Types Of Hematological Malignancies Research Articles

Virological Aspects of COVID-19 in Patients with Hematological Malignancies: Duration of Viral Shedding and Genetic Analysis.

Coronavirus disease 2019 (COVID-19) has been associated with a significant fatality rate and persistent evolution in immunocompromised patients. In this prospective study, we aimed to determine the duration of excretion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 37 Tunisian patients with hematological malignancies (40.5% with lymphoma and 37.8% with leukemia). In order to investigate the accumulation of viral mutations, we carried out genetic investigation on longitudinal nasopharyngeal samples using RT-PCR and whole-genome sequencing. Patients' samples were collected until the RT-PCR results became negative. SARS-CoV-2 infection was symptomatic in 48.6% of cases with fever, and cough was symptomatic in 61% of cases; the mortality rate was estimated to be 13.5%. The duration of viral RNA shedding ranged from 7 to 92 days after onset; it exceeded 18 days in 79.4% of cases. An intermittent PCR positivity was observed in two symptomatic patients. Persistent PCR positivity, defined as the presence of viral RNA for more than 30 days, was found in 51.4% of cases. No significant differences were observed for age, sex, type of hematological malignancy, or COVID-19 evolution between this group and a second one characterized by non-persistent PCR positivity. Lymphopenia was an independent predictor of prolonged SARS-CoV-2 RNA detection (p = 0.04). Three types of variants were detected; the most frequent was the Omicron. Globally, the mean intra-host variability in the SARS-CoV-2 genome was 1.31 × 10-3 mutations per site per year; it was 1.44 × 10-3 in the persistent group and 1.3 × 10-3 in the non-persistent group. Three types of mutations were detected; the most frequent were nucleotide substitutions in the spike (S) gene. No statistically significant difference was observed between the two groups as to the type and mean number of observed mutations in the whole genome and the S region (p = 0.650). Sequence analysis revealed the inclusion of one to eight amino acid-changing events in seventeen cases; it was characterized by genetic stability from the third to the twentieth day of evolution in six cases. For the two patients with intermittent PCR positivity, sequences obtained from samples before and after negative PCR were identical in the whole genome, confirming an intra-host evolution of the same viral strain. This study confirms the risk of persistent viral shedding in patients with hematological malignancies. However, persistence of PCR positivity seems to be correlated only with a continuous elimination of viral RNA debris. Additional studies based on cell culture analysis are needed to confirm these findings.

Beyond the Burn: Leukemia Threats Following Radioactive Iodine Ablation Therapy for Thyroid Cancer

Background: Radioactive iodine (RAI) ablation therapy is a common minimally invasive treatment for patients diagnosed with differentiated thyroid cancer (DTC). Although previous studies have identified a link between RAI and the mortality from secondary solid cancers, the connection between RAI and leukemia remains under-researched. This study investigated the differential risk of leukemia and its subtypes in DTC patients following RAI treatment. Methods: DTC patients from the Surveillance, Epidemiology, and End Results (SEER) Registry 17 (2000–2019) were analyzed. The standard incidence ratio (SIR) and excess risk (ER) compared to the reference population were calculated. Results: Out of 196,569 DTC patients, 1381 patients developed various types of hematological malignancies. Leukemia was diagnosed in 508 of these patients, and it had the highest risk among the malignancies studied, with an SIR of 1.74 (95%CI: 1.59–1.9). The RAI group had an SIR of 2.12 (95%CI: 1.87–2.39), while the non-RAI group had an SIR was 1.45 (95%CI: 1.37–1.52) (p < 0.001). Those diagnosed before the age of 55 years had a conspicuously elevated risk (SIR 2.74) compared to those diagnosed at 55 years or older (SIR 1.53). American Indian/Alaska Native survivors manifested a pronounced leukemia risk with an SIR of 7.63 (95%CI: 2.46–17.8). Conclusions: RAI treatment increased the risk of developing leukemia when serving as adjuvant therapy in surgical patients (SIR 2.12). There exists a significant association between RAI treatment in DTC patients and the incidence of leukemia. This susceptibility seems to be modulated by factors including time since diagnosis, age, gender, and racial background.

Transcriptomic and in silico analysis of BLACE (B-cell acute lymphoblastic leukemia expressed), a new non-coding RNA, as a diagnostic biomarker in B-cell ALL

ALL (acute lymphoblastic leukemia) is a type of hematological malignancy that involves developmental and differentiation arrest at the lymphoblast stage. BLACE, a gene specifically expressed in B-cell acute lymphoblastic leukemia shows little or no expression in mature B-lymphocytes. The current pilot study involves transcriptional analysis of BLACE in B-cell ALL patients. Expression of BLACE was high in both pediatric and adult ALL patients. Promoter analysis of the BLACE gene showed the presence of CAAT and TATA box promoters and G-rich sequences with a potential to form G-quadruplexes. Due to identification of TAL1 transcription factor binding sites within the BLACE promoter region, expression of TAL1 gene was measured and found to correlate with the BLACE expression. The presence of an overlapping G-rich sequence and TAL1 binding site at −1291 bps within BLACE promoter indicated a new target site for controlling BLACE expression. The docking studies performed between BLACE-TAL1 protein showed a binding score of −208.68 kcal/mol and identified 21 BLACE nucleotide - TAL1 residues interacting at the docking interface. Together, our findings suggested that BLACE gene specifically expressed in B-cell ALL could serve as a new therapeutic target. Further investigations are required to get a comprehensive understanding of the BLACE gene mechanism.

An analytical study of ophthalmological manifestations in hematological malignancies in a tertiary care centre, India

: The objective of the study was to describe the ophthalmological manifestations associated with various haematological malignancies at a tertiary care centre. This analytical cross-sectional study was conducted with 60 patients diagnosed with various types of haematological malignancies, including leukaemia, lymphomas, and multiple myeloma. Patients who had ocular media opacities which precluded fundus view like dense corneal opacity, cataracts, absolute glaucoma, and systemic conditions like hypertension, and diabetes were excluded from this study. All 60 patients underwent a comprehensive ocular examination and the collected data were analysed using IBM SPSS software version 25. Out of the 60 patients with haematological malignancies, 27 (45%) exhibited ocular features. Ocular involvement was more common in males (63%) and in the paediatric age group (1-10 years) (100%). Ocular findings were prevalent in leukaemia patients especially with chronic myeloid leukaemia showing the highest incidence (80%), compared to lymphomas and multiple myeloma. The most common ocular manifestations were in the posterior segment, such as retinal haemorrhages and Roth spots, observed across all age groups. Neurological involvement, specifically III and VI cranial nerve palsy, were also notable. At the time of presentation, the majority of patients with ocular features had good visual acuity, ranging from 6/6 to 6/9 (43%). With advancements in diagnostic and therapeutic methods, the survival rates for patients with haematological malignancies have considerably improved. This has led to an increase in the variability of ocular presentations. Consequently, routine ocular examination is essential at the time of diagnosis of haematological malignancies to prevent vision-threatening complications and improve the overall quality of life for these patients.

TRIP13 is Critical for the Survival of B-cell Lymphomas and Myeloid Leukemias In Vitro

Hematologic malignancies represent a diverse group of blood tumors accounting for approximately 10% of all cancer cases in the US. Based on the site of manifestation, presumed cell of origin, genetic abnormalities, and clinical features, we recognize more than 100 clinically important subtypes of hematologic malignancies broadly categorized into three main groups: leukemia, lymphoma, and multiple myeloma. While the prognosis for patients with specific subtypes of hematologic malignancies, such as Hodgkin lymphomas or chronic lymphocytic leukemia has significantly improved over the last several years, other subtypes such as acute myeloid leukemia or non-Hodgkin lymphomas still present with significant treatment challenges. A better understanding of molecular drivers of tumor maintenance is needed to improve existing therapies. Thyroid hormone receptor interactor 13 (TRIP13) is an AAA + ATPase that plays an important yet poorly understood role in the regulation of the mammalian cell cycle. The TRIP13 gene is highly expressed in various human tumors including colorectal carcinoma and glioblastoma, and it seems to promote tumorigenesis. Recently, we identified TRIP13 as a gene overexpressed in Peripheral T-cell lymphomas where it plays a critical role in tumor maintenance by regulating the G2-M phase of the cell cycle. However, the biological activities of TRIP13 in non-T cell hematologic malignancies have not been investigated to date. Here we used shRNA-mediated knockdown and a small molecule inhibitor to downregulate TRIP13 in B-cell lymphoid and myeloid lineages. We found genetic downregulation inhibited the proliferation of both B-cell lymphomas and acute myeloid leukemia cell lines in vitro. The pharmacologic inhibition of TRIP13 effectively induced the G0/G1 cell cycle arrest and apoptosis of B-cell lymphomas. Altogether these data demonstrate that TRIP13 is critical for the maintenance of hematologic malignancies of B-cell and myeloid malignancies in vitro. Thus, TRIP13 might be a good target in the treatment of various types of hematologic malignancies.

FOXN3-AS1: A Candidate Prognostic Marker and Epigenetic Target with Immunotherapeutic Implications in Acute Myeloid Leukemia.

We focused on the FOXN3 gene and selected its antisense transcripts (FOXN3-AS1) to investigate its potential involvement in acute myeloid leukemia (AML). Several integrated multi-omics datasets have expanded the horizons of the cancer landscape. With the emergence of new high-throughput technologies, a large number of non-coding RNAs have been confirmed to be involved in the pathogenesis of different types of hematological malignancies. We conducted experimental validation using quantitative polymerase chain reaction (qPCR) with bone marrow specimens from AML patients. Then, Kaplan-Meier (KM) and Receiver Operating Characteristic (ROC) curves were used to substantiate the prognostic association between FOXN3-AS1 and AML patients within the TCGA database. Correlation between FOXN3-AS1 expression and gene mutation, immune, and immune function using Spearman correlation analysis. To explore the physical and functional interaction between FOXN3-AS1 and the DNMT1 protein, we utilized the RPISeq web tool from Iowa State University. Subsequently, we performed qPCR experiments to test the effect of 5AzaC (DNMT1 inhibitor) on FOXN3-AS1 expression AML cell lines (THP1 and OCI-AML3). We leveraged the "OncoPredict" R package in conjunction with the Genomics of Drug Sensitivity (GDSC) database to predict drug response in AML patients expressing FOXN3-AS1. We observed a significant upregulation of FOXN3-AS1 expression in AML patients compared to healthy controls using clinical samples. The TCGA database revealed an association between high FOXN3-AS1 expression and adverse prognosis. In our subsequent analysis, genes with poor prognostic implications in AML patients were exclusively identified in the FOXN3-AS1 high-expression group, further corroborating this relationship. AML patients with higher FOXN3-AS1 expression levels may respond less optimally to immunotherapy than patients with lower levels. Besides, we computationally predicted the interaction of FOXN3- AS1 and DNMT1 protein and experimentally confirmed that DNMT1i (GSK-3484862) affects the expression level of FOXN3-AS1. We also found that the chemotherapy drugs (5-Fluorouralic, Cisplatin, Dactolisib, Sapitinib, Temozolomide, Ulixertinib, Vinorelbine, Ruxolitinib, Osimertinib and Cisplatin) showed favorable responses in AML patients with high FOXN3-AS1 expression levels. Our candidate approach identifies FOXN3-AS1 as a prognostic indicator of survival in AML with a potential immune-related role. The preliminary observations we made on FOXN3-AS1/DNMT1 crosstalk warrant more in-depth invested immunotherapeutic approaches in AML.

The Role of SIRT1 in Leukemia.

Leukemia is a type of hematological malignancy (HM) caused by uncontrolled proliferation, apoptosis, and differentiation of hematopoietic stem cells (HSCs). Leukemia cells proliferate greatly in the bone marrow (BM), infiltrate other tissues and organs, and affect the normal hematopoietic function. Although the emergence of new targeted agents and immune agents has improved the prognosis of patients, due to the complex pathogenic factors and heterogeneity of leukemia, there are still some patients with poor prognosis. Recent studies have shown that silent information regulator 1 (SIRT1) is involved in the proliferation, apoptosis, metabolism, and senescence of leukemia cells. As a double-edged sword in leukemia cells, SIRT1 can both promote and inhibit the growth of leukemia cells. Since its mechanism of action has not been elucidated, it is urgent to explore the regulatory mechanism of SIRT1 in leukemia. In this review, we discussed the mechanisms of SIRT1 in different aspects of leukemia, providing a theoretical basis for the treatment of patients with leukemia.

Effective Prevention and Treatment of Acute Leukemias in Mice by Activation of Thermogenic Adipose Tissues.

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are common hematological malignancies in adults. Despite considerable research advances, the development of standard therapies, supportive care, and prognosis for the majority of AML and ALL patients remains poor and the development of new effective therapy is urgently needed. Here, it is reported that activation of thermogenic adipose tissues (TATs) by cold exposure or β3-adrenergic receptor agonists markedly alleviated the development and progression of AML and ALL in mouse leukemia models. TAT activation (TATA) monotherapy substantially reduces leukemic cells in bone marrow and peripheral blood, and suppresses leukemic cell invasion, including hepatomegaly and splenomegaly. Notably, TATA therapy prolongs the survivals of AML- and ALL-bearing mice. Surgical removal of thermogenic brown adipose tissue (BAT) or genetic deletion of uncoupling protein 1 (UCP1) largely abolishes the TATA-mediated anti-leukemia effects. Metabolomic pathway analysis demonstrates that glycolytic metabolism, which is essential for anabolic leukemic cell growth, is severely impaired in TATA-treated leukemic cells. Moreover, a combination of TATA therapy with chemotherapy produces enhanced anti-leukemic effects and reduces chemotoxicity. These data provide a new TATA-based therapeutic paradigm for the effective treatment of AML, ALL, and likely other types of hematological malignancies.

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 seven major types of HM between 1975 and 2018 (median follow-up: 2.7 years) from the Surveillance, Epidemiology, and End Result database. The proportion of deaths, Fine-Gray subdistribution 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 disease-related deaths (SMR: 0.99-1.66; AER: -0.35 to 24.15). The proportion of deaths and cumulative mortality increased with the passage of survival time, especially in patients with Hodgkin lymphoma 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 hematological malignancies, 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.