival, they do not offer cures for advanced stages and often lead to challenges such as acquisition of drug resistance, recurrence, and severe side effects. The need for innovative therapeutic targets is vital to elevate both survival rates and patients' quality of life. Recent research has pivoted towards nuclear receptors (NRs) due to their role in modulating tumor cell characteristics including uncontrolled proliferation, differentiation, apoptosis evasion, invasion and migration. Existing evidence emphasizes NRs' critical role in HM. The regulation of NR expression through agonists, antagonists, or selective modulators, contingent upon their levels, offers promising clinical implications in HM management. Moreover, several anticancer agents targeting NRs have been approved by the Food and Drug Administration (FDA). This review highlights the integral function of NRs in HM's pathophysiology and the potential benefits of therapeutically targeting these receptors, suggesting a prospective avenue for more efficient therapeutic interventions against HM.

Delivery Aspects for Implementing siRNA Therapeutics for Blood Diseases.

Hematological disorders result in significant health consequences, and traditional therapies frequently entail adverse reactions without addressing the root cause. A potential solution for hematological disorders characterized by gain-of-function mutations lies in the emergence of small interfering RNA (siRNA) molecules as a therapeutic option. siRNAs are a class of RNA molecules composed of double-stranded RNAs that can degrade specific mRNAs, thereby inhibiting the synthesis of underlying disease proteins. Therapeutic interventions utilizing siRNA can be tailored to selectively target genes implicated in diverse hematological disorders, including sickle cell anemia, ß-thalassemia, and malignancies such as lymphoma, myeloma, and leukemia. The development of efficient siRNA silencers necessitates meticulous contemplation of variables such as the RNA backbone, stability, and specificity. Transportation of siRNA to specific cells poses a significant hurdle, prompting investigations of diverse delivery approaches, including chemically modified forms of siRNA and nanoparticle formulations with various biocompatible carriers. This review delves into the crucial role of siRNA technology in targeting and treating hematological malignancies and disorders. It sheds light on the latest research, development, and clinical trials, detailing how various pharmaceutical approaches leverage siRNA against blood disorders, mainly concentrating on cancers. It outlines the preferred molecular targets and physiological barriers to delivery while emphasizing the growing potential of various therapeutic delivery methods. The need for further research is articulated in the context of overcoming the shortcomings of siRNA in order to enrich discussions around siRNA's role in managing blood disorders and aiding the scientific community in advancing more targeted and effective treatments.

Subsequent malignant neoplasms after primary hematological malignancy in adult patients.

Patients with primary hematological malignancy (HM) are at an elevated risk of subsequent malignant neoplasms (SMNs), which is a common concern after treatment of primary cancer. We identified 45,533 patients aged ≥20 years and diagnosed with primary HM in Finland from 1992 to 2019 from the Finnish Cancer Registry and estimated standardized incidence ratios (SIR) and excess absolute risks per 1000 person-years (EAR) for SMNs. A total of 6076 SMNs were found (4604 solid and 1472 hematological SMNs). The SIRs were higher for hematological SMNs (SIR 4.9, 95% confidence interval [CI] 4.7-5.2) compared to solid SMNs (SIR 1.5, 95% CI 1.4-1.5). The SIRs for hematological SMNs were highest in the young HM patients aged 20-39 years (SIR 9.2, 95% CI 6.8-12.2 in males and SIR 10.5, 95% CI 7.2-14.7 in females) and decreased by age of first primary HM. However, EARs for hematological SMNs were highest in the older patients, aged 60-79 years at their first primary HM (EAR 5.7/1000 and 4.7/1000 in male and female patients, respectively). In conclusion, the incidence of both hematological and solid SMNs were increased in hematological cancer patients. The relative risk (SIR) was highest among younger HM patients with hematological SMNs. The absolute second cancer burden reflected by high EAR arises from solid malignancies in older patients. Our results accentuate the need for vigilance in the surveillance of HM patients.

Next-generation cytogenetics: Comprehensive assessment of 52 hematological malignancy genomes by optical genome mapping.

Somatic structural variants (SVs) are important drivers of cancer development and progression. In a diagnostic set-up, especially for hematological malignancies, the comprehensive analysis of all SVs in a given sample still requires a combination of cytogenetic techniques, including karyotyping, FISH, and CNV microarrays. We hypothesize that the combination of these classical approaches could be replaced by optical genome mapping (OGM). Samples from 52 individuals with a clinical diagnosis of a hematological malignancy, divided into simple (<5 aberrations, n = 36) and complex (≥5 aberrations, n = 16) cases, were processed for OGM, reaching on average: 283-fold genome coverage. OGM called a total of 918 high-confidence SVs per sample, of which, on average, 13 were rare and >100 kb. In addition, on average, 73 CNVs were called per sample, of which six were >5 Mb. For the 36 simple cases, all clinically reported aberrations were detected, including deletions, insertions, inversions, aneuploidies, and translocations. For the 16 complex cases, results were largely concordant between standard-of-care and OGM, but OGM often revealed higher complexity than previously recognized. Detailed technical comparison with standard-of-care tests showed high analytical validity of OGM, resulting in a sensitivity of 100% and a positive predictive value of >80%. Importantly, OGM resulted in a more complete assessment than any previous single test and most likely reported the most accurate underlying genomic architecture (e.g., for complex translocations, chromoanagenesis, and marker chromosomes). In conclusion, the excellent concordance of OGM with diagnostic standard assays demonstrates its potential to replace classical cytogenetic tests as well as to rapidly map novel leukemia drivers.

A review of the epidemiology of invasive fungal infections in Asian patients with hematological malignancies (2011-2021).

The incidence of invasive fungal infection (IFI) is increasing, especially among patients diagnosed with hematological malignancies due to their immunocompromised nature. Other risk factors include advanced age, exposure to immunosuppressants, neutropenia, and catheter use. Some of the most common IFI organisms reported are Candida and Aspergillus species, and other fungal species, including Scedosporium, Trichosporon, Cryptococcus, and Fusarium have also increasingly been reported in the past years. However, the epidemiologic data on IFI among patients with hematological malignancies in Asian countries are lacking. Therefore, we investigated published epidemiologic data on such cases from the past 10 years (2011-2021) and discuss the challenges faced in the diagnosis and management of IFIs in Asia.

Pre-existing cardiovascular disease is associated with an increased risk of cardiovascular events during Bruton tyrosine kinase inhibitor therapy.

The association between pre-existing cardiovascular disease (CVD) and the development of cardiovascular adverse events (CVAE) during Bruton tyrosine kinase inhibitor (BTKi) therapy is not well established. We compared the rate of CVAE, such as new onset or worsening atrial fibrillation (AF), supraventricular tachycardia, ventricular tachycardia, hypertension, myocardial infarction, and sudden cardiac death, between individuals with and without pre-existing CVD, during BTKi treatment. Secondary objectives were to compare the outcomes of patients treated with first generation BTKi versus second generation BTKi and characterize management decisions. A single-center retrospective review was conducted on patients treated with BTKi from 2013 to 2022 at Beth Israel Deaconess Medical Center. Adjusted logistic regression analyses were performed to evaluate the association between pre-existing CVD and CVAE. In this cohort, 11 out of 54 patients (20.4%) with pre-existing CVD developed CVAE, compared to 11 out of 135 patients (8.1%) without pre-existing CVD [age- and sex-adjusted OR 2.79; 95% CI (1.09, 7.25), P = .03]. Patients with pre-existing CVD had higher odds of developing new or worsening AF [age- and sex-adjusted OR 3.36; 95% CI (1.09, 10.71), P = .03]. Results remained robust after further adjustment of comorbidities, type of BTKi, and baseline medications. These results highlight the need for standardized approaches to prevent and promptly detect CVAE during BTKi treatment, particularly in patients with pre-existing CVD.

Performance Evaluation of a Novel Artificial Intelligence-Assisted Digital Microscopy System for the Routine Analysis of Bone Marrow Aspirates.

Bone marrow aspiration (BMA) smear analysis is essential for diagnosis, treatment, and monitoring of a variety of benign and neoplastic hematological conditions. Currently, this analysis is performed by manual microscopy. We conducted a multicenter study to validate a computational microscopy approach with an artificial intelligence-driven decision support system. A total of 795 BMA specimens (615 Romanowsky-stained and 180 Prussian blue-stained) from patients with neoplastic and other clinical conditions were analyzed, comparing the performance of the Scopio Labs X100 Full Field BMA system (test method) with manual microscopy (reference method). The system provided an average of 1,385 ± 536 (range, 0-3,131) cells per specimen for analysis. An average of 39.98 ± 19.64 fields of view (range, 0-140) per specimen were selected by the system for analysis, of them 87% ± 21% (range, 0%-100%) were accepted by the qualified operators. These regions were included in an average of 17.62 ± 7.24 regions of interest (range, 1-50) per specimen. The efficiency, sensitivity, and specificity for primary and secondary marrow aspirate characteristics (maturation, morphology, and count assessment), as well as overall interuser agreement, were evaluated. The test method showed a high correlation with the reference method for comprehensive BMA evaluation, both on Romanowsky- (90.85% efficiency, 81.61% sensitivity, and 92.88% specificity) and Prussian blue-stained samples (90.0% efficiency, 81.94% sensitivity, and 93.38% specificity). The overall agreement between the test and reference methods for BMA assessment was 91.1%. For repeatability and reproducibility, all standard deviations and coefficients of variation values were below the predefined acceptance criteria both for discrete measurements (coefficient of variation below 20%) and differential measurements (SD below 5%). The high degree of correlation between the digital decision support system and manual microscopy demonstrates the potential of this system to provide a high-quality, accurate digital BMA analysis, expediting expert review and diagnosis of BMA specimens, with practical applications including remote BMA evaluation and possibly new opportunities for the research of normal and neoplastic hematopoiesis.

Ulcerating skin lesions from blastic plasmacytoid dendritic cell neoplasm responding to low-dose radiotherapy-a case report and literature review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that can manifest with skin nodules and erythematous plaques. In most cases BPDCN progresses rapidly, causing multiple skin lesions and also affecting internal organs and bone marrow, warranting initiation of systemic therapies or hematopoietic stem cell transplantation (HCT). Although not curative, radiotherapy for isolated lesions might be indicated in case of (imminent) ulceration and large or symptomatic lesions. To this end, doses of 27.0-51.0 Gy have been reported. Here, we present the case of an 80-year-old male with BPDCN with multiple large, nodular, and ulcerating lesions of the thorax, abdomen, and face. Low-dose radiotherapy of 2â€¯× 4.0 Gy was administered to several lesions, which resolved completely within 1 week with only light residual hyperpigmentation of the skin in affected areas and reliably prevented further ulceration. Radiotoxicity was not reported. Therefore, low-dose radiotherapy can be an effective and low-key treatment in selected cases of BPDCN, especially in a palliative setting, with a favorable toxicity profile.

Exploring the promise of regulator of G Protein Signaling 20: insights into potential mechanisms and prospects across solid cancers and hematological malignancies.

RGS (Regulator of G protein signaling) proteins have long captured the fascination of researchers due to their intricate involvement across a wide array of signaling pathways within cellular systems. Their diverse and nuanced functions have positioned them as continual subjects of scientific inquiry, especially given the implications of certain family members in various cancer types. Of particular note in this context is RGS20, whose clinical relevance and molecular significance in hepatocellular carcinoma we have recently investigated. These investigations have prompted questions into the prevalence of pathogenic mutations within the RGS20 gene and the intricate network of interacting proteins that could contribute to the complex landscape of cancer biology. In our study, we aim to unravel the mutations within the RGS20 gene and the multifaceted interplay between RGS20 and other proteins within the context of cancer. Expanding on this line of inquiry, our research is dedicated to uncovering the intricate mechanisms of RGS20 in various cancers. In particular, we have redirected our attention to examining the role of RGS20 within hematological malignancies, with a specific focus on multiple myeloma and follicular lymphoma. These hematological cancers hold significant promise for further investigation, as understanding the involvement of RGS20 in their pathogenesis could unveil novel therapeutic strategies and treatment avenues. Furthermore, our exploration has extended to encompass the latest discoveries concerning the potential involvement of RGS20 in diseases affecting the central nervous system, thereby broadening the scope of its implications beyond oncology to encompass neurobiology and related fields.

Charting a path forward: Promising outcomes of convalescent plasma therapy in the care of severely B-cell depleted patients with persistent COVID-19.

BACKGROUND: Patients with severe B-cell depletion related to hematological malignancies or B-cell targeted therapy suffer from impaired antibody responses to SARS-CoV-2 and are at risk for prolonged COVID-19. In this population, COVID-19 convalescent plasma (CCP) may provide passive immunity, enhance immune response, and promote virus neutralization. This study evaluated outcomes of B-cell depleted patients with persistent COVID-19 treated with CCP. STUDY DESIGN AND METHODS: This analysis included all consecutive severely B-cell depleted patients with persistent COVID-19, receiving CCP at Rambam between 01.2022-02.2023. Persistent COVID-19 was defined as the presence of symptoms for ≥14 days in patients with negative SARS-CoV-2 nucleocapsid antibody test results. RESULTS: Twenty patients met inclusion criteria, 17 of whom had hematological malignancies, two suffered from rheumatoid arthritis and one had both. Twelve patients received anti-CD-20 treatment, one - CAR-T cells and three underwent stem cell transplantation. The median duration of COVID-19 symptoms was 27.5 days (range 14-97); 12 patients had mild-to-moderate COVID-19 and 8 had severe infection. Sixteen patients required hospitalization. The majority of patients received other COVID-19 therapies before CCP. Within a median of two days (range 1-16) post-infusion, 19/20 patients clinically improved. No CCP-associated adverse events were documented. COVID-19 symptoms recurred in 3 of the improved patients. Two patients died from COVID-19 on days 1 and 90 following the first CCP infusion. DISCUSSION: In severely B-cell depleted patients with persistent COVID-19, CCP is safe and associated with rapid clinical improvement. This subset of immunocompromised patients could particularly benefit from CCP administration.

Prognostic value of hyperlactatemia and lactate clearance in septic patients with hematological malignancies.

BACKGROUND: The coexistence of sepsis and hematological malignancies increases patient vulnerability, revealing the need for precise prognostic markers. This study explores the prognostic significance of lactate levels and clearance in septic patients with hematological malignancies. MATERIALS AND METHODS: A retrospective cohort study from January 2016 to December 2019 in a tertiary hematological intensive care unit (ICU) included 167 adults with hematological malignancies and sepsis. The relationship between lactate levels, hyperlactatemia, lactate clearance, and ICU outcomes was investigated. ICU survivors and non-survivors were compared to identify the factors affecting ICU mortality. RESULTS: Patients were primarily with lymphoma and acute leukemia (66%) and had frequent hyperlactatemia (64%) on ICU admission. ICU non-survivors demonstrated higher lactate levels and hyperlactatemia frequency at various time points (0, 6, and 12 h) than survivors. Lactate clearance and liver function tests did not differ significantly between the two groups. Invasive mechanical ventilation [OR (95% confidence interval-CI): 20.4 (2.4-79.8), p < 0.01], requirement of vasopressors [OR (95% CI): 5.6 (1.3-24.5), p < 0.01], lactate level at the 6th hour [OR (95% CI): 1.51 (1.1-2.07), p = 0.01], and APACHE II score (OR (95% CI): 1.16 (1.01-1.34), p = 0.05) were independent risk factors for ICU mortality. The Area Under the Curve for APACHE II score and lactate level at the 6th hour were 0.774 (95% CI: 0.682-0.866) and 0.703 (95% CI: 0.602-0.804), respectively. CONCLUSION: While elevated lactate levels correlate with mortality rate and lactate level at the 6th hour is an independent risk factor for mortality, the absence of a significant difference in lactate clearance challenges traditional assumptions. These results question the commonly accepted perspective regarding lactate dynamics in sepsis among individuals with hematological malignancies. ORAL PRESENTATION: Inci K, et al. "Hyperlactatemia, lactate clearance and outcome in critically ill patients with hematological malignancies," 22nd international intensive care symposium, 2019.

Vaccine challenges in CLL: a comprehensive exploration of efficacy of SARS-CoV-2 immunization for patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by disease- and treatment-related immunosuppression. Patients with CLL comprise a vulnerable population to coronavirus disease 2019 (COVID-19), while the protective effect of COVID-19 vaccination remains uncertain.We conducted a systematic review to evaluate published data reporting response to COVID-19 vaccination in patients with CLL. The primary outcome was the rate of seropositivity after full primary vaccination, while secondary outcomes were rates of positive neutralizing antibodies, cellular responses, and adverse events. Response after booster doses of vaccination was also evaluated.Twenty-three studies of full primary vaccination (12 CLL-specific with 1747 patients, 11 with mixed hematologic diseases including 1044 patients with CLL) with a total of 2791 patients, and eight studies on booster doses with 389 patients were included in the analysis. The serologic response varied between studies with a median of 55%. Where reported, the median neutralizing antibody response rate was 61.2% and the cellular response rate was 44.2%. Poor serologic response was noted in patients under active treatment with anti-CD20 monoclonal antibodies, BCL2, and BTK inhibitors.The present review highlights the substantially impaired humoral and cellular response to COVID-19 vaccination in patients with CLL with patients under active treatment being the most vulnerable.

Changing patterns of bacterial profile and antimicrobial resistance in high-risk patients during the COVID-19 pandemic at a tertiary oncology hospital.

The widespread evolution of phenotypic resistance in clinical isolates over the years, coupled with the COVID-19 pandemic onset, has exacerbated the global challenge of antimicrobial resistance. This study aimed to explore changes in bacterial infection patterns and antimicrobial resistance during the COVID-19 pandemic. This study involved the periods before and during COVID-19: the pre-pandemic and pandemic eras. The surveillance results of bacterial isolates causing infections in cancer patients at an Egyptian tertiary oncology hospital were retrieved. The Vitek®2 or Phoenix systems were utilized for species identification and susceptibility testing. Statistical analyses were performed comparing microbiological trends before and during the pandemic. Out of 2856 bacterial isolates, Gram-negative bacteria (GNB) predominated (69.7%), and Gram-positive bacteria (GPB) comprised 30.3% of isolates. No significant change was found in GNB prevalence during the pandemic (P = 0.159). Elevated rates of Klebsiella and Pseudomonas species were demonstrated during the pandemic, as was a decrease in E. coli and Acinetobacter species (P < 0.001, 0.018, < 0.001, and 0.046, respectively) in hematological patients. In surgical patients, Enterobacteriaceae significantly increased (P = 0.012), while non-fermenters significantly decreased (P = 0.007). GPB species from either hematological or surgical wards exhibited no notable changes during the pandemic. GNB resistance increased in hematological patients to carbapenems, amikacin, and tigecycline and decreased in surgical patients to amikacin and cefoxitin (P < 0.001, 0.010, < 0.001, < 0.001, and 0.016, respectively). The study highlights notable shifts in the microbial landscape during the COVID-19 pandemic, particularly in the prevalence and resistance patterns of GNB in hematological and surgical wards.

CAR-T cell therapy in hematological malignancies: Where are we now and where are we heading for?

Chimeric antigen receptor T (CAR-T) therapy has emerged as a revolutionary new pillar in cancer care, particularly in relapsed/refractory (r/r) B-cell malignancies. Following impressive clinical outcomes in hematological malignancies, the FDA-approved six CAR-T cell products for indications such as lymphoma, leukemia, and myeloma. Despite the numerous advantages of CAR-T cell treatment, several challenges exist that interfere with its therapeutic efficacy. Serious adverse effects connected with the treatment continue to be a major concern. In addition, poor persistence of therapeutics and antigen escape frequently result in tumor relapse. Exorbitant treatment cost further remains a significant barrier to its effective implementation, limiting its accessibility. This review presents progress of CAR-T research, the key obstacles that hamper promising outcomes for patients with hematological malignancies, and a few strategies to overcome them.

Application of thromboelastography to predict the severity of bleeding after chimeric antigen receptor (CAR)-T cell therapy in patients with hematological malignancy.

OBJECTIVES: We aim to analyze the predictive value of thromboelastography on bleeding severity of patients with chimeric antigen receptor (CAR)-T cell therapy. METHODS: A total of 80 patients with refractory/relapsed hematological malignancy were enrolled and divided into two groups: the severe bleeding group and the non-severe bleeding group. The thromboelastography data was collected on the day of CAR-T infusion and the 3rd, 7th, 10th, 13th, 17th, and 20th day after CAR-T cell infusion. RESULTS: The patients of the severe bleeding group had lower platelet (p < .007), maximum amplitude (p = .002), coagulation index (p = .005), and longer coagulation time (p = .019). Increasing trend in reaction time and coagulation time and decreasing trend in Alpha, maximum amplitude, and coagulation index on Days 0-10, opposite on Days 10-20. Univariate logistic regression analysis and multivariable logistic regression analysis showed maximum amplitude on the 3rd day after CAR-T cell infusion (MA3) (OR = 0.9; 95% CI = 0.84-0.95; p < .001) and cytokine release syndrome grade (OR = 2.57; 95% CI = 1.35-5.32; p = .006) were significantly associated with high bleeding severity. CONCLUSIONS: Thromboelastography was considered to be a good predictor of bleeding severity.

Health-related quality of life in older hematological cancer survivors (70+) compared to older general population-A German cancer-register-based cross-sectional comparative study.

OBJECTIVES: The extent of health-related quality of life (HRQOL) impairments in older hematological cancer survivors (HCS) has not been sufficiently studied. We therefore examined HRQOL in older HCS compared to a community sample (CS) and investigated sociodemographic, disease- and treatment-specific, geriatric, and psychosocial factors associated with reduced HRQOL. MATERIALS AND METHODS: In this cancer-register-based cross-sectional comparative study 200 HCS, aged ≥70 years, and 252 persons of an age- and gender-matched CS completed validated questionnaires including the EORTC QLQ-C30 and EORTC QLQ-ELD14. RESULTS: Older HCS reported a reduced HRQOL in the dimensions of global QOL, physical, role, and social functioning (small clinical significance) and higher symptom burden of fatigue, nausea and vomiting, appetite loss, and poorer mobility compared to the CS (fatigue and mobility with medium, the others with small clinical significance). Perceived disease burden of comorbidities, functional disabilities, psychological distress, and depression showed statistical significance for reduced HRQOL in older HCS in multiple linear regression analysis (R2 = .602, p < .001). DISCUSSION: The screening and treatment of functional limitations and individual symptoms and the integration of a geriatric assessment into oncological practice can help to identify supportive care needs, to implement individualized, patient-centered cancer survivorship care programs and to improve older HCS's HRQOL.

Relevance, Risks, and Benefits of Early-Phases Clinical Trials Participations for Patients With Hematological Malignancies From 2008 to 2023.

BACKGROUND: Early-phases clinical trials (Phases 1 and 2) have evolved from a traditional assessment of toxicity to an adaptive approach based on patients' medical needs and access to effective new therapies. The global risks, benefits, and relevance of early-phases clinical trials participation for patients with hematological malignancies remain poorly evaluated. PATIENTS AND METHODS: All early-phases clinical trials participations for patients with hematological malignancies, from 2008 to 2023, in a tertiary academic center in Europe, were reviewed. Patient's demographics, tumor type categories, therapeutic responses, mortality, overall survival (OS), and investigational product (IP) were assessed. RESULTS: Over the period 2008-2023, 736 patients participating in 92 different early-phases clinical trials, were analyzed. The most common tumor categories were diffuse large B-cell lymphoma (n = 253; 34.4%), acute myeloid leukemia/myelodysplastic syndrome (n = 164; 22.3%) and multiple myeloma (n = 100; 13.6%). The median OS was 14.8 (95% CI: 12.4-17.9) months and response rate 31.9%, including complete responses in 13.5% of patients. By tumor categories, the highest and lowest median duration of OS were observed for patients with Hodgkin lymphoma (99.8; [95% CI: 47.0-not reached] months) and peripheral T-cell lymphoma (8.9 [95% CI: 5.3-12.0] months), respectively. The on-protocol and treatment-related mortality rates were 5.43% and 0.54%, respectively. Overall response rate was 29.1% including 13.5% of complete response. Overall, 202 (27.5%) patients received an IP later approved by the health authorities, and those patients had better OS (18.2 months vs. 12.1 months HR: 1.160 [95% CI; 0.6977-1.391], p = 0.0283). CONCLUSION: In conclusion, patients with hematologic malignancies who have participated in early-phases clinical trials over the past 15 years have achieved variable therapeutic response rates, acceptable risk/benefit ratio and potentially significant therapeutic advantages. This study provides framework material for hematologists to further discuss clinical trial participation with their patients.

Microbiological risk factors, ICU survival, and 1-year survival in hematological patients with pneumonia requiring invasive mechanical ventilation.

PURPOSE: To identify pathogenic microorganisms and microbiological risk factors causing high morbidity and mortality in immunocompromised patients requiring invasive mechanical ventilation due to pneumonia. METHODS: A retrospective single-center study was performed at the intensive care unit (ICU) of the Department of Internal Medicine at Heidelberg University Hospital (Germany) including 246 consecutive patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia from 08/2004 to 07/2016. Microbiological and radiological data were collected and statistically analyzed for risk factors for ICU and 1-year mortality. RESULTS: ICU and 1-year mortality were 63.0% (155/246) and 81.0% (196/242), respectively. Pneumonia causing pathogens were identified in 143 (58.1%) patients, multimicrobial infections were present in 51 (20.7%) patients. Fungal, bacterial and viral pathogens were detected in 89 (36.2%), 55 (22.4%) and 41 (16.7%) patients, respectively. Human herpesviruses were concomitantly reactivated in 85 (34.6%) patients. As significant microbiological risk factors for ICU mortality probable invasive Aspergillus disease with positive serum-Galactomannan (odds ratio 3.1 (1.2-8.0), p = 0.021,) and pulmonary Cytomegalovirus reactivation at intubation (odds ratio 5.3 (1.1-26.8), p = 0.043,) were identified. 1-year mortality was not significantly associated with type of infection. Of interest, 19 patients had infections with various respiratory viruses and Aspergillus spp. superinfections and experienced high ICU and 1-year mortality of 78.9% (15/19) and 89.5% (17/19), respectively. CONCLUSIONS: Patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia showed high ICU and 1-year mortality. Pulmonary Aspergillosis and pulmonary reactivation of Cytomegalovirus at intubation were significantly associated with negative outcome.