Subtypes Of Hematological Malignancies Research Articles

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.

Serological Response to COVID-19 Vaccination is Impaired in Adults with Hematologic Malignancies when Compared to Adults with Solid Tumors and HIV: Observations from a Single Tertiary Institution

Background: Hematologic malignancies can impair immune responses following COVID-19 vaccination. We analyzed seroconversion rates following a primary two-dose COVID-19 vaccination series and subsequent seroconversion rates after booster doses (doses 3 and above) in patients with various subtypes of hematologic malignancies (HM), human immunodeficiency virus infection (HIV), and solid tumors (ST). Methods: We conducted a retrospective study of 299 fully vaccinated adults with HM (n=202), HIV without diagnosed cancer (n=48), HIV and cancer (n=17), ST (n=12), autoimmune diseases (n=12), or other hematologic diseases (n=10) seen in a single tertiary institution between May 2020 and July 2022. A serum spike antibody level ≥0.8U/mL was considered evidence of seroconversion as defined by the manufacturer (Roche Elecsys®). A Mann-Whitney test was utilized to analyze continuous variables and a chi-square test for categorical variables. Results: Seroconversion after initial vaccination was significantly associated with disease category and treatment. Seroconversion rates were lowest in people with B-cell lymphomas (including patients not currently receiving treatment) (44/68) and patients receiving anti-B-cell monoclonal antibodies (23/57). All individuals with HIV alone or ST (n=60) demonstrated seroconversion after initial vaccination as did 94% of individuals with HIV and cancer (16/17) and 86% of those with plasma cell dyscrasias (37/43). Of the 51 people who did not seroconvert after their primary vaccination course, 25 achieved seroconversions after one booster dose. Conclusion: Our study supports the potential utility of COVID-19 serological testing to identify those at high risk of impaired response to COVID-19 vaccination and to help physicians develop personalized vaccination strategies. Continued research is needed to refine our understanding of immune response in these patients and improve their protection against COVID-19. Keywords: COVID-19 Vaccination, Impaired Immune Response, Seroconversion, HIV, Hematologic Malignancies

Abstract 5720: Targeting CDK9 in cutaneous T-cell lymphoma using patient-derived xenograft models

Abstract Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Mycosis fungoides and Sézary syndrome (MF/SS) are the most common subtypes in CTCL. Early-stage MF/SS has a favorable prognosis. The advanced-stage CTCL has limited treatment options and a median survival of <5 years, highlighting the urgent need to develop targeted therapies in CTCL. Preclinical studies of CDK9 inhibitors have shown anti-tumor activity in various subtypes of hematologic malignancies. Several CDK9 inhibitors have entered clinical trials for lymphomas and leukemias. However, whether targeting CDK9 in CTCL is a therapeutic option is little known and has resulted in CTCL not being included in ongoing clinical investigations of CDK9 inhibitors. AZD4573 is a highly selective and potent CDK9 inhibitor currently under clinical investigation for Hodgkin and non-Hodgkin lymphomas. It was shown that AZD4573 induces tumor cell death through depletion of MCL-1. Overexpression of MCL-1 has been shown in CTCL cell lines and skin biopsy specimens of CTCL patients. MCL-1 expression appears to be particularly elevated in patients with advanced stage disease. Here, we investigated the ex vivo anti-tumor activity of AZD4573 using patient-derived CTCL xenograft models (PDXs). Primary tumor cells harvested from CTCL PDX mice were activated with CD2/CD3/CD28 beads and incubated in hIL-2 and hIL-7 at an optimal cell density. Subsequently, cells were exposed to AZD4573 at various concentrations for 8 hr, then treated cells were harvested, washed, and placed in fresh media for another 48 hr. Growth inhibition was measured by the Real-Time Glo cell viability assay, and apoptotic activity was assessed by flow cytometry analysis of Caspase 3/7 activity and Annexin V + propidium iodide (PI) double staining. Additionally, we conducted RNA-seq analysis for MCL-1 expression in CTCL PDX primary tumor cells. AZD4573 inhibited cell proliferation in a dose-dependent manner in primary tumor cells from three CTCL PDX mice (PRS-1, PRS-2 PRS-3), with GI50 of 43.5 nM, 175.4 nM, and 113.5 nM, respectively. Furthermore, AZD4573 significantly increased caspase 3/7 activity and apoptosis in PRS-1 and PRS-3, but not PRS-2 primary tumor cells. In addition, our RNA-seq analysis showed that compared with normal controls (normal PBMC from healthy donors), the MCL-1 gene expression is increased 10-fold (P-value <0.0001) in PRS1 cells. The MCL-1 gene expression in PRS2 and PRS3 cells is the same as normal control. Furthermore, PRS-1, which has the highest MCL-1 expression level, is most sensitive to AZD4573. In conclusion, AZD4573 demonstrated dose-dependent growth inhibition and apoptosis induction in primary CTCL tumor cells. In addition, the expression level of MCL-1 appeared to be correlated with the ex vivo anti-tumor activity of AZD4573. Our findings provide a rationale for clinical investigation of targeting CDK9 in CTCL. Citation Format: Yan-Jin Liu, Chi-Heng Wu, Laura Pincus, Weiyun Z. Ai. Targeting CDK9 in cutaneous T-cell lymphoma using patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5720.

Aptamer-Based Multiparameter Analysis for Molecular Profiling of Hematological Malignancies.

The subtypes of hematological malignancies (HM) with minimal molecular profile differences display an extremely heterogeneous clinical course and a discrepant response to certain treatment regimens. Profiling the surface protein markers offers a potent solution for precision diagnosis of HM by differentiating among the subtypes of cancer cells. Herein, we report the use of Cell-SELEX technology to generate a panel of high-affinity aptamer probes that are able to discriminate subtle differences among surface protein profiles between different HM cells. Experimental results show that these aptamers with apparent dissociation constants (Kd) below 10 nM display a unique recognition pattern on different HM subtypes. By combining a machine learning model on the basis of partial least-squares discriminant analysis, 100% accuracy was achieved for the classification of different HM cells. Furthermore, we preliminarily validated the effectiveness of the aptamer-based multiparameter analysis strategy from a clinical perspective by accurately classifying complex clinical samples, thus providing a promising molecular tool for precise HM phenotyping.

SARS-CoV-2 Infection and Severity in Patients with Hematologic Malignancies: A Systematic Review.

Earlier reports described the possibility of higher SARS-CoV-2 infection and severity in patients with hematological malignancies. Given the importance and incidence of these malignancies, we aimed to systematically review SARS-CoV-2 infection and severity in patients with hematologic cancers. We retrieved the relevant records by searching the keywords in online databases of PubMed, Web of Science, Cochrane, and Scopus on December 31st , 2021. A two-step screening; title/abstract and full-text screening, was employed to select the eligible studies. These eligible studies entered the final qualitative analysis. The study is adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist to ensure the reliability and validity of the results. Forty studies concerning different hematologic malignancies and the effect of COVID-19 infection on them were included in the final analysis. The findings showed that in general, the prevalence of SARS-CoV-2 infection and the severity of the disease are often higher in hematologic malignancies and the patients could experience higher morbidity and mortality compared to general populations. It appeared that individuals with hematologic malignancies are more vulnerable to COVID-19 infection and they experience more severe disease with higher mortality rates. The presence of other comorbidities could also deteriorate this situation. Further Investigation is recommended to evaluate the outcome of COVID-19 infection in different subtypes of hematologic malignancies.

Dual PI3K/HDAC Inhibitor BEBT-908 Exhibits Potent Efficacy as Monotherapy for Primary Central Nervous System Lymphoma.

The efficacy of systemic treatment for primary central nervous system lymphoma (PCNSL) is limited because of the blood-brain barrier (BBB) and the ineffectiveness of chemotherapy. The dual PI3K/HDAC inhibitor BEBT-908 has exhibited favorable in vivo distribution and activity in various cancers. The aims of this study were to assess the efficacy of BEBT-908 in brain orthotopic mouse models of hematological malignancies, to investigate its pharmacologic properties, and to elucidate the underlying mechanism of action. We evaluated the anticancer activity of BEBT-908 in various hematological malignancies through cell viability assays. The impact of BEBT-908 on c-Myc expression and ferroptosis signaling pathways was assessed using Western blotting, qPCR, ROS detection, GSH/GSSG detection, and IHC. Pharmacokinetic and pharmacodynamic profiles were assessed through LC-MS/MS and Western blotting. The effects of BEBT-908 in vivo were examined using xenografts and brain orthotopic mouse models. Our findings demonstrate that BEBT-908 exhibits promising anti-tumor activity in vitro and in vivo across multiple subtypes of hematological malignancies. Furthermore, BEBT-908 exhibits excellent BBB penetration and inhibits tumor growth in a brain orthotopic lymphoma model with prolonged survival of host mice. Mechanistically, BEBT-908 downregulated c-Myc expression, which contributed to ferroptosis, ultimately leading to tumor shrinkage. Our study provides robust evidence for the dual PI3K/HDAC inhibitor BEBT-908 as an effective anti-cancer agent for PCNSL.

Pharmacological and therapeutic potentials of cordycepin in hematological malignancies

Hematological malignancies(HMs) are highly heterogeneous diseases with globally rising incidence. Despite major improvements in the management of HMs, conventional therapies have limited efficacy, and relapses with high mortality rates are still frequent. Cordycepin, a nucleoside analog extracted from Cordyceps species, represents a wide range of therapeutic effects, including anti-inflammatory, anti-tumor, and anti-metastatic activities. Cordycepin induces apoptosis in different subtypes of HMs by triggering adenosine receptors, death receptors, and several vital signaling pathways such as MAPK, ERK, PI3K, AKT, and GSK-3β/β-catenin. This review article summarizes the impact of utilizing cordycepin on HMs, and highlights its potential as a promising avenue for future cancer research based on evidence from in vitro and in vivo studies, as well as clinical trials.

Chimeric antigen receptor T-cell therapy in a dialysis patient with lymphoma

Chimeric antigen receptor T-cell (CAR-T) therapy has become a revolutionary cancer therapy for multiple subtypes of hematologic malignancies. Despite this progress, CAR-T use in End Stage Kidney Disease (ESKD) patients is limited. We describe the successful administration of CAR-T therapy in a patient with ESKD who had developed diffuse large B-cell lymphoma (DLBCL) from an underlying chronic lymphocytic leukemia. The patient received CAR-T therapy, preceded by lymphodepleting chemotherapy with dose-reduced fludarabine and cyclophosphamide, followed by intermittent hemodialysis on a modified basis. The treatment course was complicated by pancytopenia and Grade 2 cytokine release syndrome, managed with tocilizumab. The patient underwent an initial disease response assessment, which showed a complete response, and remains in remission 12 months after CAR-T infusion. This case report highlights the importance of individualized hemodialysis schedules and lymphodepleting chemotherapy dose adjustments in ESKD patients for a successful administration of CAR-T therapy.

Incidence of cutaneous melanoma and Merkel cell carcinoma in patients with primary cutaneous B-cell lymphomas: A population study of the SEER registry.

The increased incidence of cutaneous melanoma (CM) and Merkel cell carcinoma (MCC) in patients with hematologic malignancies (HM) is well established. While the risk of CM has been assessed in some subtypes of HM including cutaneous T-cell lymphoma, the incidence in patients with primary cutaneous B-cell lymphoma (PCBCL) has not been interrogated. Here we evaluated the standardized incidence ratio (SIR) of CM and MCC in 5,179 PCBCL patients compared to approximately 1.5 billion individuals in the general population using the Surveillance, Epidemiology and End Results (SEER) database. Among patients with PCBCL, we identified subgroups that were at increased risk for CM or MCC as a second primary cancer. We found 36 cases of CM in the PCBCL cohort (SIR, 1.35; 95% CI, 0.94-1.86), among which SIR was significantly elevated for non-Hispanic White patients compared to the general population (SIR, 1.48; 95% CI, 1.03-2.06). Males had a significantly increased risk of developing CM after a diagnosis of PCBCL (SIR, 1.60; 95% CI, 1.10-2.26). We found that males in the age group of 50-59 were at increased risk for CM development (SIR, 3.02; 95% CI, 1.11-6.58). Males were at increased risk of CM 1-5 years after PCBCL diagnosis (SIR, 2.06; 95% CI, 1.18-3.34). Patients were at greater risk of developing MCC within 1 year of diagnosis of PCBCL (SIR, 23.60; 95% CI, 2.86-85.27), particularly in patients who were over the age of 80 (SIR, 46.50; 95% CI, 5.63-167.96). Males aged 60-69 with PCBCL, subtype marginal zone, were also at increased risk for MCC (SIR, 42.71; 95% CI, 1.08-237.99). There is an increased incidence of CM in White, middle-aged males within 5 years of diagnosis of PCBCL and an increased risk of MCC in elderly patients within 1 year of PCBCL diagnosis. These data suggest that certain subgroups of patients with PCBCL may require more rigid surveillance for CM and MCC.

Trends in mortality from infection among patients with hematologic malignancies: differences according to hematologic malignancy subtype.

Infection is the most important cause of non-relapse mortality in hematologic malignancy patients, leading to increased costs and prolonged hospitalization times. However, comprehensive and comparable reports on infection-specific mortality (ISM) trends in hematologic malignancy patients are lacking. We aimed to provide updated ISM trends and factors associated with ISM among hematologic malignancy patients. This is a retrospective study. Patients diagnosed with the five most common hematologic malignancies from 1983 to 2016 from the Surveillance, Epidemiology, and End Results database were included. Joinpoint regression was used to analyze mortality trends. ISM decreased beginning in 1983, 1988, and 1994, with yearly decreases of -2.1% for acute leukemia (AL), -1.3% for Hodgkin lymphoma (HL), and -14.3% for non-Hodgkin lymphoma (NHL). In contrast, ISM in patients with chronic leukemia (CL) and multiple myeloma (MM) increased dramatically beginning in 2000, with yearly increases of 2.8% and 3.3%, respectively. ISM rates were higher in males than in females across all hematologic malignancy subtypes. The mortality trends significantly differed according to race, age, sex, and stage, which could help in further etiological investigations. Moreover, male sex, older age at diagnosis, black race, and unmarried status were poor prognostic factors for ISM across all hematologic malignancy subtypes. A promising downward trend in ISM in recent years occurred in patients with AL, HL, and NHL; however, ISM increased dramatically in patients with CL and MM. Our data suggest that risk assessment and careful infection monitoring are recommended for hematologic malignancy patients, particularly those with CL and MM.

Molecular Signatures of Immune Pressure and Immune Escape in Hematological Malignancies

Downmodulation of antigen presentation machinery represents a paradigm of evasion from adaptive immune surveillance. This mechanism underpins the decrease in presentation of immunogenic peptides below the activation threshold of effector T-cells. Large genomic aberrations, fine somatic mutations, epigenetic silencing and transcriptional modifications involving directly the human leukocyte antigen (HLA) region or genes encompassing antigen degradation, transportation and processing have been invoked across large cohorts of solid tumors and hematological disorders, all as a result of a common lynchpin: the established immune pressure. During tumor growth this orchestra of mechanisms shape the oncogenic landscape and facilitate the emergence of clones with lower immunogenic potential.By analyzing genomic profiles extracted from more than 7000 patients and specimens across 25 previously published cohorts encompassing both lymphoid and myeloid diseases (Table 1), we performed a large genomic study aiming to dissect the multifaceted immunoediting processes in hematological malignanciesWe first analyzed a broad HLA genomic dysfunction in 31 classical and non-classical loci and identified 892 somatic mutations or allelic losses in 337/6694 patients (5%). Among the different subtypes of hematological malignancies, HLA mutations were found in 16% (N=138/831) of acute lymphoblastic leukemia (ALL), 7% (N=1/14) of histiocytic disorders, 7% (N=3/43) of T-cell lymphoma, 6% (N=136/2247) of myeloid disorders, 2% (N=4/205) of multiple myeloma, 1.6% (N=55/3354) of B-cell lymphoma/chronic lymphocytic leukemia (B-LNH/CLL). Most affected loci were classical A, B and DRB1, while non-classical DPB2, F and DOA were the least interested by somatic events. Interestingly, alterations were never found in non-expressed DRB genes (DRB2-4,7-9). Among the immune genes, we focused on those which, if affected by mutations (either loss or gain of function), could possibly be associated with an immune escape signature. We identified such aberrations in 13% of cases, including CREBBP (4.5%, N=450/9875), EP300 (2.5%, N=252/9831), IRF8 (2.1%, N=166/7865), B2M (2%, N=158/7868), CD70 (1.7%, N=127/7253), TNFRSF14 (2.8%, N=221/7868), IRF4 (1.4%, N=110/7869), which were the most frequently altered. The frequency of those mutations was particularly high in B-NHL/CLL (28%) and ALL (23%). These events and HLA hits were not mutually exclusive. When analyzing the pattern of co-mutations in immune aberrant vs. non-aberrant group, we found that both lymphoid and myeloid entities were enriched in genomic abnormalities also in other immune players (e.g., NOTCH4, NFKB1, IL4R, IFNAR2, C3), emphasizing how the genomic dysfunction of the immune response may be a pathophysiological link, beyond the disease ontogenic classification. Of note is that, in MN subset, aberrations in leukemic drivers, such as: NPM1 (3% vs 16%, q=4.69E-11), JAK2 (3% vs 9%, q=1.00E-04), FLT3 (7% vs 14%, q=1.26E-04), SRSF2 (4% vs 10%, q-value=2.20E-04), DNMT3A (13% vs 21%, q=.001), TP53 (6% vs 10%, q=.009), NRAS (7% vs 12%, q=.021) were enriched in the non-immune-altered group. When accounting for the total number of mutational events, we found that this was significantly increased in immune aberrant vs. non-aberrant cases (q-value=10e-10) in both lymphoid and myeloid disorders. These findings are consistent with the hypothesis that HLA and immune defective escaping clones may arise in the context of a strong anti-tumor response, as a negative feedback to the immunoediting responsible for sculpting the tumor clonal burden. While driver hits can easily gain a fitness advantage regardless of the acquisition of immune escape signatures, immune-aberrant clones (especially if lacking more strong leukemogenic hits) would accrue subclonal alterations as a result of evasion from tumor surveillance, promoting growth only when opposing immune response.In analogy with solid cancers, our results show that also in hematological malignancies, the biology underpinning immune escape mechanisms is intimately related to the processes of immunoediting and may shape malignant clonal progression. In this setting, mutations in determinants of immune responsiveness might constitute markers of operative tumor surveillance. [Display omitted] DisclosuresMaciejewski: Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Alexion: Consultancy.

In This Issue

See article, p. 568.Hematologic malignancy patients are highly susceptible to severe coronavirus disease-19 (COVID-19) illness and are a high-priority group for vaccination to mitigate COVID-19–related morbidity and mortality. Chung et al. find differential COVID-19 vaccine humoral responses between hematologic malignancy subtypes and disease-specific therapies across patient cohorts. Hematologic malignancy patients undergoing active therapy have baseline humoral responses that are further suppressed. Importantly, antibody titers alone are an imperfect measure of immunity, as many patients with positive anti–SARS-CoV-2 antibody titers have insufficient neutralizing capacity. These findings together provide important metrics for optimizing the clinical care of this vulnerable population.See article, p. 577.Cellular therapies, including allogeneic and autologous hematopoietic cell transplant (allo-HCT, auto-HCT) and chimeric antigen receptor T-cell therapy (CAR T), render patients severely immunocompromised for extended periods after therapy. Tamari et al. define predictors of response to COVID-19 vaccine to nominate important factors for optimizing response to vaccination. Type of cellular therapy, timing of vaccination post–cellular therapy, and immune recovery post–cellular therapy predict response. Many patients with positive, yet low, anti–SARS-CoV-2 antibody titers demonstrate low neutralizing capacity, highlighting the limitations of using antibody titer as the only proxy for immunity.See article, p. 586.Pediatric acute leukemias have historically been classified by immunophenotyping followed by genomic subclassification. Patients are categorized into T, B, myeloid, or mixed-lineage disease for the purpose of general treatment approach, and these regimens are then further tailored in intensity and/or targeted therapeutics when applicable. Fornerod et al. apply an integrated analysis of gene expression and mutation profiling to a cohort of pediatric patients with acute leukemias that have myeloid features. This reveals a subset of patients with shared mutational composition and gene expression that spanned three immunophenotypes: T, myeloid, and mixed-lineage acute leukemias. The authors further identify patients with the same mutations but with differential gene expression profiles and outcomes. These results suggest acute leukemia classification requires more comprehensive, sequencing-based diagnostic methods beyond flow cytometry.See article, p. 600.Waldenstrom macroglobulinemia (WM) is characterized by outgrowth of mature IgM+ B cells with MYD88 mutations. Kaushal et al. show that WM lesions originate in the presence of several alterations in the immune microenvironment, including aberrant nonmalignant extrafollicular B-cell expansion, myeloid inflammation, and WM-specific T-cell immune responses. The characteristic MyD88 mutations originate in early lymphoid progenitors prior to expansion of the malignant clone. These findings suggest a new model for the origin of WM.See article, p. 616.Overall outcomes are dismal in relapsed/refractory AML (R/R AML), and therapeutic options are limited. In this phase II study, Zeidner et al. investigate the safety, feasibility, and clinical activity of immune checkpoint blockade with pembrolizumab after high-dose cytarabine (HiDAC) chemotherapy in R/R AML. The addition of pembrolizumab to HiDAC leads to an overall complete remission rate of 38%, with encouraging clinical outcomes and self-limiting immune-related adverse events. Multifaceted immunogenomic profiling before and after therapy reveals putative biomarkers of response to pembrolizumab, warranting further investigation.See article, p. 630.Inhibitors of Bruton tyrosine kinase (BTKi) block pathogenic B-cell receptor (BCR) signaling, improving outcomes for patients with lymphoid malignancies. Nonetheless, resistance to BTK therapy is a frequent clinical problem that has previously been ascribed to genetic alterations. Shaffer et al. find a primary, early mechanism of BTKi resistance involving epigenetic reprogramming of the malignant cell. Specifically, the epigenetic upregulation of the small GTPase RAC2 increases its interaction with, and activation of, PLCγ2. This RAC2-dependent activation circumvents the requirement for BTK to phosphorylate PLCγ2 to trigger the prosurvival NF-κB pathway. Clinically available drugs are identified that can kill BTKi-resistant cells.See article, p. 648.Clinical translation of CAR T-cell therapy for AML has been limited by the lack of optimal CAR targets and the risk of on-target, off-tumor toxicity. Richards et al. report a novel anti-AML CAR T-cell therapy targeting CD93 and demonstrate antileukemic activity without toxicity to critical hematopoietic stem and progenitor cells. To mitigate tissue-specificity concerns, next-generation, NOT-gated CD93 CAR T cells were engineered. Transcriptomic analysis of AML and endothelial cells demonstrates a promising target identification strategy for further advancement of this technology.

Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q.

Simple SummaryLenalidomide is an immunomodulatory drug (IMiD) that has achieved clinical efficacies in multiple myeloma (MM) and myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)). However, many patients treated with lenalidomide relapse and become resistant. Recent studies have demonstrated that lenalidomide binds a protein called cereblon (CRBN), leading to reduced protein levels of IKZF1 and IKZF3 and casein kinase 1 alpha. We have identified signaling molecules downstream of IKZF1, G protein-coupled receptor 68 (GPR68) and regulator of calcineurin 1 (RCAN1) in myeloid malignancies, including MDS and acute myeloid leukemia (AML) with or without del(5q). This review summarizes how lenalidomide exerts anti-tumor activity and highlights novel therapeutic targets that could enhance the anti-tumor activity of lenalidomide with a focus on myeloid malignancies, especially without del(5q).Lenalidomide as well as other immunomodulatory drugs (IMiDs) have achieved clinical efficacies in certain sub-types of hematologic malignancies, such as multiple myeloma, lower-risk myelodysplastic syndromes (MDS) with a single deletion of chromosome 5q (del(5q)) and others. Despite superior clinical response to lenalidomide in hematologic malignancies, relapse and resistance remains a problem in IMiD-based therapy. The last ten years have witnessed the discovery of novel molecular mechanism of IMiD-based anti-tumor therapy. IMiDs bind human cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase complex. Binding of CRBN with IMiDs leads to degradation of the Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3) and casein kinase 1 alpha. We have found that lenalidomide-mediated degradation of IKZF1 leads to activation of the G protein-coupled receptor 68 (GPR68)/calcium/calpain pro-apoptotic pathway and inhibition of the regulator of calcineurin 1 (RCAN1)/calcineurin pro-survival pathway in MDS and acute myeloid leukemia (AML). Calcineurin inhibitor Cyclosporin-A potentiates the anti-leukemia activity of lenalidomide in MDS/AML with or without del(5q). These findings broaden the therapeutic potential of IMiDs. This review summarizes novel molecular mechanism of lenalidomide in myeloid malignancies, especially without del(5q), in the hope to highlight novel therapeutic targets.

CG '806, a First-in-Class Pan-FLT3/BTK Inhibitor, Exhibits Potent Growth Inhibition As a Single Agent and in Combination with a BET Bromodomain Inhibitor or a Bcl2 Inhibitor on Primary AML and CLL Patient Samples

CG '806, a First-in-Class Pan-FLT3/BTK Inhibitor, Exhibits Potent Growth Inhibition As a Single Agent and in Combination with a BET Bromodomain Inhibitor or a Bcl2 Inhibitor on Primary AML and CLL Patient Samples

English

BACKGROUND Hematological malignancies are a major health problem in our society due to their high mortality and morbidity. It includes diverse and biologically distinct subgroups and can be defined as clonal neoplasm of hematopoietic stem cells characterized by uncontrolled proliferation of immature cells in bone marrow and spilling into peripheral blood. The patterns of subtypes of hematological malignancies vary in different populations and geographic areas because of genetic, environmental, dietary and social factors. Research of epidemiological features of leukemia are poorly reported in Tripura. The objective of the study was to get an idea about the pattern of hematological malignancies in our institute which will help to get an idea of the disease in our state and find out the incidence of hematological malignancies in Tripura Medical College, a tertiary care hospital in Tripura. METHODS This is a one-year prospective study, conducted in the Department of Pathology, Tripura Medical College & DR BRAM teaching hospital from July 2017 to June 2018. Medical records of all patients admitted to our hospital and diagnosed as a case of hematological malignancy were reviewed for demographic and clinical characteristics at diagnosis. Data analysis was performed by using statistical package for social sciences (SPSS) version 16. RESULTS Our study included 19 diagnosed cases of hematological malignancies, of which 15 were of acute leukemia and 3 cases were of chronic leukemia. Amongst the cases of acute leukemia, 9 were diagnosed as acute myeloid leukemia (AML) whereas 6 were diagnosed as acute lymphoblastic leukemia (ALL). Out of chronic leukemic cases, all were diagnosed as CML. We reported a solitary case of multiple myeloma in a elderly male patient. Present study showed male predominance, invariably affecting the adults. Commonest form of leukemia in adults were AML followed by chronic myeloid leukemia (CML) whereas all cases of ALL were found in children.The most common peripheral blood finding in hematological malignancy was pancytopenia followed by bicytopenia. CONCLUSIONS In our study, acute leukemia was the most common subtype of leukemia in all age groups. Of all leukemia cases, majority were of AML. Demographic characteristics were almost the same as other regional reports. Our observation is mostly comparable with other studies from India and the neighborhood countries. The differences observed in few demographic parameters may be due to geographic variation and genetic difference of study population. KEY WORDS Hematological Malignancies, Acute Leukemia, Chronic Myeloid Leukemia

Biomarkers involved in evaluation of platelets function in South-Eastern Romanian patients with hematological malignancies subtypes.

At present, various researches presented how subtypes of hematological malignancies are related to stages of the immune response, because the activated immune system represents a promising form in cancer treatment. This study explores the relationship between the adaptive immune system (T cells), and the coagulation system (platelets, platelet membrane glycoproteins, platelets derivate microparticles) which seems to play an important role in host immune defense of patients with acute myeloblastic leukemia (AML) or B cell lymphoma (BCL), 2 of the most common hematological malignancies subtypes.Blood samples (n = 114) obtained from patients with AML or BCL were analyzed for platelet membrane glycoproteins (CD42b, CD61), glycoprotein found on the surface of the T helper cells (CD4+), protein complex-specific antigen for T cells (CD3+), platelet-derived microparticles (CD61 PMP) biomarkers by flow cytometry, and hematological parameters were quantified by usual methods.In patients with AML, the means of the percentage of the expressions of the molecules on platelet surfaces (CD61 and CD42b, P < .01; paired T test) were lower as compared to both control subgroups. The expression of cytoplasmic granules content (CD61 PMP) had a significantly higher value in patients with AML reported to controlling subgroups (P < .01; paired T test), which is suggesting an intravascular activation of platelets.The platelet activation status was presented in patients with low stage BCL because CD61 and CD42b expressions were significantly higher than control subgroups, but the expression of CD 61 PMP had a significantly decreased value reported to control subgroups (all P < .01; paired T test). T helper/inducer lineage CD4+ and T lymphoid lineage CD3+ expressions presented significant differences between patients with AML or low stage BCL reported to control subgroups (all P < .01; paired T test).Platelet–lymphocyte interactions are involved in malignant disorders, and CD61, CD42b present on platelet membranes, as functionally active surface receptors mediate the adhesion of active platelets to lymphocytes, endothelial cells, and cancer cells.

Comparison of End-of-Life Care Quality Outcomes and Indicators of Palliative Needs between Medicare Beneficiaries with Solid and Hematologic Malignancies

Comparison of End-of-Life Care Quality Outcomes and Indicators of Palliative Needs between Medicare Beneficiaries with Solid and Hematologic Malignancies

Assessment and reporting of quality-of-life measures in pivotal clinical trials of hematological malignancies.

158 Background: The importance of assessment and reporting of health related quality of life (QoL) has been increasingly recognized in the field of oncology. QoL measures, which reflect patient’s perceived benefits and satisfaction, might be especially important in hematological malignancies clinical trials, where the intervention may not result in cure with modest overall survival benefit. Methods: Data on health related QoL were obtained from studies’ protocols and product labeling available publicly at Drugs@FDA. Drugs approved from 2016 to 2020 were analyzed. On the basis of publicly available study protocols and Food and Drug Administration (FDA) reviews, the authors reviewed the assessment of health related QoL in 53 clinical trials supporting 50 drug approvals from 2016 to 2020. Those trials resulted in approval of medications to treat leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndrome, and multiple myeloma. Results: A total of 14,819 patients were assessed in the 5 years period after exclusion of unpublished studies. We calculated the frequency of assessment of health related QoL and if QoL measures were reported in the subsequent publications. After exclusion of 7 unpublished studies, we analyzed 46 clinical trials for reporting of HRQOL. Thirty percent of the protocols included assessment of health related QoL with only 43% of them (13% of all the analyzed clinical trials) reported the results of health related QoL. The results were consistent across all subtypes of hematological malignancies and were similar regardless of the studied primary endpoint. Conclusions: QoL measures are under studied in clinical trials of hematological malignancies. Studies that measured health related QoL didn’t report the results in more than half of the time. Although results may be reported in separate future publications, improvement in assessing and reporting of QoL will help to incorporate QoL measures in patient care and therapy choice decision. [Table: see text]

FRI0520 HOSPITALIZATIONS FOR HEMATOLOGICAL MALIGNANCIES WITH RHEUMATIC DISEASES: A NATIONAL INPATIENT SAMPLE ANALYSIS OF TEN YEARS (2005-2014)

Background:Several rheumatic conditions have been associated with increased risk of malignancies, especially hematopoietic and lymphoproliferative malignancies. Rheumatoid arthritis has been associated with a relative risk of 1.5-4 for the development of hematological malignancies (HM)1. A variety of immunosuppressive and immunomodulatory medications have also been linked to increased risk of HM2. Moreover, with advances in the field of biologic agents being used in the treatment of rheumatic diseases (RD), the landscape keeps changing. To our knowledge, data on general trends of HM as well as in RD is limited.Objectives:Our study aimed to determine the trends of hospitalizations for HM in patients with RD.Methods:We identified admissions with HM with underlying RD (including rheumatoid arthritis systemic lupus erythematosus, inflammatory myositis, scleroderma, polymyalgia rheumatica, and connective tissue disease) from the NIS database using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes from years 2005 to 2014. The primary outcome was the trends in hospitalizations for HM. We studied the yearly trends and the types of HM among hospitalizations with or without RD.Results:906,556 weighted hospitalizations were estimated for HM, and amongst those, 17,675 had underlying RD. The demographic analysis suggested that the average age of hospitalizations with HM and RD was higher, were more often females, and a higher number of comorbidities (Table 1). The average number of admissions remained stable for HM with and without HM, as described in Graph 1. There was a significant difference in the frequency of various subtypes in patients with and without RD (Graph 2). Non-Hodgkin’s Lymphoma was the most common subtype in HM without and with RD (35.8% and 47.14%).Table 1.Baseline Demographics of Hospitalizations for HM with and without RDCharacteristicsHM without RDHM with RDp valueAge (in years ± SD)62.05 ± 0.2367.41 ± 0.29&lt;0.05Gender (%)&lt;0.05 Males55.9933.35 Female44.0166.65Race (%)&lt;0.05 White71.2475.88 Black12.2711.31 Hispanic10.217.62 Asian or Pacific Islander2.662.01 Native American0.430.62 Other3.182.55Charlson Category (%)&lt;0.05 255.073.76 321.8346.93 411.5523.71 55.5412.88 &gt;=66.0112.73Type of Insurance (%)&lt;0.05 Medicare49.4966.35 Medicaid10.936.04 Private35.826.19 Self-Pay3.781.42Conclusion:To our knowledge, this is the first study to analyze trends in HM with RD. There has not been any significant change in the number of hospitalizations for HM from 2005-2014 with or without RD. The most common HM in admissions with RD were Non-Hodgkin’s Lymphomas (NHL) and myeloid leukemias, followed by multiple myeloma. The trends suggest no significant change in subtypes of HM over the study period.Graph 1.Hospitalizations per year for Hematologic Malignancies With Rheumatic Diseases 2005-2014Graph 2.Types Of Hematological Malignancies In Hospitalizations With And Without Rheumatic Diseases (%)

A Novel and Potent EZH1/2 Dual Inhibitor HM97594 for the Treatment of Hematological Malignancies

In mammals, either enhancer of zeste homologue 2 (EZH2) or its homolog EZH1 functions as the catalytic subunit of polycomb repressive complex 2 (PRC2), and plays an essential role for the maintenance of transcriptional repression by the trimethylation of histone H3 lysine 27 (H3K27me3). Hyperinduction of H3K27me3 mediated by EZH2 overexpression or EZH2 gain-of-function (GOF) mutation (e.g. Y641, A677 and A687) has been associated with lymphoma and myeloma progression. Many publications suggest that suppressing PRC2 activity by EZH2 inhibition is a potential therapeutic target for hematological malignancies. Up to date, there are known a few EZH2 selective inhibitors with showing anti-tumor activity in some preclinical and clinical studies. However, the inhibition of EZH2 can complementarily induce EZH1 activation, which reactivates PRC2 function in turn. Therefore, dual inhibition of EZH1 and EZH2 could give more effective than EZH2 inhibition alone in blocking PRC2 function as an anti-cancer therapy. Herein, we introduce a novel EZH1/2 dual inhibitor, HM97594, which simultaneously inhibits the methyltransferase activity of wild-type EZH1 as well as wild-type and GOF mutant EZH2 at nanomolar concentrations. HM97594 potently repressed trimethylation of H3K27 in lymphoma and myeloma cell lines. As a result, HM97594 showed broader and stronger activities than EZH2 selective inhibitors in in vitro studies of inhibiting the proliferation of various hematological cancer cell lines. HM97594 induced the differentiation of DLBCL to plasma cells with an increment of cell lineage specific markers (e.g. PRDM1, IRF4 and CD38) and decreased the colony forming ability. Also, HM97594 caused cell cycle G0/1 arrest and apoptosis in KARPAS-422 cells harboring EZH2 Y641 GOF mutation. In addition, HM97594 showed potent antitumor activity in KARPAS-422 lymphoma cell xenograft mouse model. Once daily orally administered HM97594 greatly inhibited tumor growth in a dose-dependent manner without body weight loss compared to the known EZH2 inhibitor. Collectively, it was demonstrated in the present studies that HM97594, EZH1/2 dual inhibitor, has promising potential as an anticancer drug for patients with subtypes of hematological malignancies. Further preclinical studies will be performed and reported soon after the establishment of a preclinical candidate. Disclosures No relevant conflicts of interest to declare.