Types Of Hematological Malignancies Research Articles

Dynamic Single-Cell RNA-Seq reveals mechanism of Selinexor-Resistance in Chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a type of hematologic malignancies caused by BCR-ABL chimeric oncogene. Resistance to tyrosine kinase inhibitors (TKIs) leads to the progression of CML into advanced stages. Selinexor is a small molecule inhibitor that targets a nuclear transporter called Exportin 1. Combined with imatinib, selinexor has been shown to disrupt nuclear-cytoplasmic transport signal of leukemia stem cells, resulting in cell death. The objective of this study was to investigate the mechanism of drug resistance to selinexor in CML. We established K562 cell line resistant to selinexor and conducted single cell dynamic transcriptome sequencing to analyze the heterogeneity within the parental and selinexor resistant cell populations. We identified specific gene expression changes associated with resistance to selinexor. Our results revealed differential expression patterns in genes such as MT2A, TFPI, MTND3, and HMGCS1 in the total RNA, as well as MT-TW, DNAJB1, and HSPB1 in the newly synthesized RNA, between the parental and drug-resistant groups. By applying pseudo-time analysis, we discovered that a specific cluster of cells exhibited characteristics of tumor stem cells. Furthermore, we observed a gradual decrease in the expression of ferroptosis-related molecules as drug resistance developed. In vitro experiments confirmed that the combination of a ferroptosis inducer called RSL3 effectively overcame drug resistance. In conclusion, this study revealed the resistance mechanism of selinexor in CML. In conclusion, we identified a subgroup of CML cells with tumor stem cell properties and demonstrated that ferroptosis inducer improved the efficacy of selinexor in overcoming drug resistance.

Long-term risks of cardiovascular death among older patients with major hematological malignancies: a population-based cohort study from SEER database.

The objective of this study was to identify the risk of cardiovascular disease (CVD)-related death in older patients with major hematological malignancies (HM). This study included 103,102 older patients diagnosed with 7 major types of HM between 1975 and 2018 (median follow-up: 2.7 years) from the Surveillance, Epidemiology, and End Result (SEER) database. The proportion of deaths, Fine-Gray sub-distribution hazards regression model, standardized mortality ratios (SMR) and absolute excess risk (AER) were used to evaluate the risk of CVD-related death. For older patients with HM, CVD-related death ranked as the second leading cause of death, surpassed only by primary malignancy. Compared to the general older population, older patients with HM had higher SMR and AER of CVD-related deaths (SMR: 1.16-1.81; AER: 41.24-308.99), heart disease-related deaths (SMR: 1.19-1.90; AER: 39.23-274.69), and cerebrovascular dis-ease-related deaths (SMR: 0.99-1.66; AER: -0.35 -24.15). The proportion of deaths and cumulative mortality increased with the passage of survival time, especially in Hodgkin lymphoma patients with stage I/II and those aged ≥85 years with chronic lymphocytic leukemia, surpassing primary malignancy. The risk of CVD-related death varied among different HM types. For older patients with HM, long-term cardiovascular risk management needs to be focused on while addressing the primary malignancy. Our results emphasize the need to manage long-term cardiovascular risk in older patients with HM, especially in those identified as high-risk cases.

Autophagy and oxidative stress modulation mediate Bortezomib resistance in prostate cancer.

Proteasome inhibitors such as Bortezomib represent an established type of targeted treatment for several types of hematological malignancies, including multiple myeloma, Waldenstrom's macroglobulinemia, and mantle cell lymphoma, based on the cancer cell's susceptibility to impairment of the proteasome-ubiquitin system. However, a major problem limiting their efficacy is the emergence of resistance. Their application to solid tumors is currently being studied, while simultaneously, a wide spectrum of hematological cancers, such as Myelodysplastic Syndromes show minimal or no response to Bortezomib treatment. In this study, we utilize the prostate cancer cell line DU-145 to establish a model of Bortezomib resistance, studying the underlying mechanisms. Evaluating the resulting resistant cell line, we observed restoration of proteasome chymotrypsin-like activity, regardless of drug presence, an induction of pro-survival pathways, and the substitution of the Ubiquitin-Proteasome System role in proteostasis by induction of autophagy. Finally, an estimation of the oxidative condition of the cells indicated that the resistant clones reduce the generation of reactive oxygen species induced by Bortezomib to levels even lower than those induced in non-resistant cells. Our findings highlight the role of autophagy and oxidative stress regulation in Bortezomib resistance and elucidate key proteins of signaling pathways as potential pharmaceutical targets, which could increase the efficiency of proteasome-targeting therapies, thus expanding the group of molecular targets for neoplastic disorders.

The potential use of recombinant immunotoxin and BCL-2 inhibitors for leukemic stem cell elimination

Leukemia is a type of hematological malignancy caused by the dysfunctional proliferation of leukocyte cells. According to the Global Burden of Disease 2019 report, there were over 643,579 new cases of leukemia cancer worldwide in 2020, killing 334,592 people. Chemotherapy, an important part of the treatment of leukemia, not only harm cancer cells but also harm healthy cells, which can lead to negative side effects. This article examines the possibility for cutting-edge therapy using targeted recombinant immunotoxins and BCL-2 inhibitors as targeted therapy against leukemic stem cells. Recombinant immunotoxin is a protein-based therapeutic agent composed of toxins combined with specific antibodies or other molecules such as growth factors, cytokines, or toxins. Diphtheria Toxin (DT) is the most commonly used toxin because it is easily expressed, making the toxin easier to take. The toxin kills cancer cells by inhibiting enzymatic cell protein synthesis. While immunotoxins enhance therapeutic outcomes by targeting leukemia stem cells, their efficacy can be compromised in certain patients due to apoptosis resistance mediated by proteins like BCL-2. The presence of anti-apoptotic protein BCL-2 enables cell survival even after exposure to immunotoxins. Consequently, combining recombinant immunotoxins and BCL-2 inhibitors holds promise for eradicating LSC and preventing relapse.

Impact of SARS-CoV-2 infection on patients with hematological malignancies: a retrospective study

ABSTRACTObjectivesThis study aimed to evaluate the characteristics of patients with hematological malignancies (HM) and SARS-CoV-2 infection and analyze the risk factors of their severity and mortality.MethodsA retrospective study including inpatients diagnosed HM and SARS-CoV-2 infection between December 2022 and February 2023 were conducted. Demographic information, medical history, comorbidities, diagnosis, treatment related information and outcomes were extracted from electronic medical database. The primary outcome of this study were the severity of SARS-CoV-2 infection and case-fatality rate. The clinical characteristic and outcomes of the patients were summarized and analyzed.ResultsA total of 74 patients with HM and SARS-CoV-2 infection were included. Out of the total cases, 85.1% (63) had a mild /moderate SARS-CoV-2 infection, and 14.9% (11) were severe/ critical infection cases. A total of 8 deaths occurred in all cases for a case-fatality rate of 10.8%. Multivariate analysis identified patients with acute myeloid leukemia (AML) (P = 0.043, OR:5.274, 95%CI:1.053-26.407), primary hematological disease in active state (P = 0.005, OR:13.905, 95%CI:2.180-88.704) were independent risk factors for the severity of SARS-CoV-2 infection and patients with AML had 11.145-fold higher risk of non-survival (P = 0.020, OR:11.145, 95%CI:1.460-85.103) in comparison to the patients with other types of HM. There were no significant differences in the severity and case-fatality rate (P > 0.05) between the patients receiving chemotherapy drugs administration waiting <14 days and ≥14 days after negative SARS-CoV-2 testing.ConclusionThe primary hematological disease in active state may be the main risk factor for negative outcome of the patents. Waiting 14 days for chemotherapy initiation after negative SARS-CoV-2 testing is unnecessary.

Racial/Ethnic Disparity for Hematologic Malignancies in Different Healthcare Systems in the U.S

Introduction: Various studies have shown that Black and certain minority patients with hematologic malignancies have worse survival outcomes than White patients in the United States. In the current study, we compared the survival outcomes of Non-Hispanic Black (NHB), Hispanic, and NH Asian/Pacific Islander (API) to Non-Hispanic White (NHW) across different types of hematologic malignancies in multiple different healthcare settings. Methods: We identified adult patients with newly diagnosed lymphoma, myeloma, or leukemia from 2011-2020 in Surveillance, Epidemiology, and End Results Program (SEER), as well as respective cancer registries linked to electronic data warehouses at Veterans Affairs (VA) national healthcare system and Harris Health System (HHS). VA is a unique single-payer system with patients covered by veteran benefits. HHS is a large safety-net county hospital system in the Houston metropolitan area with &amp;gt;80% of uninsured and charity care. These hospital systems were chosen to represent opposite ends of the spectrum of healthcare access; however, we explicitly chose not to compare survival outcomes across institutions due to inherent differences. For each patient cohort, we built unadjusted and adjusted multivariable Cox regression models to assess the impact of race/ethnicity on overall survival. The adjusted factors included age, sex, marital status, rurality, median household income, diagnosis year, cancer histologic subtype, and cancer stage (for lymphoma). Type and time to treatment were not included as these were associated with access to care. In a sensitivity analysis, we also included NCI comorbidity index and ECOG performance status (PS) in VA and HHS (not available in SEER). Results: Patient characteristics from the 3 cohorts are shown in Table 1. SEER patients (n=339,351) were more representative of the US census (71% NHW, 14% Hispanic, 8% NHB, 7% API). In contrast, VA patients (n=27,388) were mostly male (97%) with lower median income ($45,000) and with more NHB (16%); HHS patients (n=2,141) were notably younger (median 53) with lower median income ($47,409) and more Hispanic (57%) and NHB (25%). On unadjusted analysis, significant variables associated with mortality in all cohorts included older age, male sex, lower income, aggressive histology, advanced stage, higher PS, and more comorbidities. Race/ethnicity had variable association with mortality depending on the healthcare setting. On multivariable analysis adjusted for other confounders (Figure 1), race/ethnicity continued to exhibit variable association with overall mortality depending on cancer type and healthcare setting. Across all cancers, minority groups had similar or worse adjusted survivals than NHW in SEER, while they had similar or better adjusted survivals than NHW in VA. With exception of NHB vs. NHW in lymphoma, minority groups had no significant differences than NHW in HHS. Since both VA and HHS were enriched with NHB patients, we next focused on the comparison between NHB vs. NHW. For lymphoma, the adjusted hazard ratio (HR) for mortality was 1.41 (95% CI 1.36-1.45), 1.47 (95% CI 1.04-2.07), and 0.96 (95% CI 0.88-1.04) in SEER, HHS, and VA, respectively. For leukemia, the adjusted HR was 1.07 (95% CI 1.04-1.11), 1.07 (95% CI 0.65-1.75), and 0.95 (95% CI 0.87-1.03) in SEER, HHS, and VA, respectively. For myeloma, the adjusted HR was 0.99 (95% CI 0.95-1.03), 1.00 (95% CI 0.52-1.93), and 0.88 (95% CI 0.80-0.96) in SEER, HHS, and VA, respectively. The other minority groups followed a similar trend. In the sensitivity analysis where ECOG PS and NCI comorbidity index were included for HHS and VA, the overall observations by race/ethnicity were not significantly different. In additional subgroup analyses limited to older patients or males, the overall finding was also not different. Conclusions: In summary, racial/ethnic disparity persists at-large in the US (SEER) for most hematologic malignancies, even after accounting for cancer-, patient-, and socioeconomic factors. However, minority status has neutral or protective effect vs. NHW in healthcare system without barrier to access (VA), while its impact appears similar to the national trend in healthcare system with significant barriers to access due to the lack of insurance (HHS). Healthcare access may contribute to the ongoing racial/ethnic disparity for survival outcomes observed in hematologic malignancies in the US.

Risk of Severe Sars-Cov-2 Infections in COVID-19 Vaccinated Individuals with Hematologic Malignancies (SAVE HEM): A Nationwide Cohort Study in the Netherlands

Introduction COVID-19 vaccination protects against a severe course of COVID-19. Nevertheless, individuals with hematologic malignancies (HM) remain at increased risk of COVID-19-related morbidity and mortality compared to the general population. However, these relative risks are unknown for individuals with specific hematologic cancers and treatments. We aimed to quantify the risk of severe COVID-19 among individuals with HM who had completed primary COVID-19 vaccination (i.e., two-dose generally, but three-dose in patients with a malignancy history). Therefore, we compared COVID-19 outcomes to those in individuals with no malignancy (NM) and individuals with solid malignancies (SM) who had completed primary COVID-19 vaccination. Thanks to unique centrally registered data on cancer care (Netherlands Cancer Registry, NCR), we were able to stratify risk for different hematologic malignancies. Methods We conducted a nationwide cohort study including all inhabitants of the Netherlands registered in the Personal Records Database on January 1, 2020, (n = 17 407 585) through linkage of data on cancer care, COVID-19 vaccination, SARS-CoV-2 testing, COVID-19-related hospitalization, and mortality. We used data from January 1, 2010, to December 31, 2022. We included individuals who completed primary COVID-19 vaccination at age 18 years or older and were SARS-CoV-2-infected more than two weeks later. Severe disease was defined as a SARS-CoV-2 infection resulting in hospital admission or death. We fitted generalized estimating equations and calculated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the associations between an HM history and severe COVID-19, relative to a history with NM and SM. In addition, we calculated aORs for associations between malignancy history and COVID-19-related hospital admission, ICU admission, and mortality. Odds ratios were adjusted for age and sex as potential confounders. We conducted stratified analyses by type of hematologic malignancy and incidence period of SARS-CoV-2 infection. For technical reasons, we calculated aORs using a random sample of 350 000 SARS-CoV-2-infected individuals from the NM group. Results We included 8 210 individuals with HM, 350 000 individuals with NM, and 37 752 individuals with SM. We observed 8 552, 364 530, and 38 432 SARS-CoV-2 infections in individuals with HM, NM, and SM, respectively. Severe COVID-19 was recorded in 817, 2 834 and 1 412 cases, respectively. Individuals with HM were at higher risk of severe COVID-19 compared to individuals with NM and SM (aOR [95% CI] for HM vs. NM 4.6 [4.2-5.0]; for HM vs. SM 3.3 [3.0-3.7]) (Figure 1). Patients with HM were at increased risk for COVID-19-related hospitalization (aOR [95% CI] for HM vs. NM 4.6 [4.3-5.1]; for HM vs. SM 3.4 [3.1-3.7]), for COVID-19-related ICU admission (aOR [95% CI] for HM vs. NM 6.5 [5.0-8.4]; for HM vs. SM 6.3 [4.6-8.6]), and for COVID-19-related mortality (aOR [95% CI] for HM vs. NM 1.7 [0.9-3.0]; for HM vs. SM 1.9 [1.0-3.7]). Within the group of HM, those with a diagnosis of acute lymphatic leukemia/lymphoblastic lymphoma or acute myeloid leukemia were at the highest risk of severe COVID-19 compared to individuals with NM, while those with myeloproliferative malignancies or cutaneous lymphomas had the lowest risk (Figure 1). Stratified analyses by incidence period of SARS-CoV-2 infection demonstrated that the aORs for severe COVID-19 remained increased over time, comparing individuals with HM to those with NM. Adjustments for other confounders, such as socio-economic status, and stratified analyses by incidence year of malignancy, immunosuppressive treatment, and number of booster vaccinations are currently being performed. Conclusions Despite intensified COVID-19 vaccination, individuals with HM remain at increased risk for a severe course of COVID-19 compared to both individuals with NM and SM. However, the degree of vulnerability within the hematologic population depends on type of malignancy and this should be taken into account when offering additional booster vaccinations or scarce COVID-19 therapeutics, such as protease inhibitors or antibody-based therapy.

Chidamide-Based Pre-Emptive Treatment for High-Risk AML Patients after Hematopoietic Stem Cell Transplantation: A Real-World Experience from Chinese Single-Center

Background: The treatment of relapsed or refractory acute myeloid leukemia ( AML) remains challenging. Measurable residual disease (MRD) persistence at transplantation or post-transplantation has been identified as the strongest risk factor for relapse and poor outcomes for patients with hematological malignancies (HMs). Chidamide, a novel oral histone deacetylase inhibitor, has shown potential therapeutic effects in various types of HMs by inducing cell apoptosis and regulating immunity. This study aimed to evaluate the efficacy and safety of Chidamide-based prophylactic or pre-emptive treatment for patients who are MRD positive before or who have sustained MRD positive after transplantation. Aim: The rate of 6 months of conversion to MRD- and relapse-free survival of high-risk AML after Chidamide-based treatment. Methods: From December 2020 to July 2023, 50 patients with high-risk HMs received chidamide-based therapy after allo-HSCT. 39 patients were diagnosed with AML ( 4 secondary AML), 2 with myelodysplastic syndromes, 6 with acute lymphoid leukemia, and 3 with mixed-phenotype acute leukemia. 46 patients (92%) with relapsed/refractory status or detectable MRD (MRD+) at transplantation or after allo-HSCT received chidamide as pre-emptive, and the remaining 4 high-risk patients with MRD− conducted as prophylactic intervention. Patients with detectable MRD before transplantation and those who remained positive for MRD after transplantation were defined as very high-risk AML (VHR-AML). Chidamide was administered at a dose of 5 mg per day orally, 6 times per week, lasting at least 1 year after engraftment. Additional agents included hypomethylating agents (HMAs), donor lymphocyte infusion (DLI) or tyrosine kinase inhibitor (TKI) in patients with Philadelphia chromosome-positive. In this study, 28 patients received chidamide monotherapy, 13 received chidamide combined with HMAs, and 9 cases with other therapy. Results: The median age of all patients was 38 years old (range 17-67), comprising 24 males and 26 females. Up to 1st July 2023, with a median follow-up period of 376 days (25-984d), the overall rate of MRD negative showed 64%. The rate of MRD- survival, Relapse-free survival (RFS) and overall survival (OS) were 56%, 66% and 76%, respectively. The 6 months MRD negative rate, RFS and OS rate were 86%, 82%, 86% and 88%, which maintained at 82%, 82% and 86% with 12 months follow-up, respectively. In 46 cases of the pre-emptive intervention arm, the overall MRD- rate was 61.7%. Among them, 83.3% of patients (20/24) who received chidamide monotherapy exhibited a much higher conversion to MRD− than those combined with HMAs (7/13, 53.8%) or other drugs (2/9, 22.2%) (P=0.004). In 4 cases who received chidamide monotherapy as prophylactic intervention, 3 patients sustained MRD negativity up to the last follow-up, except for one patient diagnosed with MPAL(B+M) relapsed after 1 year of HSCT with taking chidamide for 6 months. A total of 30 patients (including 25 AML) with VHR diseases remained in a status of MRD+ or non-remission after transplantation. Eighteen patients (60%) achieved MRD− and sustained for a median of 251 days (range 31-531 d). VHR-AML patients account for 94.4% (17/18) of MRD- responders(Figure 1A). Similarly, the results showed a higher rate of conversion from MRD+ to MRD− in chidamide monotherapy than the combination groups (Chidamide monotherapy, 81.8%; Chidamide + HMA, 63.6% and Chidamide + others, 25%, P=0.042,Figure 1B). It highlighted that treatment with chidamide resulted in increased MRD− response, especially for AML. On the contrary, of 7 patients with B-cell malignancy, including 5 B-ALL and 2 MPAL (B + M) patients, only 2 (28.6%) patients converted to MRD−. Reversible grade 3/4 neutropenia occurred in 38% of patients, and thrombocytopenia was observed in 24% during the first four treatment cycles. Five patients experienced grade 1/2 non-hematological adverse events, such as fatigue, gastrointestinal reaction, pneumonia and infection. No new-onset GvHD was reported in patients without a prior history of GvHD during chidamide treatment. Conclusion: The chidamide-based regimen is safe and effective in pre-emptive treatment for patients with high-risk relapsed AML after transplantation. Whether as a monotherapy or combined with HMA, chidamide shows significant efficacy in eliminating MRD, warranting further clinical research.

Conformationally constrained potent inhibitors for enhancer of zeste homolog 2 (EZH2)

The enhancer of zeste homolog 2 (EZH2) plays the role of the main catalytic subunit of polycomb repressive complex 2 (PRC2) that catalyzes the methylation of histone H3 lysine 27 (H3K27). Overexpression or mutation of EZH2 has been observed in many types of hematologic malignancies and solid tumors, such as myeloma, lymphoma, prostate, breast, kidney, and lung cancers. EZH2 has been demonstrated as a promising therapeutic target for the treatment of tumors. Based on the structure of 1 (EPZ-6438), a series of novel conformationally constrained derivatives were designed and synthesized aiming to improve the EZH2 inhibition activity, especially for mutated EZH2. Structure and activity relationship (SAR) exploration and optimization at both enzymatic and cellular levels led to the discovery of 28. In vitro, 28 displayed potent EZH2 inhibition activity with an IC50 value of 0.95 nM, which is comparable to EPZ-6438 (1). 28 exhibited high anti-proliferation activity against different lymphoma cell lines including WSU-DLCL2, Pfeiffer and Karpas-422 (IC50 = 2.36, 1.73, and 1.82 nM, respectively). In vivo, 28 showed acceptable pharmacokinetic characteristics (oral bioavailability F = 36.9%) and better efficacy than 1 in both Pfeiffer and Karpas-422 xenograft mouse models, suggesting that it can be further developed as a potential therapeutic candidate for EZH2-associated cancers.

Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells.

Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off-target side effects. Prodrug design has shown promise as an approach to improve pharmacokinetic properties and to improve target tissue specificity. In this work, several bioreductive prodrugs for class I HDACs were designed based on known selective HDAC inhibitors. The zinc-binding group of the HDAC inhibitors was masked with various nitroarylmethyl residues to make them substrates of nitroreductase (NTR). The developed prodrugs showed weak HDAC inhibitory activity compared to their parent inhibitors. The prodrugs were tested against wild-type and NTR-transfected THP1 cells. Cellular assays showed that both 2-nitroimidazole-based prodrugs 5 and 6 were best activated by the NTR and exhibited potent activity against NTR-THP1 cells. Compound 6 showed the highest cellular activity (GI50 = 77 nM) and exhibited moderate selectivity. Moreover, activation of prodrug 6 by NTR was confirmed by liquid chromatography-mass spectrometry analysis, which showed the release of the parent inhibitor after incubation with Escherichia coli NTR. Thus, compound 6 can be considered a novel prodrug selective for class I HDACs, which could be used as a good starting point for increasing selectivity and for further optimization.

Epidemiological Trends of Haematological Malignancies in Belgium 2004-2018: Older Patients Show the Greatest Improvement in Survival.

(1) Background: Haematological malignancies (HMs) represent a heterogeneous group of mostly rare cancers that differ in pathophysiology, incidence, and outcome. (2) Methods: Our study aims to understand the epidemiological situation and trends of 24 main types of HMs in Belgium over a 15-year period, with a focus on the impact of age. Age-standardised incidence, average annual percentage change (AAPC), 5- and 10-year relative survival (RS) and RS trends were estimated for all HMs (N = 94,415) diagnosed between 2004 and 2018. (3) Results: Incidence rates of HM increased, mainly in the 70+ age group (AAPC: 3%). RS varied by age and HM type. For each HM type, outcome decreased with age. The greatest decrease with age in 5-year RS is observed for aggressive HM, acute myeloid leukaemia (AML), acute lymphoblastic leukaemia, and Burkitt lymphoma, from 67%, 90%, and 97% below 20 years, to 2%, 12%, and 16% above 80 years of age, respectively. The moderate improvement in 5-year RS over the 2004-2018 period for all HMs, of +5 percentage point (pp), masks highly heterogenous outcomes by HM type and age group. The most impressive improvements are observed in the 80+ group: +45, +33, +28, and +16 pp for Hodgkin lymphoma, immunoproliferative disorders, follicular lymphoma, and chronic myeloid leukaemia, respectively. (4) Conclusions: The increasing incidence and survival over the 2004-2018 period are likely explained by diagnostic and therapeutic innovations, which have spread to populations not targeted by clinical trials, especially older adults. This real-world population-based study highlights entities that need significant improvement, such as AML.

Serological Responses and Predictive Factors of Booster COVID-19 Vaccines in Patients with Hematologic Malignancies.

Patients with hematologic malignancies are reported to have a more severe course of coronavirus disease 2019 (COVID-19) and be less responsive to vaccination. In this prospective study, we aimed to evaluate the serological responses to booster COVID-19 vaccines of Taiwanese patients with hematologic malignancies and identify potential predictive markers for effective neutralizing immunity. This study enrolled 68 patients with hematologic malignancies and 68 age- and gender-matched healthy control subjects who received three doses of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 1 January 2022 to 31 October 2022. The SARS-CoV-2 immunoglobulin G (IgG) spike antibody level was measured with the Abbott assay. The effective neutralization capacity was defined as an anti-spike IgG level of ≥4160 AU/mL. Among the 68 patients with hematologic malignancies, 89.7% achieved seroconversion after booster doses. Seven patients with actively treated lymphoma remained seronegative and had the lowest humoral responses among patients with different types of hematologic malignancies. Despite comparable antibody titers between patients and healthy individuals, rates of effective neutralization (66.2% vs. 86.8%, respectively; p = 0.005) were significantly reduced in patients with hematologic malignancies. In a multivariate analysis, the independent predictors for effective neutralization were a lack of B-cell-targeted agents within six months of vaccination (odds ratio, 15.2; 95% confidence interval, 2.7-84.2; p = 0.002) and higher immunoglobulin levels (odds ratio, 4.4; 95% confidence interval, 1.3-14.7; p = 0.017). In conclusion, the majority of patients with hematologic malignancies achieved seroconversion after booster vaccination. Patients with ongoing B-cell depletion and hypogammaglobinemia were identified as having negative predictive markers for effective neutralization.

Optical genome mapping for cytogenomic analysis of hematological neoplasms.

e19016 Background: Optical genome mapping (OGM) provides a genome-wide analysis for structural variants and copy number changes in one-assay. Compared with conventional G-banded karyotyping (GBK), OGM provides significantly higher resolution and does not require metaphase cells. In this study, we assessed the added value of OGM for cytogenomic analysis of hematological neoplasms. Methods: OGM was performed on blood or bone marrow using Saphyr from Bionano Genomics on 63 patients diagnosed with various types of hematological malignancy (see Table). Variant calling was made by the Rare Variant Analysis pipeline on Bionano Access after applying recommended filters. Each patient had karyotype and/or fluorescence in situ hybridization (FISH) results available for comparison and confirmation. Only Tier 1 (pathogenic) and Tier 2 (likely pathologic) abnormalities were included for comparison purposes in this study. Results: The results were completely concordant between GBK/FISH and OGM in 30 (47.6%) patients, including 10 patients who showed no cytogenetic abnormality (normal). Fully discordant results were found in 8 (12.7%) patients: 2 had an abnormal karyotype but normal OGM, the discrepancy was mainly due to the clonal size (&lt;20%) below the limitation of detection of OGM; 6 had a normal karyotype but cytogenetic abnormalities were detected by OGM, the discrepancy was mainly due to failure of tumor cells growth (n=5) or subtle cytogenetic abnormality undetectable by GBK (n=1). Partially concordant results between karyotype/FISH and OGM were observed in 25 (40%) patients, some abnormalities were detected by both, some were detected by GBK alone (n=4) or by OGM alone (n=25), the latter group included 10 cases with chromothripsis which only be detected by OGM. Overall, OGM provided clinically significant information in 14 (22%) patients regarding diagnosis, risk stratification, and/or identifying therapeutic targets. The added value was more common in lymphoid neoplasms (9 of 27 patients, 33%). Conclusions: OGM provides additional clinically relevant cytogenetic information in the workup of hematological neoplasms. This added value is more apparent in lymphoid neoplasms. These improvements are largely contributable to the higher resolution provided by OGM and analysis independent of metaphase cells. A major limitation of OGM usage is the need for a clonal size of at least 20%. [Table: see text]

Estimating the prevalence of pediatric hematological malignancies in Al-Madinah Al-Munawwarah, Saudi Arabia.

To provide an updated estimate to the prevalence of pediatric hematological malignancies (HMs) in the Al-Madinah Al-Munawwara, Saudi Arabia. This is a retrospective study that was carried out between 2016 and 2022. The study population was comprised of 171 children under 16 who had been diagnosed with HMs. The data was compiled from King Salman Medical City's Maternity and Children's Hospital, Al-Madinah Al-Munawwarah, Saudi Arabia. Among the 171 HM patients (64% males and 36% females), 13 subtypes were identified, with B-cell acute lymphoblastic leukemia having the highest incidence (70.3%). Acute myelomonocytic leukemia (8.7%), T-cell acute lymphoblastic leukemia (4.7%), and acute promyelocytic leukemia (3.5%) were the next most common types of HMs. Other rare cases were also found. Prevalence rate can be utilized to monitor the progression of disease incidence. Here, HMs demonstrated a pattern of increasing incidence in males over a 7-year period, with a higher rate in early childhood. There were 13 types of HMs diagnosed, with B-acute lymphocytic leukemia having the highest incidence. Although juvenile cancer is rare, it is nonetheless a significant cause of mortality in children. A successful prognosis requires prompt and accurate diagnosis and treatment.

Efficacy of Colistin Therapy in Patients with Hematological Malignancies: What if There is Colistin Resistance?

Objective: The objective of this study was to evaluate the clinical efficacy and appropriateness of colistin therapy in patients with hematological malignancies. Methods: Age, gender, type of hematologic malignancy, and potential carbapenem-resistant microorganism risk factors were all noted in this retrospective study. In empirical and agent-specific treatment groups, differences in demographic features, risk factors, treatment responses, and side effects were compared. Results: Sixty-three patients were included, 54% were male, and the median age was 49. In the last three months, the hospitalization rate history was 68%, and four patients had a hospitalization history in the ICU. Carbapenem-resistant K. pneumoniae colonization was present in 22 patients (35%). Gram-negative microorganisms were isolated in 34 patients (54%). The carbapenem, quinolone, and colistin resistance rates were 82%, 76%, and 4% respectively. Clinical and microbiological response rates were 60% and 69%. 7 and 28-day mortality rates were 17% and 35%. There was no significant difference in demographic data and comorbidities in empirical (n=48) and agent-specific (n=15) treatment groups. The rate of carbapenem and glycopeptide treatments before colistin was higher in the empirical treatment group (p = 0.004; p = 0.001). The rate of starting combined antibiotics was higher inthe empirical treatment group (p = 0.016). Two of the patients developed renal failure in the first week after treatment. Conclusion: The use of empirical colistin may be unavoidable given the risk considerations. Shortly, colistin-resistant strains may also be a factor affecting treatment success negatively.

Core-binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis

AbstractAdenosine-to-inosine RNA editing, which is catalyzed by adenosine deaminases acting on RNA (ADAR) family of enzymes, ADAR1 and ADAR2, has been shown to contribute to multiple cancers. However, other than the chronic myeloid leukemia blast crisis, relatively little is known about its role in other types of hematological malignancies. Here, we found that ADAR2, but not ADAR1 and ADAR3, was specifically downregulated in the core-binding factor (CBF) acute myeloid leukemia (AML) with t(8;21) or inv(16) translocations. In t(8;21) AML, RUNX1-driven transcription of ADAR2 was repressed by the RUNX1-ETO additional exon 9a fusion protein in a dominant-negative manner. Further functional studies confirmed that ADAR2 could suppress leukemogenesis specifically in t(8;21) and inv16 AML cells dependent on its RNA editing capability. Expression of 2 exemplary ADAR2-regulated RNA editing targets coatomer subunit α and component of oligomeric Golgi complex 3 inhibits the clonogenic growth of human t(8;21) AML cells. Our findings support a hitherto, unappreciated mechanism leading to ADAR2 dysregulation in CBF AML and highlight the functional relevance of loss of ADAR2-mediated RNA editing to CBF AML.

Role of Fyn in hematological malignancies.

Tyrosine kinase Fyn is a member of the Src family of kinases. In addition to the wild type, three mRNA splice isoforms of Fyn have been identified; Fyn-B, Fyn-T, and Fyn-C. Fyn-T is highly expressed in T lymphocytes, and its expression level is significantly higher in mature T cells than in immature T cells. The abnormal expression of Fyn is closely related to the metabolism, proliferation, and migration of tumor cells. Recent studies have shown that Fyn is expressed in a variety of tumor tissues, and its expression and function vary among different tumors. In some tumors, Fyn acts as a pro-oncogene to promote tumor proliferation and metastasis. Moreover, Fyn mutations have been detected in many hematological tumors in recent years, suggesting a critical regulatory role of Fyn in the development of malignancies. This review analyzed the relevant literature in PubMed and other databases. The aim of this study was to systemically review recent research findings on various aspects of Fyn in the pathogenesis and treatment of different types of hematological malignancies and suggests possible future research directions for targeted tumor therapy. Fyn could be a novel prognostic marker and therapeutic target. Treatment option targeting Fyn might be beneficial for future studies.

RUNX3 improves CAR-T cell phenotype and reduces cytokine release while maintaining CAR-T function.

CAR-T therapy has shown successful in the treatment of certain types of hematological malignancy, while the efficacy of CAR-T cell in treating solid tumors has been limited due to the exhaustion of CAR-T caused by the tumor microenvironment in solid tumors. Therefore, improving the exhaustion of CAR-T cell is one of the inspiring strategies for CAR-T treatment of solid tumors. As an important regulator in T cell immunity, the transcription factor RUNX3 not only negatively regulates the terminal differentiation T-bet gene, reducing the ultimate differentiation of T cells, but also increases the residency of T cells in non-lymphoid tissues and tumors. By overexpressing RUNX3 in CAR-T cells, we found that increasing the expression of RUNX3 maintained the low differentiation of CAR-T cells, further improving the exhaustion of CAR-T cells during antigen stimulation. In vitro, we found that RUNX3 could reduce the release of cytokines while maintaining CAR-T cells function. In re-challenge experiments, CAR-T cells overexpressing RUNX3 (Runx3-OE CAR-T) were safer than conventional CAR-T cells, while RUNX3 could also maintain the anti-tumor efficacy of CAR-T cells in vivo. Collectively, we found that Runx3-OE CAR-T cells can improve CAR-T phenotype and reduce cytokines release while maintaining CAR-T cells function, which may improve the safety of CAR-T therapy in clinical trials.

Radiation exposure in acute myeloid leukaemia, diffuse large B-cell lymphoma, and multiple myeloma patients in the first year following diagnosis.

Radiological examinations are critical in the evaluation of patients with haematological malignancies for diagnosis and treatment. Any dose of radiation has been shown in studies to be harmful. In this regard, we assessed the radiation exposure of 3 types of haematological malignancies (diffuse large B-cell lymphoma [DLBCL], acute myeloid leukaemia [AML], and multiple myeloma [MM]) in our centre during the first year after diagnosis. In the first year after diagnosis we retrospectively reviewed the radiation exposure data of 3 types of haematological malignancies (DLBCL, AML, and MM). The total and median CED value (cumulative effective radiation dose in millisieverts [mSv]) of each patient was used. Each patient's total and median estimated CED value was calculated using a web-based calculator and recorded in millisieverts (mSv). The total radiation doses in one year after diagnosis (CED value) were 46.54 ± 37.12 (median dose: 36.2) in the AML group; 63.00 ± 42.05 (median dose: 66.4) in the DLBCL group; and 28.04 ± 19.81 (median dose: 26.0) in the MM group (p = 0.0001). There was a significant difference between DLBCL and MM groups. In all 3 haematological malignancies, the radiation exposure was significant, especially in the DBLCL group, within the first year of diagnosis. It is critical to seek methods to reduce these dosage levels. In diagnostic radiology, reference values must be established to increase awareness and self-control and reduce patient radiation exposure. This paper is also the first to offer thorough details on the subject at hand, and we think it can serve as a guide for further investigation.

Synthesis and evaluation of biological activities of two belinostat analogs bearing fluorine at the CAP

Histone deacetylase enzymes are overexpressed in many types of hematologic malignancies (acute myelogenous leukemia, myelofibrosis, cutaneous T-cell lymphoma, and Hodgkin lymphoma) and their inhibition of HDACs could result in the inhibition of cell proliferation and induction of apoptosis. Thus, HDAC inhibitors are candidates of anticancer drug development. Belinostat is a histone deacetylase inhibitor which was approved by the US FDA in 2014 for the treatment of refractory T-cell lymphoma and solid tumor. This paper reported the synthesis of two belinostat analogues (including a firstly synthesized compound) by introducing fluorine atoms at the hydrophobic capping group (CAP) of belinostat. The resulted compounds were then tested by molecular docking analysis and in vitro evaluation of their antioxidant and anti-cancer activities. The new compound 8a displayed the highest anti-cancer efficacy against human breast (MCF-7) and liver (Hep-G2) cancer cell lines with EC50 values of 1.5‒4.0 μg/mL. Two compounds showed the antioxidant activity with an EC50 value of 8.30‒13.60 μg/mL. These results suggested that the synthesized belinostat analogs might have anti-cancer potential for further investigation.