Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological malignancies. The preclinical pharmacokinetics (PK) of amdizalisib were extensively characterized in vitro and in vivo to support the further development of amdizalisib. We characterized the plasma protein binding, blood-to-plasma partition ratio, cell permeability, hepatic microsomal metabolic stability, and drug-drug interaction potential of amdizalisib using in vitro experiments. In vivo PK assessment was undertaken in mice, rats, dogs, and monkeys following a single intravenous or oral administration of amdizalisib. The tissue distribution and excretion of amdizalisib were evaluated in rats. The PK parameters (CL and Vss) of amdizalisib in preclinical species (mice, rats, dogs, and monkeys) were utilized for the human PK projection using the allometric scaling (AS) approach. Amdizalisib was well absorbed and showed low-to-moderate clearance in mice, rats, dogs, and monkeys. It had high cell permeability without P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate liability. Plasma protein binding of amdizalisib was high (approximately 90%). It was extensively distributed but with a low brain-to-plasma exposure ratio in rats. Amdizalisib was extensively metabolized in vivo, and the recovery rate of the prototype drug was low in the excreta. Amdizalisib and/or its metabolites were primarily excreted via the bile and urine in rats. Amdizalisib showed inhibition potential on P-gp but not on BCRP and was observed to inhibit CYP2C8 and CYP2C9 with IC50 values of 30.4 and 10.7 μM, respectively. It exhibited induction potential on CYP1A2, CYP2B6, CYP3A4, and CYP2C9. The preclinical data from these ADME studies demonstrate a favorable pharmacokinetic profile for amdizalisib, which is expected to support the future clinical development of amdizalisib as a promising anti-cancer agent.

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UNASSIGNED: Patients with hematological malignancies (HM) have a high risk of severe coronavirus disease 2019 (COVID-19), also in the Omicron period.
UNASSIGNED: Retrospective single-center study including HM patients with severe acute respiratory syndrome Coronavirus 2 (SARS-CoV2) infection from January 2022 to March 2023. Study outcomes were respiratory failure (RF), mechanical ventilation (MV), and COVID-related mortality, comparing patients according to SARS-CoV2 serology.
UNASSIGNED: Note that, 112 patients were included: 39% had negative SARS-CoV2 serology. Seronegative were older (71.5 vs. 65.0 years, p = 0.04), had more often a lymphoid neoplasm (88.6% vs. 69.1%, p = 0.02), underwent anti-CD20 therapy (50.0% vs. 30.9% p = 0.04) and had more frequently a severe disease (23.0% vs. 3.0%, p = 0.02) than seropositive.Kaplan-Meier showed a higher risk for seronegative patients for RF (p = 0.014), MV (p = 0.044), and COVID-related mortality (p = 0.021). Negative SARS-CoV2 serostatus resulted in a risk factor for RF (hazards ratio [HR] 2.19, 95% confidence interval [CI] 1.03-4.67, p = 0.04), MV (HR 3.37, 95% CI 1.06-10.68, p = 0.04), and COVID-related mortality (HR 4.26, 95% CI 1.09-16.71, p = 0.04).
UNASSIGNED: : HM patients with negative SARS-CoV2 serology, despite vaccinations and previous infections, have worse clinical outcomes compared to seropositive patients in the Omicron era. The use of serology for SARS-CoV2 diagnosis could be an easy tool to identify patients prone to developing complications.

Immunotherapy for hematological malignancies is a rapidly advancing field that has gained momentum in recent years, primarily encompassing chimeric antigen receptor T-cell (CAR-T) therapies, immune checkpoint inhibitors, and other modalities. However, its clinical efficacy remains limited, and drug resistance poses a significant challenge. Therefore, novel immunotherapeutic targets and agents need to be identified. Recently, N6-methyladenosine (m6A), the most prevalent RNA epitope modification, has emerged as a pivotal factor in various malignancies. Reportedly, m6A mutations influence the immunological microenvironment of hematological malignancies, leading to immune evasion and compromising the anti-tumor immune response in hematological malignancies. In this review, we comprehensively summarize the roles of the currently identified m6A modifications in various hematological malignancies, with a particular focus on their impact on the immune microenvironment. Additionally, we provide an overview of the research progress made in developing m6A-targeted drugs for hematological tumor therapy, to offer novel clinical insights.

Chimeric antigen receptor (CAR) therapy is one of the most unprecedented advancements in the treatment of hematological malignancies, especially B-cell malignancies. The fundamental notion behind the success of this therapy is to generate a synthetic protein (CAR) capable of redirecting T lymphocytes to act against cancer cells. New insights into the genetic and molecular base of hematological malignancies have more recently given rise to the development of targeted treatments. CAR T-cell therapy is one of these immunological treatment techniques that has recently received a lot of attention and paved a light of hope for the effective cure of relapsed and refractory hematological malignancies and some solid malignancies. Researchers of today might not know what the future holds for CAR T-cell therapy, but from whatever research has been done so far, this therapy has proven to be a success despite its limitations, and it can be assumed that the spectrum of its application is expanding with each passing day.

Bloodstream infections caused by multidrug-resistant organisms such as Klebsiella pneumoniae are a significant challenge in managing hematological malignancies. This study aims to characterize the epidemiology of Klebsiella pneumoniae bloodstream infections specifically in patients with hematological malignancies, delineate the patterns of initial antibiotic therapy, assess the prevalence of resistant strains, identify risk factors for these resistant strains, and evaluate factors influencing patient outcomes. A retrospective analysis was conducted at a single center from January 2017 to December 2020, focusing on 182 patients with hematological malignancies who developed Klebsiella pneumoniae bloodstream infections. We compared the 30-day mortality rates between patients receiving appropriate and inappropriate antibiotic treatments, including the effectiveness of both single-drug and combination therapies. Kaplan-Meier survival analysis and multivariate logistic and Cox regression were used to identify factors influencing mortality risk. The 30-day all-cause mortality rate was 30.2% for all patients. The 30-day all-cause mortality rates were 77.2% and 8.8% in patients who received inappropriate initial treatment and appropriate initial treatment (p < 0.001). Inappropriate initial treatment significantly influenced mortality and was a key predictor of 30-day mortality, along with septic shock and previous intensive care unit (ICU) stays. Patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections exhibited more severe clinical symptoms compared to the CSKP group. The study demonstrates a significant association between empirical carbapenem administration and the escalating prevalence of CRKP and multidrug-resistant K. pneumoniae (MDR-KP) infections. Furthermore, the study identified inappropriate initial antibiotic therapy, septic shock, and ICU admission as independent risk factors for 30-day mortality.

Patients with hematologic malignancies (HMs) are at a significantly higher risk of contracting COVID-19 and experiencing severe outcomes compared to individuals without HMs. This heightened risk is influenced by various factors, including the underlying malignancy, immunosuppressive treatments, and patient-related factors. Notably, immunosuppressive regimens commonly used for HM treatment can lead to the depletion of B cells and T cells, which is associated with increased COVID-19-related complications and mortality in these patients. As the pandemic transitions into an endemic state, it remains crucial to acknowledge and address the ongoing risk for individuals with HMs. In this review, we aim to summarize the current evidence to enhance our understanding of the impact of HMs on COVID-19 risks and outcomes, identify particularly vulnerable individuals, and emphasize the need for specialized clinical attention and management. Furthermore, the impaired immune response to COVID-19 vaccination observed in these patients underscores the importance of implementing additional mitigation strategies. This may include targeted prophylaxis and treatment with antivirals and monoclonal antibodies as indicated. To provide practical guidance and considerations, we present two illustrative cases to highlight the real-life challenges faced by physicians caring for patients with HMs, emphasizing the need for individualized management based on disease severity, type, and the unique circumstances of each patient.

Introduction: FLT3 mutations are closely associated with the occurrence of hematological and solid malignancies, especially with acute myeloid leukemia. Currently, several FLT3 inhibitors are in clinical trials, and some have been applied in clinic. However, the safety, efficacy and pharmacodynamics of these FLT3 inhibitors have not been systemically analyzed before. Methods: We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023. Results: Our results showed the most common adverse events (AEs) were gastrointestinal adverse reactions, including diarrhea, hand-foot syndrome and nausea, while the most common hematological AEs were febrile neutropenia, anemia, and thrombocytopenia. Based on the published data, the mean overall survival (OS) and the mean progression-free survival (PFS) were 9.639 and 5.905 months, respectively. The incidence of overall response rate (ORR), complete remission (CR), partial response (PR), and stable disease (SD) for all these FLT3 inhibitors was 29.0%, 8.7%, 16.0%, and 42.3%, respectively. The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h. Discussion: FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.

Prussian blue nanoparticle-based photothermal therapy (PBNP-PTT) is an effective tumor treatment capable of eliciting an antitumor immune response. Motivated by the ability of PBNP-PTT to potentiate endogenous immune responses, we recently demonstrated that PBNP-PTT could be used ex vivo to generate tumor-specific T cells against glioblastoma (GBM) cell lines as an adoptive T cell therapy (ATCT). In this study, we further developed this promising T cell development platform. First, we assessed the phenotype and function of T cells generated using PBNP-PTT. We observed that PBNP-PTT facilitated CD8+ T cell expansion from healthy donor PBMCs that secreted IFNγ and TNFα and upregulated CD107a in response to engagement with target U87 cells, suggesting specific antitumor T cell activation and degranulation. Further, CD8+ effector and effector memory T cell populations significantly expanded after co-culture with U87 cells, consistent with tumor-specific effector responses. In orthotopically implanted U87 GBM tumors in vivo, PBNP-PTT-derived T cells effectively reduced U87 tumor growth and generated long-term survival in >80% of tumor-bearing mice by Day 100, compared to 0% of mice treated with PBS, non-specific T cells, or T cells expanded from lysed U87 cells, demonstrating an enhanced antitumor efficacy of this ATCT platform. Finally, we tested the generalizability of our approach by generating T cells targeting medulloblastoma (D556), breast cancer (MDA-MB-231), neuroblastoma (SH-SY5Y), and acute monocytic leukemia (THP-1) cell lines. The resulting T cells secreted IFNγ and exerted increased tumor-specific cytolytic function relative to controls, demonstrating the versatility of PBNP-PTT in generating tumor-specific T cells for ATCT.

Hematological malignancies (HMs) encompass a diverse group of blood neoplasms with significant morbidity and mortality. Immunotherapy has emerged as a validated and crucial treatment modality for patients with HMs. Despite notable advancements having been made in understanding and implementing immunotherapy for HMs over the past decade, several challenges persist. These challenges include immune-related adverse effects, the precise biodistribution and elimination of therapeutic antigens in vivo, immune tolerance of tumors, and immune evasion by tumor cells within the tumor microenvironment (TME). Nanotechnology, with its capacity to manipulate material properties at the nanometer scale, has the potential to tackle these obstacles and revolutionize treatment outcomes by improving various aspects such as drug targeting and stability. The convergence of nanotechnology and immunotherapy has given rise to nano-immunotherapy, a specialized branch of anti-tumor therapy. Nanotechnology has found applications in chimeric antigen receptor T cell (CAR-T) therapy, cancer vaccines, immune checkpoint inhibitors, and other immunotherapeutic strategies for HMs. In this review, we delineate recent developments and discuss current challenges in the field of nano-immunotherapy for HMs, offering novel insights into the potential of nanotechnology-based therapeutic approaches for these diseases.